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GLYCOGEN SYNTHASE KINASE 3 INHIBITORS AND USES THEREOF

20250313563 · 2025-10-09

Assignee

Inventors

Cpc classification

International classification

Abstract

The present disclosure provides compounds of Formulae I-A, I-B, II-A, II-B, III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, and VI-B, and compounds shown in Table 13, Table 13A, and Table 14, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, which are GSK3 inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.

Claims

1. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-A or I-B: ##STR02354## wherein: custom-character is a single or double bond; R.sup.1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.A, SCN, SR.sup.A, SSR.sup.A, N.sub.3, NO, N(R.sup.A).sub.2, NO.sub.2, C(O)R.sup.A, C(O)OR.sup.A, C(O)SR.sup.A, C(O)N(R.sup.A).sub.2, C(NR.sup.A) R.sup.A, C(NR.sup.A)OR.sup.A, C(NR.sup.A)SR.sup.A, C(NR.sup.A)N(R.sup.A).sub.2, S(O)R.sup.A, S(O)OR.sup.A, S(O)SR.sup.A, S(O)N(R.sup.A).sub.2, S(O).sub.2R.sup.A, S(O)OR.sup.A, S(O)SR.sup.A, S(O).sub.2N(R.sup.A).sub.2, OC(O)R.sup.A, OC(O)OR.sup.A, OC(O)SR.sup.A, OC(O)N(R.sup.A).sub.2, OC(NR.sup.A)R.sup.A, OC(NR.sup.A)OR.sup.A, OC(NR.sup.A)SR.sup.A, OC(NR.sup.A)N(R.sup.A).sub.2, OS(O)R.sup.A, OS(O)OR.sup.A, OS(O)SR.sup.A, OS(O)N(R.sup.A).sub.2, OS(O).sub.2R.sup.A, OS(O).sub.2OR.sup.A, OS(O).sub.2SR.sup.A, OS(O).sub.2N(R.sup.A).sub.2, ON(R.sup.A).sub.2, SC(O)R.sup.A, SC(O)OR.sup.A, SC(O)SR.sup.A, SC(O)N(R.sup.A).sub.2, SC(NR.sup.A)R.sup.A, SC(NR.sup.A)OR.sup.A, SC(NR.sup.A)SR.sup.A, SC(NR.sup.A)N(R.sup.A).sub.2, NR.sup.AC(O)R.sup.A, NR.sup.AC(O)OR.sup.A, NR.sup.AC(O)SR.sup.A, NR.sup.AC(O)N(R.sup.A).sub.2, NR.sup.AC(NR.sup.A)R.sup.A, NR.sup.AC(NR.sup.A)OR.sup.A, NR.sup.AC(NR.sup.A)SR.sup.A, NR.sup.AC(NR.sup.A)N(R.sup.A).sub.2, NR.sup.AS(O)R.sup.A, NR.sup.AS(O)OR.sup.A, NR.sup.AS(O)SR.sup.A, NR.sup.AS(O)N(R.sup.A).sub.2, NR.sup.AS(O)R.sup.A, NR.sup.AS(O)OR.sup.A, NR.sup.AS(O).sub.2SR.sup.A, NR.sup.AS(O).sub.2N(R.sup.A).sub.2, Si(R.sup.A).sub.2, Si(R.sup.A).sub.2OR.sup.A, Si(R.sup.A)(OR.sup.A).sub.2, Si(OR.sup.A).sub.3, OSi(R.sup.A).sub.2, OSi(R.sup.A).sub.2OR.sup.A, OSi(R.sup.A)(OR.sup.A).sub.2, or OSi(OR.sup.A).sub.3; each of R.sup.4a and R.sup.4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of R.sup.A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and or R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; R.sup.6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and n1 is 0 or 1; when n1 is 1: each of R.sup.5a and R.sup.5b independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; provided that the compound is not of the formula: ##STR02355##

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n1 is 0.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n1 is 1.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.6 is hydrogen.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.6 is or optionally substituted alkyl.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.6 is optionally substituted aryl or optionally substituted heteroaryl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.6 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.5a and R.sup.5b is independently hydrogen, halogen, or optionally substituted alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.5a and R.sup.5b are CH.sub.3.

10. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.5a and R.sup.5b are hydrogen.

11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.5a and R.sup.56 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring.

13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.4a and R.sup.4b is independently hydrogen, halogen, or optionally substituted alkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.1 is optionally substituted aryl.

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, thereof, wherein R.sup.1 is ##STR02356## wherein: each instance of R.sup.7 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NRDS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3; and n2 is 0, 1, 2, 3, 4, or 5.

17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.1 is ##STR02357##

18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n2 is 1.

19. The compound of any one of claims 16-18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.7 is C.sub.1-4 haloalkyl.

20. The compound of any one of claims 16-18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.7 is optionally substituted heteroaryl comprising one or more N atoms.

21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.7 is optionally substituted pyridinyl or optionally substituted pyrazolyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.2 is optionally substituted alkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.2 is unsubstituted C.sub.1-C.sub.4 alkyl.

24. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sub.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.

25. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sub.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring.

26. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted piperidinyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.3 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.

29. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 1: TABLE-US-00027 TABLE 1 embedded image 947799 embedded image 947859 embedded image 948176 embedded image 948180 embedded image 948418 embedded image 949917 embedded image 950563 embedded image 950252 embedded image 950055 embedded image 946001 embedded image 948150 embedded image 948022 embedded image 947861 embedded image 947862 embedded image 949336 embedded image 950494 embedded image 951606 embedded image 947403 embedded image 947877 embedded image 948305 embedded image 948421 embedded image 950484 embedded image 950497 embedded image 951740 embedded image 947404 embedded image 947568 embedded image 947677 embedded image 947811 embedded image 947819 embedded image 948179 embedded image 948768 embedded image 949183 embedded image 950323 embedded image 951948 embedded image 947800 embedded image 947814 embedded image 948185 embedded image 948307 embedded image 948314 embedded image 948419 embedded image 949010 embedded image 949175 embedded image 951607 embedded image 949395 embedded image 949002 embedded image 945634 embedded image 949392 embedded image 949008 embedded image 948227 embedded image 948524 embedded image 947415 embedded image 948514 embedded image 945384 embedded image 949393 embedded image 949328 embedded image 949389 embedded image 949114 embedded image 948148 embedded image 948826 embedded image 948526 embedded image 947907 embedded image 913475 embedded image 948141 embedded image 949390 embedded image 949332 embedded image 948183 embedded image 929389 embedded image 949106 embedded image 949512 embedded image 945362 embedded image 947815 embedded image 949517 embedded image 948662 embedded image 949110 embedded image 949176 embedded image 926299 embedded image 949265 embedded image 945621 embedded image 948365 embedded image 930332 embedded image 948646 embedded image 944071 embedded image 949327 embedded image 948664 embedded image 948824 embedded image 926302 embedded image 951944 embedded image 948363 embedded image 948309 embedded image 948188 embedded image 949127 embedded image 947908 embedded image 949184 embedded image 949329 embedded image 948225 embedded image 949400 embedded image 948360 embedded image 948819 embedded image 948019 embedded image 948366 embedded image 949007 embedded image 945480 embedded image 945921 embedded image 949041 embedded image 948773 embedded image 952563 embedded image 945602 embedded image 947413 embedded image 945363 embedded image 949388 embedded image 948813 embedded image 949836 embedded image 949334 embedded image 947409 embedded image 952478 embedded image 948146 embedded image 947566 embedded image 945617 embedded image 952411 embedded image 949119 embedded image 951605 embedded image 949516 embedded image 952566 embedded image 948645 embedded image 948380 embedded image 949518 embedded image 951598 embedded image 952024 embedded image 950061 embedded image 948367 embedded image 949179 embedded image 948014 embedded image 946004 embedded image 947822 embedded image 949178 embedded image 949271 embedded image 948127 embedded image 948145 embedded image 949868 embedded image 948552 embedded image 950255 embedded image 913156 embedded image 948021 embedded image 927390 embedded image 897749 embedded image 948522 embedded image 949911 embedded image 949644 embedded image 951707 embedded image 949421 embedded image 951843 embedded image 948151 embedded image 951946 embedded image 943965 embedded image 948652 embedded image 948417 embedded image 949647 embedded image 949267 embedded image 927326 embedded image 945723 embedded image 948311 embedded image 947805 embedded image 918313 embedded image 949311 embedded image 948531 embedded image 947823 embedded image 952912 embedded image 947825 embedded image 947573 embedded image 950056 embedded image 914344 embedded image 952016 embedded image 948770 embedded image 952208 embedded image 951742 embedded image 947912 embedded image 948825 embedded image 948772 embedded image 947909 embedded image 948530 embedded image 950821 embedded image 948296 embedded image 949001 embedded image 917158 embedded image 917294 embedded image 870263 embedded image 949003 embedded image 826791 embedded image 951842 embedded image 945996 embedded image 952022 embedded image 948642 embedded image 950490 embedded image 947399 embedded image 945377 embedded image 952207 embedded image 951845 embedded image 949354 embedded image 948422 embedded image 949111 embedded image 912097 embedded image 913357 embedded image 949337 embedded image 951618 embedded image 917295 embedded image 952023 embedded image 949186 embedded image 950486 embedded image 950162 embedded image 951836 embedded image 913225 embedded image 949599 embedded image 948776 embedded image 948769 embedded image 945367 embedded image 947809 embedded image 952018 embedded image 912622 embedded image 945379 embedded image 951837 embedded image 912005 embedded image 950493 embedded image 948520 embedded image 948020 embedded image 947820 embedded image 947564 embedded image 913178 embedded image 950608 embedded image 947874 embedded image 949000 embedded image 949642 embedded image 952561 embedded image 948181 embedded image 951838 embedded image 951599 embedded image 917284 embedded image 950822 embedded image 943371 embedded image 947905 embedded image 949128 embedded image 947807 embedded image 950254 embedded image 949353 embedded image 952913 embedded image 948521 embedded image 947576 embedded image 950151 embedded image 919318 embedded image 951849 embedded image 950612 embedded image 917162 embedded image 948550 embedded image 926212 embedded image 948052 embedded image 917159 embedded image 945382 embedded image 911957 embedded image 948763 embedded image 947870 embedded image 943496 embedded image 948827 embedded image 949266 embedded image 943912 embedded image 825755 embedded image 912104 embedded image 950614 embedded image 945378 embedded image 950776 embedded image 948241 embedded image 952210 embedded image 948523 embedded image 912206 embedded image 914930 embedded image 948423 embedded image 950564 embedded image 951736 embedded image 951939 embedded image 950060 embedded image 930331 embedded image 948639 embedded image 913473 embedded image 947563 embedded image 950562 embedded image 948513 embedded image 949748 embedded image 952754 embedded image 947798 embedded image 949109 embedded image 947748 embedded image 948299 embedded image 948143 embedded image 952630 embedded image 949012 embedded image 857336 embedded image 947835 embedded image 947674 embedded image 948149 embedded image 913439 embedded image 949105 embedded image 930330 embedded image 944022 embedded image 952565 embedded image 947871 embedded image 947332 embedded image 943966 embedded image 952017 embedded image 948300 embedded image 950561 embedded image 917211 embedded image 949180 embedded image 950777 embedded image 944021 embedded image 948370 embedded image 926300 embedded image 949522 embedded image 948238 embedded image 952629 embedded image 950565 embedded image 950062 embedded image 911956 embedded image 947812 embedded image 948302 embedded image 952019 embedded image 917282 embedded image 913451 embedded image 945383 embedded image 948152 embedded image 949398 embedded image 949118 embedded image 947836 embedded image 948312 embedded image 948551 embedded image 945603 embedded image 952257 embedded image 948224 embedded image 943959 embedded image 947675 embedded image 948226 embedded image 949326 embedded image 948794 embedded image 948368 embedded image 947673 embedded image 949520 embedded image 947402 embedded image 945922 embedded image 952909 embedded image 948764 embedded image 951604 embedded image 945361 embedded image 912098 embedded image 949004 embedded image 929474 embedded image 929388 embedded image 949040 embedded image 948766 embedded image 913198 embedded image 927325 embedded image 948144 embedded image 949011 embedded image 949330 embedded image 951848 embedded image 949867 embedded image 952758 embedded image 944027 embedded image 949394 embedded image 945608 embedded image 950828 embedded image 951840 embedded image 948140 embedded image 948655 embedded image 948420 embedded image 943962 embedded image 950615 embedded image 950813 embedded image 912096 embedded image 951844 embedded image 948661 embedded image 949112 embedded image 948999 embedded image 823130 embedded image 957518 embedded image 949351 embedded image 949333 embedded image 945993 embedded image 949170 embedded image 950479 embedded image 945637 embedded image 948528 embedded image 945614 embedded image 943961 embedded image 944074 embedded image 949006 embedded image 949761 embedded image 948516 embedded image 945635 embedded image 913454 embedded image 951706 embedded image 945459 embedded image 949173 embedded image 914971 embedded image 949835 embedded image 947410 embedded image 947906 embedded image 951733 embedded image 918252 embedded image 947837 embedded image 950830 embedded image 949310 embedded image 949126 embedded image 944028 embedded image 948177 embedded image 948640 embedded image 948306 embedded image 948184 embedded image 945994 embedded image 948815 embedded image 949270 embedded image 949331 embedded image 947864 embedded image 948761 embedded image 948187 embedded image 945464 embedded image 945604 embedded image 949910 embedded image 947676 embedded image 949182 embedded image 948379 embedded image 948147 embedded image 948765 embedded image 949338 embedded image 947865 embedded image 947401 embedded image 945920 embedded image 949108 embedded image 948015 embedded image 952910 embedded image 947432 embedded image 945731 embedded image 948527 embedded image 945465 embedded image 949115 embedded image 945722 embedded image 945599 embedded image 943963 embedded image 883979 embedded image 947565 embedded image 948529 embedded image 951949 embedded image 948361 embedded image 913006 embedded image 948644 embedded image 927389 embedded image 949417 embedded image 950059 embedded image 952209 embedded image 945597 embedded image 944020 embedded image 948777 embedded image 948762 embedded image 949171 embedded image 947804 embedded image 945470 embedded image 944030 embedded image 949352 embedded image 948998 embedded image 948653 embedded image 945461 embedded image 826790 embedded image 945462 embedded image 948301 embedded image 949651 embedded image 945999 embedded image 950163 embedded image 948812 embedded image 948178 embedded image 947396 embedded image 948778 embedded image 948828 embedded image 952560 embedded image 948525 embedded image 948175 embedded image 948359 embedded image 902202 embedded image 948549 embedded image 948358 embedded image 948017 embedded image 949172 embedded image 948660 embedded image 949324 embedded image 947911 embedded image 947910 embedded image 949169 embedded image 883980 embedded image 947803 embedded image 948303 embedded image 949757 embedded image 945598 embedded image 952410 embedded image 947414 embedded image 949649 embedded image 947562 embedded image 950824 embedded image 949177 embedded image 949650 embedded image 948517 embedded image 947826 embedded image 952021 embedded image 947869 embedded image 949422 embedded image 948767 embedded image 914308 embedded image 945460 embedded image 947817 embedded image 949185 embedded image 947858 embedded image 952025 embedded image 948297 embedded image 943960 embedded image 949174 embedded image 951612 embedded image 948774 embedded image 947801 embedded image 947395 embedded image 948775 embedded image 943964 embedded image 949648 embedded image 948313 embedded image 947408 embedded image 948304 embedded image 948371 embedded image 947574 embedded image 948018 embedded image 948512 embedded image 948142 embedded image 949005 embedded image 947806 embedded image 950320 embedded image 948515 embedded image 947575 embedded image 950318 embedded image 947863 embedded image 947876 embedded image 949181 embedded image 949747 embedded image 947860 embedded image 949013 embedded image 947821 embedded image 949919 embedded image 947866 embedded image 947405 embedded image 947567 embedded image 948771 embedded image 947835 embedded image 947836 embedded image 943959 embedded image 947837 embedded image 943963 embedded image 943960

30. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 1A: TABLE-US-00028 TABLE 1A embedded image 108005 embedded image 108791 embedded image 114531 embedded image 114532 or embedded image 114679

31. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 2: TABLE-US-00029 TABLE 2 embedded image 913452 embedded image 913495 embedded image 917157 embedded image 918251 embedded image 930333 embedded image 945368 embedded image 945376 embedded image 945380 embedded image 945381 embedded image 857362 embedded image 883867 embedded image 883981 embedded image 883982 embedded image 912006 embedded image 912099 embedded image 912205 embedded image 912668 embedded image 913004 embedded image 917283 embedded image 929475 embedded image 943967 embedded image 945364 embedded image 945385 embedded image 945611 embedded image 945633 embedded image 945727 embedded image 945923 embedded image 947433 embedded image 948016 embedded image 948153 embedded image 948308 embedded image 948362 embedded image 948369 embedded image 948414 embedded image 948493 embedded image 948518 embedded image 948519 embedded image 948638 embedded image 948641 embedded image 948643 embedded image 948647 embedded image 948648 embedded image 948649 embedded image 948650 embedded image 948651 embedded image 948654 embedded image 948656 embedded image 948657 embedded image 948658 embedded image 948659 embedded image 948663 embedded image 948814 embedded image 948816 embedded image 948817 embedded image 948818 embedded image 948829 embedded image 949009 embedded image 949107 embedded image 949116 embedded image 949129 embedded image 949263 embedded image 949264 embedded image 949335 embedded image 949396 embedded image 949509 embedded image 949510 embedded image 949511 embedded image 949513 embedded image 949515 embedded image 949519 embedded image 949600 embedded image 949641 embedded image 949643 embedded image 949646 embedded image 949752 embedded image 949756 embedded image 950817 embedded image 950825 embedded image 951592 embedded image 951954 embedded image 952262 embedded image 952479 embedded image 952636 embedded image 952638 embedded image 952760 or embedded image 957497

32. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 2A: TABLE-US-00030 TABLE 2A embedded image 108006 embedded image 108794 or embedded image 114744

33. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 31 or 32.

34. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula II-A or II-B: ##STR03010## wherein: each instance of custom-character is independently a single or double bond; R.sup.11 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.12 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and or R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms; and m1 is 0 or 1; when m1 is 1: each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; or R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; or R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; provided that the compound is not of the formula: ##STR03011## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of the atoms marked with * is independently optionally substituted.

35. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR03012##

36. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m1 is 0.

37. The compound of claim 34 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m1 is 1.

38. The compound of any one of claims 34-37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of custom-character is a single bond.

39. The compound of any one of claims 34-37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of custom-characteris a double bond.

40. The compound of any one of claims 34-38, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is hydrogen.

41. The compound of any one of claims 34-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene or optionally substituted alkenylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms.

42. The compound of any one of claims 34-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.14a and R.sup.14b are hydrogen.

43. The compound of any one of claims 34-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.17a and R.sup.17b are independently hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl.

44. The compound of any one of claims 34-43, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.11 is optionally substituted aryl.

45. The compound of claim 44, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.11 is ##STR03013## wherein: each instance of R.sup.18 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3; and m2 is 0, 1, 2, 3, 4, or 5.

46. The compound of claim 45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.11 is ##STR03014##

47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m2 is 1.

48. The compound of any one of claims 34-47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.12 is optionally substituted alkyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.12 is unsubstituted C.sub.1-C.sub.4 alkyl.

50. The compound of any one of claims 34-43, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic carbocyclic ring.

51. The compound of any one of claims 34-43, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sub.1 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic heterocyclic ring.

52. The compound of claim 51, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted tetrahydropyranyl.

53. The compound of any one of claims 34-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.13 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

54. The compound of claim 53, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.13 is hydrogen.

55. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 3: TABLE-US-00031 TABLE 3 embedded image 952562 embedded image 952757 embedded image 943921 embedded image 951566 embedded image 952205 embedded image 861716 embedded image 950283 embedded image 943920 embedded image 912081 embedded image 791270 embedded image 949805 embedded image 950815 embedded image 950819 embedded image 950818 embedded image 901464 embedded image 791269 embedded image 949742 embedded image 949840 embedded image 912080 embedded image 949639 embedded image 951565 embedded image 950272 embedded image 950282 embedded image 952557 embedded image 943917 embedded image 952752 embedded image 943916 embedded image 952212 embedded image 951702 embedded image 952759 embedded image 952564 embedded image 948205 embedded image 949743

56. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 4: TABLE-US-00032 TABLE 4 embedded image 791266 embedded image 791268 embedded image 950273 embedded image 950826 embedded image 950827 embedded image 951710

57. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 56.

58. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula III-A or III-B: ##STR03054## wherein: R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring or an optionally substituted, monocyclic heterocyclic ring; optionally two substituents on the monocyclic carbocyclic ring or monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring; R.sup.23 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.C, SCN, SR.sup.C, SSR.sup.C, N.sub.3, NO, N(R.sup.C).sub.2, NO.sub.2, C(O)R.sup.C, C(O)OR.sup.C, C(O)SR.sup.C, C(O)N(R.sup.C).sub.2, C(NR.sup.C)R.sup.C, C(NR.sup.C)OR.sup.C, C(NR.sup.C)SR.sup.C, C(NR.sup.CN(R.sup.C).sub.2, S(O)R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, S(O)N(R.sup.C).sub.2, S(O).sub.2R.sup.C, S(O).sub.2OR.sup.C, S(O).sub.2SR.sup.C, S(O).sub.2N(R.sup.C).sub.2, OC(O)R.sup.C, OC(O)OR.sup.C, OC(O)SR.sup.C, OC(O)N(R.sup.C).sub.2, OC(NR.sup.C)R.sup.C, OC(NR.sup.C)OR.sup.C, OC(NR.sup.C)SR.sup.C, OC(NR.sup.C)N(R.sup.C).sub.2, OS(O)R.sup.C, OS(O)OR.sup.C, OS(O)SR.sup.C, OS(O)N(R.sup.C).sub.2, OS(O).sub.2R.sup.C, OS(O).sub.2OR.sup.C, OS(O).sub.2SR.sup.C, OS(O)N(R.sup.C).sub.2, ON(R.sup.C).sub.2, SC(O)R.sup.C, SC(O)OR.sup.C, SC(O)SR.sup.C, SC(O)N(R.sup.C).sub.2, SC(NR.sup.C)R.sup.C, SC(NR.sup.C)OR.sup.C, SC(NR.sup.C)SR.sup.C, SC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CC(O)R.sup.C, NR.sup.CC(O)OR.sup.C, NR.sup.CC(O)SR.sup.C, NR.sup.CC(O)N(R.sup.C).sub.2, NR.sup.CC(NR.sup.C)R.sup.C, NR.sup.CC(NR.sup.C)OR.sup.C, NR.sup.CC(NR.sup.C)SR.sup.C, NR.sup.CC(NR.sup.CN(R.sup.C).sub.2, NR.sup.CS(O)R.sup.C, NR.sup.CS(O)OR.sup.C, NR.sup.CS(O)SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, NR.sup.CS(O).sub.2R.sup.C, NR.sup.CS(O).sub.2OR.sup.C, NR.sup.CS(O).sub.2SR.sup.C, NR.sup.CS(O).sub.2N(R.sup.C).sub.2, Si(R.sup.C).sub.3, Si(R.sup.C).sub.2OR.sup.C, Si(R.sup.C)(OR.sup.C).sub.2, Si(OR.sup.C).sub.3, OSi(R.sup.C).sub.3, OSi(R.sup.C).sub.2OR.sup.C, OSi(R.sup.C)(OR.sup.C).sub.2, or OSi(OR.sup.C).sub.3; each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each instance of R.sup.C is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.C attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; provided that the compound is not of the formula: ##STR03055## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

59. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.26a and R.sup.26b is independently hydrogen, halogen, or optionally substituted alkyl.

60. The compound of claim 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one of R.sup.26a and R.sup.26b is fluorine.

61. The compound of any one of claims 58-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.25a and R.sup.25b is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl.

62. The compound of claim 61, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.25a and R.sup.25b are CH.sub.3.

63. The compound of any one of claims 58-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.

64. The compound of any one of claims 58-60, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R.sup.25a and R.sup.2Sb are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring.

65. The compound of any one of claims 58-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.24a and R.sup.24b is independently hydrogen, halogen, or optionally substituted alkyl.

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one of R.sup.24a and R.sup.24b is fluorine.

67. The compound of any one of claims 58-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic C.sub.4-7 carbocyclic ring.

68. The compound of any one of claims 58-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted, 4- to 7-membered monocyclic heterocyclic ring.

69. The compound of claim 68, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted, 5- to 6-membered monocyclic heterocyclic ring.

70. The compound of claim 68 or 69, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the monocyclic heterocyclic ring comprises O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring.

71. The compound of any one of claims 68-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted piperidine ring.

72. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form ##STR03056## wherein R.sup.28 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group.

73. The compound of any one of claims 68-71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional 4- to 7-membered optionally substituted, monocyclic, carbocyclic or heterocyclic ring.

74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form ##STR03057## wherein R.sup.29 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

75. The compound of any one of claims 68-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.21 and R.sup.22 are taken together with their intervening atom to form optionally substituted tetrahydropyranyl.

76. The compound of any one of claims 58-75, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.23 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

77. The compound of claim 76, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.23 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.

78. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 5: TABLE-US-00033 TABLE 5 embedded image 884111 embedded image 901477 embedded image 893309 embedded image 884112 embedded image 901478 embedded image 889572 embedded image 912078 embedded image 912079 embedded image 893316 embedded image 913128 embedded image 913127 embedded image 913129 embedded image 909206 embedded image 926861 embedded image 948437 embedded image 948439 embedded image 947306 embedded image 948037 embedded image 889573 embedded image 912075 embedded image 912094 embedded image 912113 embedded image 909209 embedded image 912170 embedded image 946078 embedded image 932653 embedded image 942301 embedded image 949323 embedded image 884013 embedded image 889577 embedded image 884023 embedded image 889583 embedded image 893314 embedded image 946080 embedded image 912217 embedded image 874319 embedded image 929446 embedded image 947813 embedded image 874320 embedded image 924309 embedded image 917145 embedded image 884014 embedded image 924298 embedded image 884016 embedded image 897755 embedded image 945477 embedded image 884024 embedded image 889575 embedded image 912106 embedded image 826763 embedded image 907328 embedded image 889584 embedded image 907329 embedded image 945395 embedded image 913184 embedded image 874536 embedded image 899559 embedded image 924311 embedded image 877314 embedded image 826649 embedded image 884113 embedded image 883846 embedded image 826765 embedded image 947301 embedded image 913214 embedded image 889568 embedded image 949640 embedded image 883833 embedded image 897756 embedded image 913185 embedded image 945394 embedded image 947732 embedded image 874537 embedded image 943895 embedded image 899560 embedded image 943958 embedded image 912076 embedded image 943956 embedded image 948222 embedded image 874529 embedded image 883794 embedded image 889574 embedded image 913185 embedded image 883834 embedded image 913002 embedded image 893319 embedded image 913215 embedded image 901475 embedded image 913213 embedded image 948217 embedded image 883836 embedded image 947257 embedded image 911083 embedded image 901476 embedded image 917160 embedded image 907326 embedded image 952434 embedded image 907327 embedded image 945483 embedded image 912073 embedded image 884120 embedded image 912173 embedded image 945396 embedded image 949322 embedded image 917129 embedded image 993935 embedded image 948320 embedded image 884114 embedded image 945658 embedded image 889569 embedded image 948039 embedded image 913442 embedded image 913263 embedded image 912112 embedded image 901458 embedded image 949320 embedded image 826713 embedded image 884022 embedded image 947251 embedded image 947262 embedded image 913216 embedded image 945478 embedded image 909210 embedded image 896013 embedded image 918315 embedded image 913056 embedded image 945679 embedded image 924306 embedded image 926823 embedded image 949318 embedded image 924299 embedded image 950477 embedded image 889576 embedded image 877313 embedded image 826648 embedded image 913138 embedded image 884021 embedded image 911973 embedded image 913139 embedded image 918270 embedded image 883840 embedded image 945397 embedded image 948036 embedded image 948221 embedded image 926872 embedded image 924308 embedded image 924307 embedded image 912072 embedded image 883962 embedded image 883841 embedded image 952437 embedded image 945906 embedded image 893318 embedded image 947473 embedded image 917128 embedded image 893307 embedded image 947736 embedded image 946072 embedded image 947284 embedded image 909208 embedded image 918316 embedded image 909211 embedded image 946073 embedded image 947294 embedded image 874527 embedded image 924715 embedded image 883977 embedded image 912074 embedded image 945407 embedded image 897751 embedded image 932659 embedded image 947274 embedded image 889567 embedded image 932660 embedded image 918277 embedded image 948156 embedded image 917136 embedded image 945674 embedded image 952435 embedded image 947285 embedded image 947287 embedded image 948040 embedded image 889664 embedded image 951839 embedded image 874528 embedded image 926832 embedded image 917142 embedded image 945473 embedded image 917140 embedded image 944075 embedded image 947466 embedded image 883865 embedded image 947839 embedded image 947471 embedded image 945662 embedded image 913126 embedded image 947270 embedded image 932641 embedded image 927343 embedded image 917134 embedded image 893308 embedded image 918284 embedded image 883973 embedded image 947245 embedded image 874532 embedded image 948122 embedded image 883972 embedded image 884107 embedded image 923675 embedded image 945678 embedded image 932661 embedded image 884119 embedded image 947267 embedded image 951846 embedded image 883864 embedded image 947308 embedded image 942344 embedded image 874975 embedded image 947265 embedded image 948416 embedded image 897750 embedded image 948319 embedded image 947304 embedded image 932639 embedded image 893320 embedded image 947472 embedded image 917135 embedded image 932632 embedded image 917137 embedded image 947271 embedded image 947459 embedded image 874535 embedded image 926827 embedded image 947609 embedded image 947268 embedded image 917141 embedded image 943894 embedded image 912084 embedded image 947898 embedded image 947463 embedded image 947282 embedded image 893321 embedded image 947291 embedded image 917232 embedded image 948438 embedded image 945669 embedded image 947278 embedded image 948415 embedded image 918275 embedded image 947299 embedded image 947276 embedded image 913057 embedded image 947460 embedded image 943957 embedded image 949321 embedded image 918285 embedded image 951708 embedded image 947474 embedded image 893312 embedded image 947486 embedded image 947302 embedded image 948298 embedded image 877320 embedded image 951709 embedded image 947470 embedded image 884005 embedded image 917081 embedded image 943898 embedded image 942462 embedded image 947256 embedded image 947261 embedded image 889578 embedded image 951790 embedded image 918282 embedded image 945667 embedded image 947467 embedded image 943961 embedded image 917133 embedded image 947468 embedded image 943896 embedded image 951862 embedded image 947249 embedded image 947241 embedded image 913356 embedded image 912092 embedded image 950478 embedded image 913260 embedded image 945675 embedded image 942432 embedded image 948117 embedded image 947259 embedded image 917161 embedded image 947289 embedded image 945719 embedded image 945677 embedded image 918283 embedded image 947477 embedded image 947297 embedded image 951713 embedded image 952436 embedded image 947607 embedded image 945664 embedded image 932649 embedded image 947615 embedded image 947610 embedded image 947277 embedded image 947307 embedded image 947475 embedded image 947283 embedded image 947292 embedded image 943483 embedded image 947487 embedded image 917082 embedded image 926815 embedded image 947608 embedded image 947606 embedded image 947303 embedded image 917138 embedded image 932640 embedded image 951788 embedded image 951864 embedded image 945657 embedded image 945676 embedded image 947904 embedded image 945671 embedded image 947612 embedded image 951726 embedded image 947300 embedded image 948219 embedded image 947247 embedded image 913264 embedded image 932648 embedded image 884004 embedded image 947900 embedded image 947479 embedded image 917231 embedded image 947273 embedded image 943543 embedded image 949319 embedded image 918278 embedded image 947480 embedded image 947250 embedded image 947465 embedded image 947901 embedded image 947286 embedded image 945673 embedded image 947605 embedded image 865193 embedded image 945680 embedded image 947897 embedded image 947290 embedded image 880776 embedded image 947298 embedded image 947293 embedded image 951703 embedded image 945660 embedded image 945665 embedded image 947279 embedded image 901471 embedded image 945663 embedded image 947903 embedded image 945659 embedded image 945655 embedded image 947272 embedded image 943488 embedded image 947266 embedded image 901466 embedded image 947296 embedded image 948119 embedded image 943489 embedded image 951724 embedded image 943482 embedded image 926808 embedded image 918276 embedded image 943486 embedded image 950814 embedded image 945714 embedded image 947244 embedded image 947462 embedded image 901467 embedded image 945666 embedded image 948121 embedded image 947280 embedded image 913251 embedded image 945661 embedded image 947478 embedded image 947482 embedded image 948120 embedded image 947899 embedded image 874530 embedded image 943955 embedded image 943481 embedded image 917143 embedded image 942366 embedded image 874477 embedded image 947295 embedded image 947252 embedded image 947616 embedded image 901468 embedded image 947263 embedded image 947613 embedded image 947243 embedded image 947246 embedded image 947733 embedded image 947248 embedded image 947481 embedded image 947483 embedded image 929440 embedded image 947735 embedded image 947258 embedded image 901474 embedded image 943484 embedded image 947269 embedded image 947281 embedded image 947253 embedded image 945670 embedded image 901469 embedded image 947902 embedded image 893311 embedded image 947254 embedded image 945672 embedded image 947469 embedded image 947275 embedded image 917139 embedded image 945656 embedded image 947242 embedded image 943485 embedded image 951725 embedded image 945805 embedded image 913261 embedded image 948123 embedded image 947305 embedded image 947611 embedded image 948118 embedded image 948038 embedded image 947288 embedded image 889665 embedded image 874534 embedded image 951789 embedded image 948223 embedded image 948215 embedded image 929437 embedded image 947484 embedded image 951861 embedded image 893310 embedded image 901470 embedded image 947464 embedded image 947614 embedded image 951701 embedded image 951787 embedded image 901465 embedded image 917144 embedded image 947485 embedded image 913259 embedded image 913262 embedded image 945712 embedded image 913058 embedded image 945668 embedded image 948440 embedded image 951863 embedded image 947461 embedded image 943487 embedded image 947476 embedded image 951723 embedded image 909207 embedded image 947255 embedded image 947264 embedded image 951714 embedded image 947838 embedded image 947260 embedded image 945718

79. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, thereof, wherein the compound is any one of the formulae shown in Table 5A: TABLE-US-00034 TABLE 5A embedded image 90285 embedded image 90709 embedded image 90991 embedded image 92737 embedded image 93429 embedded image 107828 embedded image 107829 embedded image 109152

80. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 6: TABLE-US-00035 TABLE 6 embedded image 912105 embedded image 901472 embedded image 901473 embedded image 877295 embedded image 912168 embedded image 826714 embedded image 841867 embedded image 880765 embedded image 889571 embedded image 893313 embedded image 893315 embedded image 911958 embedded image 912077 embedded image 912107 embedded image 913265 embedded image 924310 embedded image 929436 embedded image 929438 embedded image 929439 embedded image 929441 embedded image 929448 embedded image 932633 embedded image 932650 embedded image 932651 embedded image 932652 embedded image 932654 embedded image 943544 embedded image 943545 embedded image 943914

81. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 6A: TABLE-US-00036 TABLE 6A embedded image 90330 or embedded image 92315

82. The compound of claim 58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 80 or 81.

83. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula IV-A or IV-B: ##STR03568## wherein: R.sup.31 is ##STR03569## optionally substituted naphthyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridinyl, optionally optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted bicyclic heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R.sup.32 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; each of R.sup.33 and R.sup.38 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, Osi(R.sup.D).sub.2OR.sup.D, Osi(R.sup.D)(OR.sup.D).sub.2, or Osi(OR.sup.D).sub.3; each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; and or R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; q1 is 0, 1, 2, 3, or 4; and R.sup.37 is Br, I, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D) s, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3; provided that R.sup.37 is not-C(CH.sub.3).sub.3, CF.sub.3, CN, or C(O) NH.sub.2; and provided that each of Formulae IV-A and IV-B is not ##STR03570##

84. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.36a and R.sup.36b is independently hydrogen, halogen, or optionally substituted alkyl.

85. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one of R.sup.36a and R.sup.36b is fluorine.

86. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.36a and R.sup.36b are hydrogen.

87. The compound of any one of claims 83-86, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.35a and R.sup.35b is independently hydrogen, halogen, or optionally substituted alkyl.

88. The compound of claim 87, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.35a and R.sup.35b are CH.sub.3.

89. The compound of any one of claims 83-86, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring.

90. The compound of any one of claims 83-89, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein each of R.sup.34a and R.sup.34b is independently hydrogen, halogen, or optionally substituted alkyl.

91. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one of R.sup.34a and R.sup.34b is fluorine.

92. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.34a and R.sup.34b are hydrogen.

93. The compound of any one of claims 83-92, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.31 is ##STR03571##

94. The compound of any one of claims 83-93, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.37 is Br, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.D, SR.sup.D, N(R.sup.D).sub.2, S(O).sub.2R.sup.D, NR.sup.DC(O)R.sup.D, or NR.sup.DS(O).sub.2SR.sup.D.

95. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.37 is optionally substituted heteroaryl comprising one or more N atoms.

96. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.37 is optionally substituted pyridinyl or optionally substituted pyrazolyl.

97. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, hydrate, thereof, wherein R.sup.37 is optionally substituted heterocyclyl.

98. The compound of any one of claims 83-97, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein q1 is 0.

99. The compound of any one of claims 83-98, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.32 is optionally substituted alkyl.

100. The compound of claim 99, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.32 is unsubstituted C.sub.1-C.sub.4 alkyl.

101. The compound of any one of claims 83-100, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.33 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

102. The compound of claim 101, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.33 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.

103. The compound of claim 101, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.33 is C.sub.1-4 haloalkyl.

104. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula; ##STR03572##

105. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 7: TABLE-US-00037 TABLE 7 embedded image 806604 embedded image 810362 embedded image 810379 embedded image 801313 embedded image 810365 embedded image 945713 embedded image 947867 embedded image 945532 embedded image 912171 embedded image 942642 embedded image 945328 embedded image 945546 embedded image 948545 embedded image 913047 embedded image 943990 embedded image 917291 embedded image 945481 embedded image 945704 embedded image 947384 embedded image 911992 embedded image 913043 embedded image 810366 embedded image 884117 embedded image 913035 embedded image 945531 embedded image 948546 embedded image 943913 embedded image 946099 embedded image 947333 embedded image 947658 embedded image 811565 embedded image 816885 embedded image 917293 embedded image 945527 embedded image 945710 embedded image 947511 embedded image 816800 embedded image 913032 embedded image 947324 embedded image 947326 embedded image 947372 embedded image 911989 embedded image 945619 embedded image 811561 embedded image 945958 embedded image 949268 embedded image 918327 embedded image 944035 embedded image 945728 embedded image 959342 embedded image 947665 embedded image 819560 embedded image 819639 embedded image 913046 embedded image 929452 embedded image 810489 embedded image 913041 embedded image 924543 embedded image 811558 embedded image 945482 embedded image 826651 embedded image 883872 embedded image 945618 embedded image 945726 embedded image 811563 embedded image 917151 embedded image 929445 embedded image 927339 embedded image 944036 embedded image 949514 embedded image 945545 embedded image 957510 embedded image 875608 embedded image 943546 embedded image 947816 embedded image 874315 embedded image 946101 embedded image 949391 embedded image 912004 embedded image 865170 embedded image 911972 embedded image 837803 embedded image 826719 embedded image 947412 embedded image 929449 embedded image 945486 embedded image 789561 embedded image 9121272 embedded image 929453 embedded image 945612 embedded image 913034 embedded image 948779 embedded image 943515 embedded image 810375 embedded image 927341 embedded image 913256 embedded image 947383 embedded image 949399 embedded image 946092 embedded image 816886 embedded image 947499 embedded image 917148 embedded image 893324 embedded image 945471 embedded image 913039 embedded image 943547 embedded image 949113 embedded image 946102 embedded image 911976 embedded image 950330 embedded image 889582 embedded image 947818 embedded image 946096 embedded image 957509 embedded image 946003 embedded image 912090 embedded image 865196 embedded image 947872 embedded image 949131 embedded image 913051 embedded image 865195 embedded image 912088 embedded image 819576 embedded image 913049 embedded image 909215 embedded image 790734 embedded image 874261 embedded image 902969 embedded image 911991 embedded image 946094 embedded image 950331 embedded image 874533 embedded image 913134 embedded image 943517 embedded image 865194 embedded image 837753 embedded image 883875 embedded image 946090 embedded image 874299 embedded image 945939 embedded image 913141 embedded image 947824 embedded image 947365 embedded image 945544 embedded image 909203 embedded image 913033 embedded image 816799 embedded image 913038 embedded image 917079 embedded image 826716 embedded image 932643 embedded image 943995 embedded image 912167 embedded image 913048 embedded image 885237 embedded image 885402 embedded image 947571 embedded image 924312 embedded image 828850 embedded image 947337 embedded image 913016 embedded image 945729 embedded image 913054 embedded image 885355 embedded image 947490 embedded image 945463 embedded image 889604 embedded image 915630 embedded image 913019 embedded image 943918 embedded image 945479 embedded image 801318 embedded image 865172 embedded image 946100 embedded image 913024 embedded image 943991 embedded image 885099 embedded image 947364 embedded image 801446 embedded image 909202 embedded image 930569 embedded image 946055 embedded image 884118 embedded image 823724 embedded image 913040 embedded image 947657 embedded image 915401 embedded image 947656 embedded image 917289 embedded image 917087 embedded image 943519 embedded image 945329 embedded image 946103 embedded image 889565 embedded image 792342 embedded image 811567 embedded image 819575 embedded image 853910 embedded image 789513 embedded image 885367 embedded image 885382 embedded image 945466 embedded image 917149 embedded image 810452 embedded image 948057 embedded image 945620 embedded image 917292 embedded image 915340 embedded image 948061 embedded image 957504 embedded image 874316 embedded image 947548 embedded image 947334 embedded image 945600 embedded image 801447 embedded image 947570 embedded image 932645 embedded image 885088 embedded image 945601 embedded image 917089 embedded image 801320 embedded image 810363 embedded image 924504 embedded image 884115 embedded image 947328 embedded image 913044 embedded image 789514 embedded image 912089 embedded image 913022 embedded image 913017 embedded image 932626 embedded image 926304 embedded image 913350 embedded image 885217 embedded image 948088 embedded image 885188 embedded image 801317 embedded image 918326 embedded image 918272 embedded image 889631 embedded image 943988 embedded image 913252 embedded image 913026 embedded image 913124 embedded image 913122 embedded image 889622 embedded image 801368 embedded image 930334 embedded image 945467 embedded image 885120 embedded image 929450 embedded image 911969 embedded image 947492 embedded image 943536 embedded image 877310 embedded image 885228 embedded image 816752 embedded image 957505 embedded image 865171 embedded image 791272 embedded image 883989 embedded image 909220 embedded image 801367 embedded image 819574 embedded image 932629 embedded image 785736 embedded image 806637 embedded image 791273 embedded image 945610 embedded image 901480 embedded image 947407 embedded image 927338 embedded image 932657 embedded image 948548 embedded image 947512 embedded image 947325 embedded image 932647 embedded image 810369 embedded image 948093 embedded image 810510 embedded image 912070 embedded image 945708 embedded image 913222 embedded image 950326 embedded image 889558 embedded image 947653 embedded image 789277 embedded image 913121 embedded image 811559 embedded image 790730 embedded image 917130 embedded image 947664 embedded image 948089 embedded image 950333 embedded image 913140 embedded image 909201 embedded image 801323 embedded image 889580 embedded image 943538 embedded image 874260 embedded image 909212 embedded image 947327 embedded image 883985 embedded image 912003 embedded image 932634 embedded image 885110 embedded image 912065 embedded image 947493 embedded image 932658 embedded image 801448 embedded image 947434 embedded image 911993 embedded image 945475 embedded image 883996 embedded image 947659 embedded image 913348 embedded image 932628 embedded image 929442 embedded image 944025 embedded image 917147 embedded image 932642 embedded image 854926 embedded image 902970 embedded image 810360 embedded image 945715 embedded image 913334 embedded image 883990 embedded image 929402 embedded image 810508 embedded image 840857 embedded image 913037 embedded image 947494 embedded image 913255 embedded image 816871 embedded image 917209 embedded image 884000 embedded image 883997 embedded image 959341 embedded image 837683 embedded image 823720 embedded image 917152 embedded image 810488 embedded image 883987 embedded image 885204 embedded image 945474 embedded image 945476 embedded image 948091 embedded image 945992 embedded image 947652 embedded image 801397 embedded image 874294 embedded image 883850 embedded image 789560 embedded image 943532 embedded image 943992 embedded image 819622 embedded image 884110 embedded image 874312 embedded image 912067 embedded image 947406 embedded image 918274 embedded image 943919 embedded image 789565 embedded image 945472 embedded image 801319 embedded image 917212 embedded image 943540 embedded image 913125 embedded image 912066 embedded image 893323 embedded image 932666 embedded image 947810 embedded image 789312 embedded image 819638 embedded image 945607 embedded image 945943 embedded image 944023 embedded image 856947 embedded image 957506 embedded image 913346 embedded image 883998 embedded image 911970 embedded image 865168 embedded image 947655 embedded image 949083 embedded image 801312 embedded image 918273 embedded image 912071 embedded image 811564 embedded image 943537 embedded image 893306 embedded image 911981 embedded image 957511 embedded image 926844 embedded image 945730 embedded image 944029 embedded image 932664 embedded image 950324 embedded image 918281 embedded image 801322 embedded image 883999 embedded image 944018 embedded image 945703 embedded image 947569 embedded image 785738 embedded image 911988 embedded image 823721 embedded image 945468 embedded image 948090 embedded image 912068 embedded image 913027 embedded image 913020 embedded image 819577 embedded image 874318 embedded image 929399 embedded image 883988 embedded image 918321 embedded image 949082 embedded image 918280 embedded image 912069 embedded image 946104 embedded image 943531 embedded image 926836 embedded image 945609 embedded image 902971 embedded image 927342 embedded image 883984 embedded image 944019 embedded image 912064 embedded image 927344 embedded image 913254 embedded image 946097 embedded image 791271 embedded image 948793 embedded image 883993 embedded image 950329 embedded image 929401 embedded image 810451 embedded image 913053 embedded image 884002 embedded image 913028 embedded image 917146 embedded image 893305 embedded image 909205 embedded image 877311 embedded image 913253 embedded image 884109 embedded image 927348 embedded image 865169 embedded image 932636 embedded image 948058 embedded image 913310 embedded image 948615 embedded image 944017 embedded image 946091 embedded image 889556 embedded image 929444 embedded image 913258 embedded image 947650 embedded image 801316 embedded image 947498 embedded image 932631 embedded image 874317 embedded image 889557 embedded image 875568 embedded image 913015 embedded image 810358 embedded image 889581 embedded image 918271 embedded image 883994 embedded image 945458 embedded image 944024 embedded image 945933 embedded image 949401 embedded image 927347 embedded image 943535 embedded image 790733 embedded image 943514 embedded image 913274 embedded image 946095 embedded image 883992 embedded image 874531 embedded image 943541 embedded image 947397 embedded image 874298 embedded image 885344 embedded image 932655 embedded image 918279 embedded image 945606 embedded image 929387 embedded image 943994 embedded image 801413 embedded image 932630 embedded image 945543 embedded image 947491 embedded image 819564 embedded image 810450 embedded image 945998 embedded image 949397 embedded image 885331 embedded image 810373 embedded image 929398 embedded image 913021 embedded image 913029 embedded image 917131 embedded image 915400 embedded image 909214 embedded image 945995 embedded image 948547 embedded image 945613 embedded image 948060 embedded image 915316 embedded image 957507 embedded image 949521 embedded image 913018 embedded image 929454 embedded image 947398 embedded image 944031 embedded image 913031 embedded image 889579 embedded image 912169 embedded image 913123 embedded image 917086 embedded image 945997 embedded image 911975 embedded image 943534 embedded image 945605 embedded image 943539 embedded image 883851 embedded image 945724 embedded image 811557 embedded image 883986 embedded image 913352 embedded image 963155 embedded image 913050 embedded image 947400 embedded image 913030 embedded image 945530 embedded image 883852 embedded image 929400 embedded image 911980 embedded image 912166 embedded image 874314 embedded image 913257 embedded image 949103 embedded image 901479 embedded image 943542 embedded image 946089 embedded image 884116 embedded image 945529 embedded image 959343 embedded image 947336 embedded image 917132 embedded image 932625 embedded image 837646 embedded image 944032 embedded image 913351 embedded image 945469 embedded image 826717 embedded image 913349 embedded image 943533 embedded image 911990 embedded image 913045 embedded image 929447 embedded image 883991 embedded image 884003 embedded image 909204 embedded image 917088 embedded image 919840 embedded image 926840 embedded image 883874 embedded image 913135 embedded image 947802 embedded image 943492 embedded image 947631 embedded image 946093 embedded image 801324 embedded image 932663 embedded image 945725 embedded image 883873 embedded image 943516 embedded image 927346 embedded image 944033 embedded image 932627 embedded image 947651 embedded image 913347 embedded image 913036 embedded image 943518 embedded image 883995 embedded image 943996 embedded image 944026 embedded image 947808 embedded image 819561 embedded image 913023 embedded image 913052 embedded image 801445 embedded image 917150 embedded image 917076 embedded image 826718 embedded image 889639 embedded image 913025 embedded image 913311 embedded image 947363 embedded image 945528 embedded image 810506 embedded image 810507 embedded image 884001 embedded image 947329 embedded image 948092 embedded image 949104

106. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 7A: TABLE-US-00038 TABLE 7A embedded image 108954 embedded image 108956 embedded image 114687 embedded image 125976 embedded image 125977 embedded image 126012 embedded image 126013 embedded image 126014 embedded image 126190 embedded image 126191 embedded image 126192 embedded image 126193 embedded image 126366 embedded image 126393 embedded image 126394 embedded image 126395 embedded image 126397 embedded image 126398 embedded image 126399 or embedded image 126400

107. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 8: TABLE-US-00039 TABLE 8 embedded image 945485 embedded image 957508 embedded image 959344 embedded image 810453 embedded image 823726 embedded image 932637 embedded image 932638 embedded image 947411 embedded image 950325 embedded image 950332 embedded image 801366 embedded image 801369 embedded image 801412 embedded image 810359 embedded image 810364 embedded image 810371 embedded image 810509 embedded image 889632 embedded image 909213 embedded image 909223 embedded image 912091 embedded image 913042 embedded image 913223 embedded image 917210 embedded image 918322 embedded image 924520 embedded image 927340 embedded image 927345 embedded image 929443 embedded image 929451 embedded image 929455 embedded image 932635 embedded image 932644 embedded image 932646 embedded image 932656 embedded image 932662 embedded image 932665 embedded image 932667 embedded image 943915 embedded image 943989 embedded image 943993 embedded image 944034 embedded image 945484 embedded image 945615 embedded image 945616 embedded image 946000 embedded image 946002 embedded image 946098 embedded image 949132

108. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 8A: TABLE-US-00040 TABLE 8A embedded image 126015 embedded image 126367 or embedded image 126396

109. The compound of claim 83, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 107 or 108.

110. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula V-A or V-B: ##STR04255## wherein: R.sup.41 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.42 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; R.sup.43 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.E, SCN, SR.sup.E, SSR.sup.E, N.sub.3, NO, N(R.sup.E).sub.2, NO.sub.2, C(O)R.sup.E, C(O)OR.sup.E, C(O)SR.sup.E, C(O)N(R.sup.E).sub.2, C(NR.sup.E)R.sup.E, C(NR.sup.E)OR.sup.E, C(NR.sup.E)SR.sup.E, C(NR.sup.E)N(R.sup.E).sub.2, S(O)R.sup.E, S(O)OR.sup.E, S(O)SR.sup.E, S(O)N(R.sup.E).sub.2, S(O).sub.2R.sup.E, S(O).sub.2OR.sup.E, S(O).sub.2SR.sup.E, S(O).sub.2N(R.sup.E).sub.2, OC(O)R.sup.E, OC(O)OR.sup.E, OC(O)SR.sup.E, OC(O)N(R.sup.E), OC(NR.sup.E)R.sup.E, OC(NR.sup.E)OR.sup.E, OC(NR.sup.E)SR.sup.E, OC(NR.sup.E)N(R.sup.E).sub.2, OS(O)R.sup.E, OS(O)OR.sup.E, OS(O)SR.sup.E, OS(O)N(R.sup.E).sub.2, OS(O).sub.2R.sup.E, OS(O).sub.2OR.sup.E, OS(O).sub.2SR.sup.E, OS(O).sub.2N(R.sup.E).sub.2, ON(R.sup.E).sub.2, SC(O)R.sup.E, SC(O)OR.sup.E, SC(O)SR.sup.E, SC(O)N(R.sup.E).sub.2, SC(NR.sup.E)R.sup.E, SC(NR.sup.E)OR.sup.E, SC(NR.sup.E)SR.sup.E, SC(NR.sup.E)N(R.sup.E).sub.2, NR.sup.EC(O)R.sup.E, NR.sup.EC(O)OR.sup.E, NR.sup.EC(O)SR.sup.E, NR.sup.EC(O)N(R.sup.E).sub.2, NR.sup.EC(NR.sup.E)R.sup.E, NR.sup.EC(NR.sup.E)OR.sup.E, NR.sup.EC(NR.sup.E)SR.sup.E, NR.sup.EC(NR.sup.E)N(R.sup.E).sub.2, NR.sup.ES(O)R.sup.E, NR.sup.ES(O)OR.sup.E, NR.sup.ES(O)SR.sup.E, NR.sup.ES(O)N(R.sup.E).sub.2, NR.sup.ES(O).sub.2R.sup.E, NR.sup.ES(O).sub.2OR.sup.E, NR.sup.ES(O).sub.2SR.sup.E, NR.sup.ES(O).sub.2N(R.sup.E).sub.2, Si(R.sup.E).sub.3, Si(R.sup.E).sub.2OR.sup.E, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.E).sub.3, OSi(R.sup.E).sub.3, OSi(R.sup.E).sub.2OR.sup.E, OSi(R.sup.E)(OR.sup.E).sub.2, or OSi(OR.sup.E).sub.3; each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or OR.sup.E; and each instance of R.sup.E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.E attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.45b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; provided that at least one of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b is not hydrogen.

111. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.46a and R.sup.4bh is independently hydrogen, halogen, optionally substituted alkyl, or OR.sup.E.

112. The compound of claim 110 or 111, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R.sup.46a and R.sup.46b is hydrogen.

113. The compound of any one of claims 110-112, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.45a and R.sup.45b is independently hydrogen, halogen, or optionally substituted alkyl.

114. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.45a and R.sup.45b are CH.sub.3.

115. The compound of any one of claims 110-114, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.44a and R.sup.44b is independently hydrogen, halogen, or optionally substituted alkyl.

116. The compound of claim 115, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R.sup.44a and R.sup.44b is hydrogen.

117. The compound of any one of claims 110-116, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.41 is optionally substituted aryl.

118. The compound of claim 117, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.41 is ##STR04256## wherein: each instance of R.sup.47 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O)R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O)SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3; r1 is 0, 1, 2, 3, 4, or 5.

119. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, thereof, wherein R.sup.41 is ##STR04257##

120. The compound of claim 118 or 119, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein r1 is 1.

121. The compound of any one of claims 110-120, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.42 is optionally substituted alkyl.

122. The compound of claim 121, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.42 is unsubstituted C.sub.1-C.sub.4 alkyl.

123. The compound of any one of claims 110-116, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.

124. The compound of any one of claims 110-116, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring.

125. The compound of claim 124, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted cyclohexyl, piperidinyl, or tetrahydropyranyl.

126. The compound of any one of claims 110-125, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.43 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

127. The compound of claim 126, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.43 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.

128. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR04258##

129. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 9: TABLE-US-00041 TABLE 9 embedded image 948545 embedded image 948546 embedded image 959342 embedded image 865199 embedded image 957510 embedded image 946101 embedded image 837803 embedded image 945486 embedded image 946102 embedded image 957509 embedded image 946056 embedded image 837753 embedded image 835310 embedded image 865198 embedded image 957403 embedded image 909217 embedded image 947657 embedded image 957197 embedded image 957405 embedded image 947656 embedded image 946103 embedded image 957504 embedded image 826766 embedded image 909216 embedded image 957200 embedded image 957505 embedded image 865201 embedded image 893316 embedded image 826768 embedded image 948548 embedded image 947653 embedded image 945475 embedded image 959341 embedded image 837683 embedded image 945476 embedded image 835314 embedded image 947652 embedded image 819622 embedded image 957506 embedded image 826764 embedded image 947655 embedded image 957511 embedded image 946104 embedded image 947650 embedded image 948547 embedded image 835315 embedded image 957507 embedded image 963155 embedded image 959343 embedded image 837646 embedded image 947651 embedded image 883833 embedded image 883834 embedded image 883836 embedded image 883835 embedded image 912072 embedded image 917136 embedded image 951839 embedded image 917134 embedded image 918284 embedded image 951705 embedded image 951705 embedded image 951846 embedded image 917135 embedded image 951711 embedded image 951711 embedded image 918285 embedded image 951708 embedded image 951709 embedded image 918282 embedded image 917133 embedded image 918283 embedded image 951713 embedded image 951703 embedded image 950814 embedded image 951701

130. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 10: TABLE-US-00042 TABLE 10 embedded image 945485 embedded image 957508 embedded image 959344 embedded image 826767 embedded image 826769 embedded image 835312 embedded image 835313 embedded image 865202 embedded image 909218 embedded image 909219 embedded image 957196 embedded image 957199 embedded image 957404 embedded image 957406

131. The compound of claim 110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 130.

132. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula VI-A or VI-B: ##STR04349## wherein: R.sup.51 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.52 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; or R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; R.sup.53 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.F, SCN, SR.sup.F, SSR.sup.F, N.sub.3, NO, N(R.sup.F).sub.2, NO.sub.2, C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, C(O)N(R.sup.F).sub.2, C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, C(NR.sup.F)N(R.sup.F).sub.2, S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, S(O).sub.2N(R.sup.F).sub.2, OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, ON(R.sup.F).sub.2, SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, SC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, NR.sup.FS(O).sub.2N(R.sup.F).sub.2, Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, OSi(R.sup.F).sub.3, Osi(R.sup.F).sub.2OR.sup.F, Osi(R.sup.F)(OR.sup.F).sub.2, or Osi(OR.sup.F).sub.3; each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of R.sup.F is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.1 attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and R.sup.55a and R.sup.55b are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.F, SCN, SR.sup.F, SSR.sup.F, N.sub.3, NO, N(R.sup.F).sub.2, NO.sub.2, C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, C(O)N(R.sup.F).sub.2, C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, C(NR.sup.F)N(R.sup.F).sub.2, S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, S(O).sub.2N(R.sup.F).sub.2, OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.E, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, ON(R.sup.F).sub.2, SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, SC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, NR.sup.FS(O).sub.2N(R.sup.F).sub.2, Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, Osi(R.sup.F).sub.2, Osi(R.sup.F).sub.2OR.sup.F, Osi(R.sup.F)(OR.sup.F).sub.2, or Osi(OR.sup.F).sub.3; or R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring; or R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; or R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; provided that at least one of R.sup.55a and R.sup.55b is not CH.sub.3.

133. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.56a and R.sup.565 is independently hydrogen, halogen, or optionally substituted alkyl.

134. The compound of claim 133, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R.sup.56a and R.sup.56b is hydrogen.

135. The compound of any one of claims 132-134, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.55a and R.sup.55b are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted aryl.

136. The compound of claim 135, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R.sup.55a and R.sup.55b is hydrogen.

137. The compound of claim 135 or 136, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.55a and R.sup.55b are both hydrogen.

138. The compound of any one of claims 132-134, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring.

139. The compound of any one of claims 132-138, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R.sup.54a and R.sup.54b is independently hydrogen, halogen, or optionally substituted alkyl.

140. The compound of claim 139, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R.sup.54a and R.sup.54b is hydrogen.

141. The compound of any one of claims 132-140, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.51 is optionally substituted aryl.

142. The compound of claim 141, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.51 is ##STR04350## wherein: each instance of R.sup.57 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, Osi(R.sup.D).sub.3, Osi(R.sup.D).sub.2OR.sup.D, Osi(R.sup.D)(OR.sup.D).sub.2, or Osi(OR.sup.D).sub.3; s1 is 0, 1, 2, 3, 4, or 5.

143. The compound of claim 142, or a pharmaceutically acceptable salt, solvate, hydrate, thereof, wherein R.sup.51 is ##STR04351##

144. The compound of claim 142 or 143, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein s1 is 1.

145. The compound of any one of claims 132-144, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.52 is optionally substituted alkyl.

146. The compound of claim 145, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.52 is unsubstituted C.sub.1-C.sub.4 alkyl.

147. The compound of any one of claims 132-140, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.

148. The compound of any one of claims 132-140, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring.

149. The compound of claim 148, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted tetrahydropyranyl.

150. The compound of any one of claims 132-149, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.53 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen.

151. The compound of claim 150, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.53 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.

152. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 11: TABLE-US-00043 TABLE 11 embedded image 949753 embedded image 865199 embedded image 950161 embedded image 884111 embedded image 874315 embedded image 947412 embedded image 791265 embedded image 950160 embedded image 791264 embedded image 950330 embedded image 950331 embedded image 816884 embedded image 806608 embedded image 949760 embedded image 816875 embedded image 835310 embedded image 806609 embedded image 901477 embedded image 828849 embedded image 789013 embedded image 865198 embedded image 828850 embedded image 816796 embedded image 819569 embedded image 893309 embedded image 884112 embedded image 789334 embedded image 901478 embedded image 889572 embedded image 912078 embedded image 909217 embedded image 823724 embedded image 912079 embedded image 789332 embedded image 810452 embedded image 816873 embedded image 874316 embedded image 789010 embedded image 816878 embedded image 816881 embedded image 819565 embedded image 816879 embedded image 819568 embedded image 909216 embedded image 816752 embedded image 865201 embedded image 893316 embedded image 947407 embedded image 932657 embedded image 950326 embedded image 950333 embedded image 826653 embedded image 932658 embedded image 810486 embedded image 823720 embedded image 810487 embedded image 826652 embedded image 801397 embedded image 947406 embedded image 856947 embedded image 950324 embedded image 823721 embedded image 874318 embedded image 950329 embedded image 810451 embedded image 874317 embedded image 810450 embedded image 826715 embedded image 828848 embedded image 828847 embedded image 901458 embedded image 901476 embedded image 901475 embedded image 889573

153. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is any one of the formulae shown in Table 12: TABLE-US-00044 TABLE 12 embedded image 865202 embedded image 909218 embedded image 909219 embedded image 810453 embedded image 823726 embedded image 932637 embedded image 932638 embedded image 947411 embedded image 950325 embedded image 950332 embedded image 789009 embedded image 789011 embedded image 789331 embedded image 789333 embedded image 791262 embedded image 791263 embedded image 806607 embedded image 806611 embedded image 810484 embedded image 810485 embedded image 816872 embedded image 816874 embedded image 816876 embedded image 816877 embedded image 816880 embedded image 816882 embedded image 819570 embedded image 819571 embedded image 826654 embedded image 826655 embedded image 949754 embedded image 949759 embedded image 950164 embedded image 950165.

154. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is not a compound of claim 153.

155. A compound of any one of the formulae shown in Table 13: TABLE-US-00045 TABLE 13 embedded image 816839 embedded image 792339 embedded image 791256 embedded image 806632 embedded image 801351 embedded image 819563 embedded image 810505 embedded image 819562 embedded image 874313 embedded image 801406 embedded image 786065 embedded image 884019 embedded image 786061 embedded image 862028 embedded image 883978 embedded image 874509 embedded image 913441 embedded image 786072 embedded image 790666 embedded image 897752 embedded image 826650 embedded image 816797 embedded image 816837 embedded image 811596 embedded image 874323 embedded image 789461 embedded image 810460 embedded image 930565 embedded image 790619 embedded image 806605 embedded image 789504 embedded image 789497 embedded image 810464 embedded image 772965 embedded image 806568 embedded image 801309 embedded image 806840 embedded image 945550 embedded image 810590 embedded image 810591 embedded image 784440 embedded image 945552 embedded image 801357 embedded image 789583 embedded image 801310 embedded image 789505 embedded image 947873 embedded image 790755 embedded image 810368 embedded image 785735 embedded image 810495 embedded image 801315 embedded image 801352 embedded image 806938 embedded image 874324 embedded image 789584 embedded image 841868 embedded image 816838 embedded image 789457 embedded image 828845 embedded image 785739 embedded image 810377 embedded image 811595 embedded image 789337 embedded image 782425 embedded image 789460 embedded image 856949 embedded image 789524 embedded image 789330 embedded image 782424 embedded image 792341 embedded image 917226 embedded image 811555 embedded image 913219 embedded image 806633 embedded image 790615 embedded image 874511 embedded image 791257 embedded image 792338 embedded image 819573 embedded image 930566 embedded image 810376 embedded image 806603 embedded image 785737 embedded image 816795 embedded image 789562 embedded image 913136 embedded image 801356 embedded image 790745 embedded image 816798 embedded image 789336 embedded image 801358 embedded image 801321 embedded image 811556 embedded image 945549 embedded image 883866 embedded image 790612 embedded image 792343 embedded image 945551 embedded image 789459 embedded image 945548 embedded image 806569 embedded image 785762 embedded image 810367 embedded image 802358 embedded image 789564 embedded image 806939 embedded image 947868 embedded image 790617 embedded image 790754 embedded image 789566 embedded image 810466 embedded image 874510 embedded image 801311 embedded image 801314 embedded image 792340 embedded image 801308 embedded image 945547 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

156. A compound of any one of the formulae shown in Table 13A: TABLE-US-00046 TABLE 13A embedded image 117093 embedded image 119047 embedded image 119048 embedded image 125978 embedded image 125979 embedded image 127429 embedded image 127430 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

157. A compound of any one of the formulae shown in Table 14: TABLE-US-00047 TABLE 14 embedded image 913137 embedded image 790632 embedded image 790611 embedded image 789458 embedded image 789563 embedded image 790616 embedded image 819572 embedded image 856948 embedded image 841866 embedded image 877294 embedded image 884020 embedded image 889570 embedded image 877288 embedded image 806940 embedded image 811512 embedded image 913355 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

158. A compound of the formula: ##STR04601## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

159. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt thereof.

160. A pharmaceutical composition comprising: the compound of any one of claims 1-159, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

161. The pharmaceutical composition of claim 160 further comprising an additional pharmaceutical agent.

162. A kit comprising: the compound of any one of claims 1-159, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition of claim 160 or 161; and instructions for using the compound, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or pharmaceutical composition.

163. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of: the compound of any one of claims 1-159, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of the formula: ##STR04602## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, each instance of the atoms marked with * is independently optionally substituted; custom-character is a single or double bond; R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.BOC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or the pharmaceutical composition of claim 160 or 161.

164. A method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of: the compound of any one of claims 1-159, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of the formula: ##STR04603## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: each instance of the atoms marked with * is independently optionally substituted; custom-character is a single or double bond; R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O)OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.DS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or the pharmaceutical composition of claim 160 or 161.

165. The method of claim 163 or 164, wherein the disease is associated with aberrantly high activity and/or production of a glycogen synthase kinase 3 (GSK3).

166. The method of any one of claims 163-165, wherein the effective amount is effective in inhibiting the activity and/or production of the GSK3.

167. The method of any one of claims 163-166, wherein the disease is associated with aberrantly high activity and/or production of catenin beta-1.

168. The method of any one of claims 163-167, wherein the disease is associated with a mutation and/or overexpression of the CTNNB1 gene.

169. The method of any one of claims 163-168, wherein the disease is a mental or behavioral disease.

170. The method of claim 169, wherein the disease is fragile X syndrome.

171. The method of claim 169, wherein the disease is autism.

172. The method of claim 169, wherein the disease is schizophrenia.

173. The method of claim 169, wherein the disease is bipolar disorder.

174. The method of claim 169, wherein the disease is attention deficit hyperactivity disorder.

175. The method of any one of claims 163-168, wherein the disease is a neurological disease.

176. The method of claim 175, wherein the disease is seizure.

177. The method of claim 175, wherein the disease is Alzheimer's disease.

178. The method of claim 175, wherein the disease is Huntington's disease.

179. The method of claim 175, wherein the disease is Parkinson's disease.

180. The method of claim 175, wherein the disease is amyotrophic lateral sclerosis.

181. The method of any one of claims 163-168, wherein the disease is a cancer.

182. The method of claim 181, wherein the disease is a hematological malignancy.

183. The method of claim 181, wherein the disease is leukemia.

184. The method of claim 181, wherein the disease is acute myeloid leukemia.

185. The method of claim 181, wherein the disease is acute lymphoblastic leukemia.

186. The method of claim 181, wherein the disease is colon cancer.

187. The method of claim 181, wherein the disease is pancreatic cancer.

188. The method of any one of claims 163-168, wherein the disease is a metabolic disease.

189. The method of claim 188, wherein the disease is diabetes.

190. The method of claim 188, wherein the disease is Type II diabetes.

191. The method of claim 188, wherein the disease is obesity.

192. A method of inhibiting the activity and/or production of a glycogen synthase kinase 3 (GSK3) in a subject in need thereof, the method comprising administering to the subject an effective amount of: the compound of any one of claims 1-159, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, a compound of the formula: ##STR04604## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: each instance of the atoms marked with * is independently optionally substituted; custom-character is a single or double bond; R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.3).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; each of R.sup.143, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or the pharmaceutical composition of claim 160 or 161.

193. The method of any one of claims 163-192, wherein the subject is a human.

194. The method of claim 193, wherein the subject is a human aged 18 and older.

195. A method of inhibiting the activity and/or production of a glycogen synthase kinase 3 (GSK3) in a cell, tissue, or biological sample the method comprising contacting the cell, tissue, or biological sample with an effective amount of: the compound of any one of claims 1-159, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of the formula: ##STR04605## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, each instance of the atoms marked with * is independently optionally substituted; custom-character is a single or double bond; R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B), S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.E).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each instance of R.sup.E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; or the pharmaceutical composition of claim 160 or 161.

196. The method of claim 195, wherein the cell, tissue, or biological sample is in vitro.

197. The method of any one of claims 163-196, wherein the GSK3 is glycogen synthase kinase 3 (GSK3).

198. The method of claim 197, wherein the compound, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is at least three times more selective for inhibiting the activity and/or production of GSK3 than glycogen synthase kinase 3 (GSK3) in an in vitro assay.

199. The method of any one of claims 163-196, wherein the GSK3 is glycogen synthase kinase 3 (GSK3).

200. The method of claim 199, wherein the compound, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is at least three times more selective for inhibiting the activity and/or production of GSK3 than glycogen synthase kinase 3 (GSK3) in an in vitro assay.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0135] FIGS. 1A to ID show that both GSK3 and GSK isoforms phosphorylated tau at multiple epitopes including the disease enriched epitopes Thr231 and S202/Thr205 (FIG. 1A). The percent inhibition of pTh231 was then compared using AZ1080 (FIG. 1B), BRD0705 (BRD-0705; FIG. 1C), and 837646 (FIG. 1D).

[0136] FIGS. 2A to 2B show binding of GSK3 small molecule inhibitors as a function of concentration at ATP binding pocket and had similar residence times. Inhibitor compounds bound competitively with the kinase tracer (FIG. 2A). Inhibitors had similar residence times for GSK isoforms (FIG. 2B).

[0137] FIGS. 3A to 3C show the combined inhibition of both GSK3 paralogs may be necessary for nuclear translocation of -catenin in SH-SYSY cells. FIGS. 3A to 3C show IC.sub.50 curves demonstrating potency of GSK3 inhibitors to cause -catenin translocation to the nucleus, exemplary pictures at the 20 M, and IC.sub.50 data for -catenin, Thr231 assay for GSK, and Thr231 assay for GSK for compound BRD-0705 (FIG. 3A), 837646 (FIG. 3B), and AZ 1080 (FIG. 3C).

[0138] FIGS. 4A to 4D show selective GSK3 inhibition by 837646 reduced tau phosphorylation at disease relevant sites in vivo. FIG. 4A shows T231 normalized to total tau versus time post dose. FIG. 4B shows total concentration over time. FIG. 4C shows percent engagement of GSK3 over time. FIG. 4D shows percent engagement of GSK3 over time.

[0139] FIG. 5 shows the elucidation of a GSK3 crystal structure.

[0140] FIGS. 6A to 6D show Thr231 cell-based assay results comparing percent inhibition of pThr231, percent to untreated mBU, and BRET ratios in 947651 and 948546. FIG. 6A shows potency of 947651 and 948546 as determined by Thr231 cell-based assay. FIG. 6B shows potency of 947651 and 948546 as determined by nanobret assay. FIG. 6C shows residence times of 947651 and 948546 for GSK3. FIG. 6D shows potency of 947651 and 948546 to induce translocation of -catenin to the nucleus.

[0141] FIGS. 7A to 7B depict 948546 bound GSK3 versus GSK (FIG. 7A), as well as / pocket surface overlay (FIG. 7B).

[0142] FIG. 8 shows the GSK3 isoform phosphorylation of disease-relevant epitopes of tau.

[0143] FIG. 9 shows the specificity of Thr231 using a plate based assay.

[0144] FIGS. 10A to 10B show activity of GSK3 inhibitors BRD0705 (FIG. 10A) and 837646 (FIG. 10B) on tau phosphorylation at Ser202 and Thr205 as a function of log concentration.

[0145] FIG. 11 shows the EC.sub.50 for Tracer 8 at GSK3 (GSK-A; FIG. 11A) and GSK3 (GSK-B; FIG. 11B) in HEK293T cells transiently transfected with either NanoLuc-GSK3 or NanoLuc-GSK3 plasmids, treated for two hours with NanoBRET Tracer-8 the following day, and incubated in the presence or absence of a saturating dose of GSK3 inhibitor compound 837646 at 10 M.

[0146] FIG. 12 shows the PK properties for PPB Fu % (rat) 837646.

[0147] FIG. 13 depicts free drug concentration based on plasma protein binding for 837646.

[0148] FIG. 14 shows the activation of -catenin following treatment with 947651 or 948546.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0149] The present disclosure provides compounds (e.g., compounds of Formulae I-A, I-B, II-A, II-B, III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, and VI-B, and shown in Table 13, Table 13A, and Table 14, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof), and pharmaceutical compositions and kits thereof. Also provided herein are methods of treating and/or preventing a disease in a subject in need thereof, as well as methods of inhibiting the activity and/or production GSK3 in a subject in need thereof, cell, or tissue in vivo or in vitro.

[0150] The contents of International PCT Application Publication Number WO 2018/187630 are incorporated herein by reference in their entirety.

Compounds

[0151] In one aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-A or I-B:

##STR00015##

wherein: [0152] custom-character is a single or double bond; [0153] R.sup.1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0154] R.sup.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; [0155] or R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; [0156] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.A, SCN, SR.sup.A, SSR.sup.A, N.sub.3, NO, N(R.sup.A).sub.2, NO.sub.2, C(O)R.sup.A, C(O)OR.sup.A, C(O)SR.sup.A, C(O)N(R.sup.A).sub.2, C(NR.sup.A)R.sup.A, C(NR.sup.A)OR.sup.A, C(NR.sup.A)SR.sup.A, C(NR.sup.A)N(R.sup.A).sub.2, S(O)R.sup.A, S(O)OR.sup.A, S(O)SR.sup.A, S(O)N(R.sup.A).sub.2, S(O).sub.2R.sup.A, S(O).sub.2OR.sup.A, S(O).sub.2SR.sup.A, S(O)N(R.sup.A), OC(O)R.sup.A, OC(O)OR.sup.A, OC(O)SR.sup.A, OC(O)N(R.sup.A).sub.2, OC(NR.sup.A)R.sup.A, OC(NR.sup.A)OR.sup.A, OC(NR.sup.A)SR.sup.A, OC(NR.sup.A)N(R.sup.A).sub.2, OS(O)R.sup.A, OS(O)OR.sup.A, OS(O)SR.sup.A, OS(O)N(R.sup.A).sub.2, OS(O)R.sup.A, OS(O)OR.sup.A, OS(O).sub.2SR.sup.A, OS(O).sub.2N(R.sup.A).sub.2, ON(R.sup.A).sub.2, SC(O)R.sup.A, SC(O)OR.sup.A, SC(O)SR.sup.A, SC(O)N(R.sup.A).sub.2, SC(NR.sup.A)R.sup.A, SC(NR.sup.A)OR.sup.A, SC(NR.sup.A)SR.sup.A, SC(NR.sup.A)N(R.sup.A).sub.2, NR.sup.AC(O)R.sup.A, NR.sup.AC(O)OR.sup.A, NR.sup.AC(O)SR.sup.A, NR.sup.AC(O)N(R.sup.A).sub.2, NR.sup.AC(NR.sup.A)R.sup.A, NR.sup.AC(NR.sup.A)OR.sup.A, NR.sup.AC(NR.sup.A)SR.sup.A, NR.sup.AC(NR.sup.A)N(R.sup.A).sub.2, NR.sup.AS(O)R.sup.A, NR.sup.AS(O)OR.sup.A, NR.sup.AS(O)SR.sup.A, NR.sup.AS(O)N(R.sup.A).sub.2, NR.sup.AS(O).sub.2R.sup.A, NR.sup.AS(O).sub.2OR.sup.A, NR.sup.AS(O).sub.2SR.sup.A, NR.sup.AS(O).sub.2N(R.sup.A).sub.2, Si(R.sup.A).sub.3, Si(R.sup.A).sub.2OR.sup.A, Si(R.sup.A)(OR.sup.A).sub.2, Si(OR.sup.A).sub.3, OSi(R.sup.A).sub.3, OSi(R.sup.A).sub.2OR.sup.A, OSi(R.sup.A)(OR.sup.A).sub.2, or OSi(OR.sup.A).sub.3; [0157] each of R.sup.4a and R.sup.4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0158] each instance of R.sup.A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and [0159] or R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0160] R.sup.6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and [0161] n1 is 0 or 1; [0162] when n1 is 1: [0163] each of R.sup.5a and R.sup.5b independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0164] or R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; [0165] provided that the compound is not of the formula:

##STR00016##

[0166] In some embodiments, the compound is of the formula:

##STR00017##

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

[0167] In some embodiments, the compound is of the formula:

##STR00018##

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

[0168] In some embodiments, the compound is of the formula:

##STR00019##

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

[0169] In some embodiments, the compound is of the formula:

##STR00020##

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

[0170] In some embodiments, custom-character is a single bond. In some embodiments, custom-character is a double bond.

[0171] In some embodiments, n1 is 0. In some embodiments, n1 is 1.

[0172] In some embodiments,

##STR00021##

respectively. In some embodiments,

##STR00022##

respectively.

[0173] In some embodiments, R.sup.1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.1 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl.

[0174] In some embodiments, R.sup.1 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.1 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.1 is saturated carbocyclyl. In some embodiments, R.sup.1 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0175] In some embodiments, R.sup.1 is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R.sup.1 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.1 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.1 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.1 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.1 is saturated heterocyclyl. In some embodiments, R.sup.1 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0176] In some embodiments, R.sup.1 is optionally substituted aryl. In some embodiments, R.sup.1 is optionally substituted monocyclic aryl. In some embodiments, R.sup.1 is optionally substituted bicyclic aryl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.1 is optionally substituted phenyl. In some embodiments, R.sup.1 is optionally substituted naphthyl.

[0177] In some embodiments, R.sup.1 is optionally substituted heteroaryl. In some embodiments, R.sup.1 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.1 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.1 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.1 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.1 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.1 is optionally substituted 9- to 10-membered bicyclic heteroaryl.

[0178] In some embodiments, R.sup.1 is optionally substituted aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted phenyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted naphthyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0179] In some embodiments, R.sup.1 is optionally substituted aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted phenyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted naphthyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0180] In some embodiments, R.sup.1 is optionally substituted heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0181] In some embodiments, R.sup.1 is optionally substituted heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-14 membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0182] In some embodiments, R.sup.1 is

##STR00023##

[0183] Each instance of R.sup.7 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3.

[0184] n2 is 0, 1, 2, 3, 4, or 5. In some embodiments, n2 is 0, 1, 2, 3, or 4. In some embodiments, n2 is 0, 1, 2, or 3. In some embodiments, n2 is 0, 1, or 2. In some embodiments, n2 is 0 or 1. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5.

[0185] In some embodiments, R.sup.1 is

##STR00024##

In some embodiments, R.sup.1 is

##STR00025##

In some embodiments, R.sup.1 is

##STR00026##

In some embodiments, R.sup.1 is

##STR00027##

In some embodiments, R.sup.1 is

##STR00028##

In some embodiments, R.sup.1 is

##STR00029##

In some embodiments, R.sup.1 is

##STR00030##

In some embodiments, R.sup.1 is

##STR00031##

In some embodiments, R.sup.1 is

##STR00032##

In some embodiments, R.sup.1 is

##STR00033##

[0186] In some embodiments, R.sup.7 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, R.sup.7 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.7 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.7 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.7 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.7 is CF.sub.3.

[0187] In some embodiments, R.sup.7 is halogen. In some embodiments, R.sup.7 is bromine, chlorine, or fluorine. In some embodiments, R.sup.7 is bromine or chlorine. In some embodiments, R.sup.7 is chlorine or fluorine. In some embodiments, R.sup.7 is bromine. In some embodiments, R.sup.7 is chlorine. In some embodiments, R.sup.7 is fluorine.

[0188] In some embodiments, R.sup.7 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is OH. In some embodiments, R.sup.7 is SH. In some embodiments, R.sup.7 is NH.sub.2. In some embodiments, R.sup.7 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.7 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.7 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0189] In some embodiments, R.sup.7 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.7 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.7 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.7 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.7 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.7 is saturated carbocyclyl. In some embodiments, R.sup.7 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0190] In some embodiments, R.sup.7 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.2 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.1 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.7 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.7 is saturated heterocyclyl. In some embodiments, R.sup.7 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0191] In some embodiments, R.sup.7 is optionally substituted monocyclic aryl. In some embodiments, R.sup.7 is optionally substituted bicyclic aryl. In some embodiments, R.sup.7 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.7 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.7 is optionally substituted phenyl. In some embodiments, R.sup.7 is optionally substituted naphthyl.

[0192] In some embodiments, R.sup.7 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.7 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.7 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.7 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.7 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.7 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R.sup.7 is optionally substituted pyridinyl, optionally substituted isoquinolinyl, optionally substituted quinolinyl, or optionally substituted pyrazolyl. In some embodiments, R.sup.7 is optionally substituted pyridinyl or optionally substituted pyrazolyl.

[0193] In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.D is 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. In some embodiments, two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0194] In some embodiments, R.sup.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-4 alkenyl, or optionally substituted C.sub.1-4 alkynyl. In some embodiments, R.sup.2 is optionally substituted alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.2 is unsubstituted C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.2 is unsubstituted methyl. In some embodiments, R.sup.2 is unsubstituted ethyl.

[0195] In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered carbocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form optionally substituted piperidinyl. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atom to form

##STR00034##

[0196] R.sup.8 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group. In some embodiments, R.sup.8 is hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, optionally substituted C.sub.1-10 heteroalkynyl, optionally substituted C.sub.3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C.sub.6-14 aryl, optionally substituted 5-14-membered heteroaryl, or a sulfur protecting group.

[0197] In some embodiments, R.sup.3 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.A, SR.sup.A, or N(R.sup.A).sub.2. In some embodiments, R.sup.3 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.3 is Cie haloalkyl. In some embodiments, R.sup.3 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.3 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.3 is CF.sub.3. In some embodiments, R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.3 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.3 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.3 is hydrogen or halogen. In some embodiments, R.sup.3 is hydrogen or fluorine. In some embodiments, R.sup.3 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.3 is hydrogen, unsubstituted C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.3 is hydrogen.

[0198] In some embodiments, R.sup.3 is halogen. In some embodiments, R.sup.3 is bromine, chlorine, or fluorine. In some embodiments, R.sup.3 is bromine or chlorine. In some embodiments, R.sup.3 is chlorine or fluorine. In some embodiments, R.sup.3 is bromine. In some embodiments, R.sup.3 is chlorine. In some embodiments, R.sup.3 is fluorine.

[0199] In some embodiments, R.sup.3 is OR.sup.A, SR.sup.A, or N(R.sup.A).sub.2 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is OH. In some embodiments, R.sup.3 is SH. In some embodiments, R.sup.3 is NH.sub.2. In some embodiments, R.sup.3 is CN, SCN, SSR.sup.A, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.3 is C(O)R.sup.A, C(O)OR.sup.A, C(O)SR.sup.A, or C(O)N(R.sup.A), (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is C(NR.sup.A)R.sup.A, C(NR.sup.A)OR.sup.A, C(NR.sup.A)SR.sup.A, or C(NR.sup.A)N(R.sup.A), (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is S(O)R.sup.A, S(O)OR.sup.A, S(O)SR.sup.A, S(O)N(R.sup.A).sub.2, S(O).sub.2R.sup.A, S(O).sub.2OR.sup.A, S(O).sub.2SR.sup.A, or S(O).sub.2N(R.sup.A).sub.2 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is OC(O)R.sup.A, OC(O)OR.sup.A, OC(O)SR.sup.A, OC(O)N(R.sup.A).sub.2, OC(NR.sup.A)R.sup.A, OC(NR.sup.A)OR.sup.A, OC(NR.sup.A)SR.sup.A, OC(NR.sup.A)N(R.sup.A).sub.2, OS(O)R.sup.A, OS(O)OR.sup.A, OS(O)SR.sup.A, OS(O)N(R.sup.A).sub.2, OS(O).sub.2R.sup.A, OS(O).sub.2OR.sup.A, OS(O).sub.2SR.sup.A, OS(O).sub.2N(R.sup.A).sub.2, or ON(R.sup.A).sub.2 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is SC(O)R.sup.A, SC(O)OR.sup.A, SC(O)SR.sup.A, SC(O)N(R.sup.A).sub.2, SC(NR.sup.A)R.sup.A, SC(NR.sup.A)OR.sup.A, SC(NR.sup.A)SR.sup.A, or SC(NR.sup.A)N(R.sup.A).sub.2 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is NR.sup.AC(O)R.sup.A, NR.sup.AC(O)OR.sup.A, NR.sup.AC(O)SR.sup.A, NR.sup.AC(O)N(R.sup.A).sub.2, NR.sup.AC(NR.sup.A)R.sup.A, NR.sup.AC(NR.sup.A)OR.sup.A, NR.sup.AC(NR.sup.A)SR.sup.A, NR.sup.AC(NR.sup.A)N(R.sup.A).sub.2, NR.sup.AS(O)R.sup.A, NR.sup.AS(O)OR.sup.A, NR.sup.AS(O)SR.sup.A, NR.sup.AS(O)N(R.sup.A).sub.2, NR.sup.AS(O).sub.2R.sup.A, NR.sup.AS(O).sub.2OR.sup.A, NR.sup.AS(O).sub.2SR.sup.A, or NR.sup.AS(O).sub.2N(R.sup.A).sub.2 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is Si(R.sup.A).sub.3, Si(R.sup.A).sub.2OR.sup.A, Si(R.sup.A)(OR.sup.A).sub.2, Si(OR.sup.A).sub.3, OSi(R.sup.A).sub.3, OSi(R.sup.A).sub.2OR.sup.A, OSi(R.sup.A)(OR.sup.A).sub.2, or OSi(OR.sup.A).sub.3 (e.g., wherein R.sup.A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0200] In some embodiments, R.sup.3 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.3 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.3 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.3 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.3 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.3 is saturated carbocyclyl. In some embodiments, R.sup.3 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0201] In some embodiments, R.sup.3 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.3 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.3 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.3 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.3 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.3 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.3 is saturated heterocyclyl. In some embodiments, R.sup.3 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0202] In some embodiments, R.sup.3 is optionally substituted monocyclic aryl. In some embodiments, R.sup.3 is optionally substituted bicyclic aryl. In some embodiments, R.sup.3 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.3 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.3 is optionally substituted phenyl. In some embodiments, R.sup.3 is optionally substituted naphthyl.

[0203] In some embodiments, R.sup.3 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.3 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.3 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.3 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.3 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0204] In some embodiments, at least one instance of R.sup.A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.A is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.A is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.A is 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. In some embodiments, two instances of R.sup.A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0205] In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.4a and R.sup.4b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen, fluorine, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen or halogen. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen or fluorine. In some embodiments, at least one of R.sup.4a and R.sup.4b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is hydrogen. In some embodiments, at least one of R.sup.4a and R.sup.4b is hydrogen. In some embodiments, at least one of R.sup.4a and R.sup.4b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is unsubstituted methyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is unsubstituted methyl. In some embodiments, at least one of R.sup.4a and R.sup.4b is fluorine.

[0206] In some embodiments, R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.4a and R.sup.4b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0207] In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted phenyl ring. In some embodiments, R.sup.4b and R.sup.5a are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring.

[0208] In some embodiments, at least one of R.sup.5a and R.sup.5b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one of R.sup.5a and R.sup.5b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.5a and R.sup.5b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is independently hydrogen, CH.sub.3, or CF.sub.3. In some embodiments, at least one of R.sup.5a and R.sup.5b is hydrogen. In some embodiments, at least one of R.sup.5a and R.sup.5b is independently optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is independently optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is independently optionally substituted C.sub.1-10 alkyl or optionally substituted C.sub.1-10 heteroalkyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is CH.sub.3. In some embodiments, at least one of R.sup.5a and R.sup.5b is CF.sub.3. In some embodiments, at least one of R.sup.5a and R.sup.5b is optionally substituted C.sub.1-4 heteroalkyl. In some embodiments, at least one of R.sup.5a and R.sup.5b is optionally substituted C.sub.1-4 heteroalkyl comprising an O atom. In some embodiments, at least one of R.sup.5a and R.sup.3b is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one of R.sup.5a and R.sup.5b is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one of R.sup.5a and R.sup.5b is optionally substituted phenyl. In some embodiments, R.sup.5a and R.sup.5b are CH.sub.3. In some embodiments, R.sup.5a and R.sup.5b are hydrogen.

[0209] In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.5a and R.sup.5b are taken together with their intervening atom to form optionally substituted tetrahydrofuran, optionally substituted tetrahydropyran, optionally substituted pyrrolidine.

[0210] In some embodiments, R.sup.6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.6 is hydrogen. In some embodiments, R.sup.6 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or C.sub.1-10 alkynyl. In some embodiments, R.sup.6 is optionally substituted alkyl. In some embodiments, R.sup.6 is optionally substituted C.sub.1-10 alkyl. In some embodiments, R.sup.6 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.6 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.6 is unsubstituted methyl. In some embodiments, R.sup.6 is benzyl.

[0211] In some embodiments, R.sup.6 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.6 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.6 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.6 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.6 is saturated carbocyclyl. In some embodiments, R.sup.6 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0212] In some embodiments, R.sup.6 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.6 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.6 is optionally substituted heterocyclyl comprising one or more O and/or S atoms, but no N atoms. In some embodiments, R.sup.6 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.6 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.6 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.6 is saturated heterocyclyl. In some embodiments, R.sup.6 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0213] In some embodiments, R.sup.6 is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R.sup.6 is optionally substituted monocyclic aryl. In some embodiments, R.sup.6 is optionally substituted bicyclic aryl. In some embodiments, R.sup.6 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.6 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.6 is optionally substituted phenyl. In some embodiments, R.sup.6 is optionally substituted naphthyl.

[0214] In some embodiments, R.sup.6 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.6 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.6 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.6 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.6 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.6 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R.sup.6 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted isothiazolyl. In some embodiments, R.sup.6 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.

[0215] In some embodiments, Formula I-A or I-B is any one of the formulae shown in Table 1:

TABLE-US-00001 TABLE 1 [00035]embedded image 947799 [00036]embedded image 947859 [00037]embedded image 948176 [00038]embedded image 948180 [00039]embedded image 948418 [00040]embedded image 949917 [00041]embedded image 950563 [00042]embedded image 950252 [00043]embedded image 950055 [00044]embedded image 946001 [00045]embedded image 948150 [00046]embedded image 948022 [00047]embedded image 947861 [00048]embedded image 947862 [00049]embedded image 949336 [00050]embedded image 950494 [00051]embedded image 951606 [00052]embedded image 947403 [00053]embedded image 947877 [00054]embedded image 948305 [00055]embedded image 948421 [00056]embedded image 950484 [00057]embedded image 950497 [00058]embedded image 951740 [00059]embedded image 947404 [00060]embedded image 947568 [00061]embedded image 947677 [00062]embedded image 947811 [00063]embedded image 947819 [00064]embedded image 948179 [00065]embedded image 948768 [00066]embedded image 949183 [00067]embedded image 950323 [00068]embedded image 951948 [00069]embedded image 947800 [00070]embedded image 947814 [00071]embedded image 948185 [00072]embedded image 948307 [00073]embedded image 948314 [00074]embedded image 948419 [00075]embedded image 949010 [00076]embedded image 949175 [00077]embedded image 951607 [00078]embedded image 949395 [00079]embedded image 949002 [00080]embedded image 945634 [00081]embedded image 949392 [00082]embedded image 949008 [00083]embedded image 948227 [00084]embedded image 948524 [00085]embedded image 947415 [00086]embedded image 948514 [00087]embedded image 945384 [00088]embedded image 949393 [00089]embedded image 949328 [00090]embedded image 949389 [00091]embedded image 949114 [00092]embedded image 948148 [00093]embedded image 948826 [00094]embedded image 948526 [00095]embedded image 947907 [00096]embedded image 913475 [00097]embedded image 948141 [00098]embedded image 949390 [00099]embedded image 949332 [00100]embedded image 948183 [00101]embedded image 929389 [00102]embedded image 949106 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[00545]embedded image 914308 [00546]embedded image 945460 [00547]embedded image 947817 [00548]embedded image 949185 [00549]embedded image 947858 [00550]embedded image 952025 [00551]embedded image 948297 [00552]embedded image 943960 [00553]embedded image 949174 [00554]embedded image 951612 [00555]embedded image 948774 [00556]embedded image 947801 [00557]embedded image 947395 [00558]embedded image 948775 [00559]embedded image 943964 [00560]embedded image 949648 [00561]embedded image 948313 [00562]embedded image 947408 [00563]embedded image 948304 [00564]embedded image 948371 [00565]embedded image 947574 [00566]embedded image 948018 [00567]embedded image 948512 [00568]embedded image 948142 [00569]embedded image 949005 [00570]embedded image 947806 [00571]embedded image 950320 [00572]embedded image 948515 [00573]embedded image 947575 [00574]embedded image 950318 [00575]embedded image 947863 [00576]embedded image 947876 [00577]embedded image 949181 [00578]embedded image 949747 [00579]embedded image 947860 [00580]embedded image 949013 [00581]embedded image 947821 [00582]embedded image 949919 [00583]embedded image 947866 [00584]embedded image 947405 [00585]embedded image 947567 [00586]embedded image 948771 [00587]embedded image 947835 [00588]embedded image 947836 [00589]embedded image 943959 [00590]embedded image 947837 [00591]embedded image 943963 [00592]embedded image 943960

[0216] In some embodiments, Formula I-A or I-B is any one of the formulae shown in Table 1A:

TABLE-US-00002 TABLE 1A [00593]embedded image 108005 [00594]embedded image 108791 [00595]embedded image 114531 [00596]embedded image 114532 or [00597]embedded image 114679

[0217] In some embodiments, Formula I-A or I-B is any one of the formulae shown in Table 2:

TABLE-US-00003 TABLE 2 [00598]embedded image 913452 [00599]embedded image 913495 [00600]embedded image 917157 [00601]embedded image 918251 [00602]embedded image 930333 [00603]embedded image 945368 [00604]embedded image 945376 [00605]embedded image 945380 [00606]embedded image 945381 [00607]embedded image 857362 [00608]embedded image 883867 [00609]embedded image 883981 [00610]embedded image 883982 [00611]embedded image 912006 [00612]embedded image 912099 [00613]embedded image 912205 [00614]embedded image 912668 [00615]embedded image 913004 [00616]embedded image 917283 [00617]embedded image 929475 [00618]embedded image 943967 [00619]embedded image 945364 [00620]embedded image 945385 [00621]embedded image 945611 [00622]embedded image 945633 [00623]embedded image 945727 [00624]embedded image 945923 [00625]embedded image 947433 [00626]embedded image 948016 [00627]embedded image 948153 [00628]embedded image 948308 [00629]embedded image 948362 [00630]embedded image 948369 [00631]embedded image 948414 [00632]embedded image 948493 [00633]embedded image 948518 [00634]embedded image 948519 [00635]embedded image 948638 [00636]embedded image 948641 [00637]embedded image 948643 [00638]embedded image 948647 [00639]embedded image 948648 [00640]embedded image 948649 [00641]embedded image 948650 [00642]embedded image 948651 [00643]embedded image 948654 [00644]embedded image 948656 [00645]embedded image 948657 [00646]embedded image 948658 [00647]embedded image 948659 [00648]embedded image 948663 [00649]embedded image 948814 [00650]embedded image 948816 [00651]embedded image 948817 [00652]embedded image 948818 [00653]embedded image 948829 [00654]embedded image 949009 [00655]embedded image 949107 [00656]embedded image 949116 [00657]embedded image 949129 [00658]embedded image 949263 [00659]embedded image 949264 [00660]embedded image 949335 [00661]embedded image 949396 [00662]embedded image 949509 [00663]embedded image 949510 [00664]embedded image 949511 [00665]embedded image 949513 [00666]embedded image 949515 [00667]embedded image 949519 [00668]embedded image 949600 [00669]embedded image 949641 [00670]embedded image 949643 [00671]embedded image 949646 [00672]embedded image 949752 [00673]embedded image 949756 [00674]embedded image 950817 [00675]embedded image 950825 [00676]embedded image 951592 [00677]embedded image 951954 [00678]embedded image 952262 [00679]embedded image 952479 [00680]embedded image 952636 [00681]embedded image 952638 [00682]embedded image 952760 or [00683]embedded image 957497

[0218] In some embodiments, Formula I-A or I-B is any one of the formulae shown in Table 2A:

TABLE-US-00004 TABLE 2A [00684]embedded image 108006 [00685]embedded image 108794 or [00686]embedded image 114744

[0219] In some embodiments, Formula I-A or I-B is not any one of the formulae shown in Table 2. In some embodiments, Formula I-A or I-B is not any one of the formulae shown in Table 2A.

[0220] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula II-A or II-B:

##STR00687##

wherein: [0221] each instance of custom-character is independently a single or double bond; [0222] R.sup.11 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0223] R.sup.12 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; [0224] or R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; [0225] R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.DS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; [0226] each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0227] each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and [0228] or R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0229] or R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0230] or R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms; and [0231] m1 is 0 or 1; [0232] when m1 is 1: [0233] 2 each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0234] or R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; [0235] or R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0236] or R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; [0237] or R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0238] or R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring; provided that the compound is not of the formula:

##STR00688##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of the atoms marked with * is independently optionally substituted.

[0239] In some embodiments, the compound is of the formula:

##STR00689##

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

[0240] In some embodiments, the compound is of the formula:

##STR00690##

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

[0241] In some embodiments, the compound is of the formula:

##STR00691##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein yy is 2, 3, or 4. In some embodiments, yy is 2 or 3. In some embodiments, yy is 3 or 4. In some embodiments, yy is or 4. In some embodiments, yy is 2. In some embodiments, yy is 3. In some embodiments, yy is 4.

[0242] In some embodiments, the compound is of the formula:

##STR00692##

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

[0243] In some embodiments, the compound is of the formula:

##STR00693##

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

[0244] In some embodiments, at least one instance of custom-character is a single bond. In some embodiments, one instance of custom-character is a single bond. In some embodiments, two instances of custom-character are single bonds. In some embodiments, each instance of custom-character is a single bond. In some embodiments, at least one instance of custom-character is a double bond. In some embodiments, one instance of custom-character is a double bond. In some embodiments, two instances of custom-character are double bonds.

[0245] In some embodiments, m1 is 0. In some embodiments, m1 is 1.

[0246] In some embodiments,

##STR00694##

respectively. In some embodiments,

##STR00695##

respectively.

[0247] In some embodiments, R.sup.11 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.11 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl.

[0248] In some embodiments, R.sup.11 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.11 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.11 is saturated carbocyclyl. In some embodiments, R.sup.11 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0249] In some embodiments, R.sup.11 is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R.sup.11 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.11 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.11 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.11 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.11 is saturated heterocyclyl. In some embodiments, R.sup.11 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0250] In some embodiments, R.sup.11 is optionally substituted aryl. In some embodiments, R.sup.11 is optionally substituted monocyclic aryl. In some embodiments, R.sup.11 is optionally substituted bicyclic aryl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.1 is optionally substituted phenyl. In some embodiments, R.sup.11 is optionally substituted naphthyl.

[0251] In some embodiments, R.sup.11 is optionally substituted heteroaryl. In some embodiments, R.sup.11 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.1l is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.11 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.11 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.11 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.11 is optionally substituted 9- to 10-membered bicyclic heteroaryl.

[0252] In some embodiments, R.sup.11 is optionally substituted aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.1 is optionally substituted phenyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted naphthyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0253] In some embodiments, R.sup.11 is optionally substituted aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted phenyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted naphthyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0254] In some embodiments, R.sup.11 is optionally substituted heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.11 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0255] In some embodiments, R.sup.11 is optionally substituted heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.11 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0256] In some embodiments, R.sup.11 is

##STR00696##

[0257] Each instance of R.sup.18 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O) ZN(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3.

[0258] m2 is 0, 1, 2, 3, 4, or 5. In some embodiments, m2 is 0, 1, 2, 3, or 4. In some embodiments, m2 is 0, 1, 2, or 3. In some embodiments, m2 is 0, 1, or 2. In some embodiments, m2 is 0 or 1. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3. In some embodiments, m2 is 4. In some embodiments, m2 is 5.

[0259] In some embodiments, R.sup.11 is

##STR00697##

In some embodiments, R.sup.11 is

##STR00698##

In some embodiments, R.sup.11 is

##STR00699##

In some embodiments, R.sup.11 is

##STR00700##

In some embodiments, R.sup.11 is

##STR00701##

In some embodiments, R.sup.1 is

##STR00702##

In some embodiments, R.sup.11 is

##STR00703##

In some embodiments, R.sup.11 is

##STR00704##

In some embodiments, R.sup.11 is

##STR00705##

In some embodiments, R.sup.11 is

##STR00706##

[0260] In some embodiments, at least one instance of R.sup.18 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, at least one instance of R.sup.18 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one instance of R.sup.18 is C.sub.1-10 haloalkyl. In some embodiments, at least one instance of R.sup.18 is C.sub.1-4 haloalkyl. In some embodiments, at least one instance of R.sup.18 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, at least one instance of R.sup.18 is CF.sub.3.

[0261] In some embodiments, at least one instance of R.sup.18 is halogen. In some embodiments, at least one instance of R.sup.18 is bromine, chlorine, or fluorine. In some embodiments, at least one instance of R.sup.18 is bromine or chlorine. In some embodiments, at least one instance of R.sup.18 is chlorine or fluorine. In some embodiments, at least one instance of R.sup.12 is bromine. In some embodiments, at least one instance of R.sup.13 is chlorine. In some embodiments, at least one instance of R.sup.18 is fluorine.

[0262] In some embodiments, at least one instance of R.sup.18 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is OH. In some embodiments, at least one instance of R.sup.18 is SH. In some embodiments, at least one instance of R.sup.18 is NH.sub.2. In some embodiments, at least one instance of R.sup.18 is NHR.sup.D. In some embodiments, at least one instance of R.sup.18 is NMeR.sup.D. In some embodiments, at least one instance of R.sup.18 is N(heteroaryl) R.sup.D. In some embodiments, at least one instance of R.sup.18 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, at least one instance of R.sup.18 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.18 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0263] In some embodiments, at least one instance of R.sup.18 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, at least one instance of R.sup.18 is saturated carbocyclyl. In some embodiments, at least one instance of R.sup.18 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0264] In some embodiments, at least one instance of R.sup.18 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.18 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, at least one instance of R.sup.18 is saturated heterocyclyl. In some embodiments, at least one instance of R.sup.18 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0265] In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic aryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted bicyclic aryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted phenyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted naphthyl.

[0266] In some embodiments, at least one instance of R.sup.18 is optionally substituted monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted bicyclic heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.18 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, at least one instance of R.sup.18 is optionally substituted pyridinyl, optionally substituted triazolyl, or optionally substituted pyrazolyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted pyridinyl. In some embodiments, at least one instance of R.sup.18 is optionally substituted pyrazolyl.

[0267] In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.D is 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. In some embodiments, two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0268] In some embodiments, R.sup.12 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R.sup.12 is optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-4 alkenyl, or optionally substituted C.sub.1-4 alkynyl. In some embodiments, R.sup.12 is optionally substituted alkyl. In some embodiments, R.sup.12 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.12 is unsubstituted C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.12 is unsubstituted methyl. In some embodiments, R.sup.12 is unsubstituted ethyl.

[0269] In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered carbocyclic ring. In some embodiments, R.sup.1 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.11 and R.sup.12 are taken together with their intervening atom to form optionally substituted tetrahydropyranyl.

[0270] In some embodiments, R.sup.13 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.B, SR.sup.B, or N(R.sup.B).sub.2. In some embodiments, R.sup.13 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.10 heteroalkynyl. In some embodiments, R.sup.13 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.13 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.13 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.13 is CF.sub.3. In some embodiments, R.sup.13 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.13 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.13 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.13 is hydrogen or halogen. In some embodiments, R.sup.13 is hydrogen or fluorine. In some embodiments, R.sup.13 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.13 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.13 is hydrogen.

[0271] In some embodiments, R.sup.13 is halogen. In some embodiments, R.sup.13 is bromine, chlorine, or fluorine. In some embodiments, R.sup.13 is bromine or chlorine. In some embodiments, R.sup.13 is chlorine or fluorine. In some embodiments, R.sup.13 is bromine. In some embodiments, R.sup.13 is chlorine. In some embodiments, R.sup.13 is fluorine.

[0272] In some embodiments, R.sup.13 is OR.sup.B, SR.sup.B, or N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is OH. In some embodiments, R.sup.13 is SH. In some embodiments, R.sup.13 is NH.sub.2. In some embodiments, R.sup.13 is CN, SCN, SSR.sup.B, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.13 is C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, or C(O)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, or C(NR.sup.B)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, or S(O).sub.2N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, or ON(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, or SC(NR.sup.B)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, or NR.sup.BS(O).sub.2N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0273] In some embodiments, R.sup.13 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.13 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.13 is saturated carbocyclyl. In some embodiments, R.sup.13 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0274] In some embodiments, R.sup.13 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.13 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.13 is optionally substituted 3-14 to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.33 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.13 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.13 is saturated heterocyclyl. In some embodiments, R.sup.13 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0275] In some embodiments, R.sup.13 is optionally substituted monocyclic aryl. In some embodiments, R.sup.13 is optionally substituted bicyclic aryl. In some embodiments, R.sup.13 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.13 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.13 is optionally substituted phenyl. In some embodiments, R.sup.13 is optionally substituted naphthyl.

[0276] In some embodiments, R.sup.13 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.13 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0277] In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.B is 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. In some embodiments, two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0278] In some embodiments, each of R.sup.14a. R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is hydrogen. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a and R.sup.17b is hydrogen. In some embodiments, at least one of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is unsubstituted methyl.

[0279] In some embodiments, R.sup.14a and R.sup.14b are independently hydrogen or optionally substituted C.sub.1-6 alkyl. In some embodiments, at least one of R.sup.14a and R.sup.14b is hydrogen. In some embodiments, R.sup.14a and R.sup.14b are hydrogen. In some embodiments, at least one of R.sup.14a and R.sup.14b is independently optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.14a and R.sup.14b are independently optionally substituted C.sub.1-6 alkyl.

[0280] In some embodiments, R.sup.17a and R.sup.17b are independently hydrogen or optionally substituted C.sub.1-6 alkyl. In some embodiments, at least one of R.sup.17a and R.sup.17b is hydrogen. In some embodiments, R.sup.17a and R.sup.17b are hydrogen. In some embodiments, at least one of R.sup.17a and R.sup.17b is independently optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.17a and R.sup.17b are independently optionally substituted C.sub.1-6 alkyl. In some embodiments, at least one of R.sup.17a and R.sup.17b is unsubstituted methyl. In some embodiments, R.sup.17a and R.sup.17b are unsubstituted methyl.

[0281] In some embodiments, R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.14a and R.sup.14 are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.14a and R.sup.14b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0282] In some embodiments, R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.17a and R.sup.17b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0283] In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene or optionally substituted alkenylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, comprising 1 or 2 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, comprising 1 backbone atom. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkylene, comprising 2 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted alkenylene, comprising 3 or 4 backbone atoms.

[0284] In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkylene or optionally substituted heteroalkenylene, each of which independently comprises 1, 2, 3, or 4 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkylene, comprising 1 or 2 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkylene, comprising 1 backbone atom. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkylene, comprising 2 backbone atoms. In some embodiments, R.sup.14b and R.sup.17a are taken together to form optionally substituted heteroalkenylene, comprising 3 or 4 backbone atoms.

[0285] In some embodiments, each of R.sup.15a, R.sup.15a, R.sup.16a and R.sup.16b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently hydrogen, CH.sub.3, or CF.sub.3. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is hydrogen. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is independently optionally substituted C.sub.1-10 alkyl or optionally substituted C.sub.1-10 heteroalkyl. In some embodiments, at least one of R.sup.15a. R.sup.15b, R.sup.16a and R.sup.16b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is CH.sub.3. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is CF.sub.3. In some embodiments, at least one of R.sup.15a. R.sup.15b, R.sup.16a and R.sup.16b is optionally substituted C.sub.1-4 heteroalkyl. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is optionally substituted C.sub.1-4 heteroalkyl comprising an O atom. In some embodiments, at least one of R.sup.15a. R.sup.15b, R.sup.16a and R.sup.16b is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one of R.sup.15a, R.sup.15b, Rica and R.sup.16b is optionally substituted phenyl. In some embodiments, each of R.sup.15a, R.sup.15b, R.sup.16a and R.sup.16b is hydrogen.

[0286] In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted phenyl ring. In some embodiments, R.sup.14b and R.sup.15a are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring.

[0287] In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.15a and R.sup.15b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring.

[0288] In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted phenyl ring. In some embodiments, R.sup.15b and R.sup.16a are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring.

[0289] In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.16a and R.sup.16b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring.

[0290] In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, aryl, or heteroaryl ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted phenyl ring. In some embodiments, R.sup.16b and R.sup.17a are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring.

[0291] In some embodiments, Formula II-A or II-B is any one of the formulae shown in Table 3:

TABLE-US-00005 TABLE 3 [00707]embedded image 952562 [00708]embedded image 952757 [00709]embedded image 943921 [00710]embedded image 951566 [00711]embedded image 952205 [00712]embedded image 861716 [00713]embedded image 950283 [00714]embedded image 943920 [00715]embedded image 912081 [00716]embedded image 791270 [00717]embedded image 949805 [00718]embedded image 950815 [00719]embedded image 950819 [00720]embedded image 950818 [00721]embedded image 901464 [00722]embedded image 791269 [00723]embedded image 949742 [00724]embedded image 949840 [00725]embedded image 912080 [00726]embedded image 949639 [00727]embedded image 951565 [00728]embedded image 950272 [00729]embedded image 950282 [00730]embedded image 952557 [00731]embedded image 943917 [00732]embedded image 952752 [00733]embedded image 943916 [00734]embedded image 952212 [00735]embedded image 951702 [00736]embedded image 952759 [00737]embedded image 952564 [00738]embedded image 948205 [00739]embedded image 949743

[0292] In some embodiments, Formula II-A or II-B is any one of the formulae shown in Table 4:

TABLE-US-00006 TABLE 4 [00740]embedded image 791266 [00741]embedded image 791268 [00742]embedded image 950273 [00743]embedded image 950826 [00744]embedded image 950827 [00745]embedded image 951710

[0293] In some embodiments, Formula II-A or II-B is not any one of the formulae shown in Table 4.

[0294] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula III-A or III-B:

##STR00746##

wherein: [0295] R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring or an optionally substituted, monocyclic heterocyclic ring; [0296] optionally two substituents on the monocyclic carbocyclic ring or monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0297] R.sup.23 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.C, SCN, SR.sup.C, SSR.sup.C, N.sub.3, NO, N(R.sup.C).sub.2, NO.sub.2, C(O)R.sup.C, C(O)OR.sup.C, C(O)SR.sup.C, C(O)N(R.sup.C).sub.2, C(NR.sup.C)R.sup.C, C(NR.sup.C)OR.sup.C, C(NR.sup.C)SR.sup.C, C(NR.sup.C)N(R.sup.C).sub.2, S(O)R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, S(O)N(R.sup.C).sub.2, S(O).sub.2R.sup.C, S(O)OR.sup.C, S(O).sub.2SR.sup.C, S(O).sub.2N(R.sup.C).sub.2, OC(O)R.sup.C, OC(O)OR.sup.C, OC(O)SR.sup.C, OC(O)N(R.sup.C).sub.2, OC(NR.sup.C)R.sup.C, OC(NR.sup.C)OR.sup.C, OC(NR.sup.C)SR.sup.C, OC(NR.sup.C)N(R.sup.C).sub.2, OS(O)R.sup.C, OS(O)OR.sup.C, OS(O)SR.sup.C, OS(O)N(R.sup.C).sub.2, OS(O).sub.2R.sup.C, OS(O).sub.2OR.sup.C, OS(O).sub.2SR.sup.C, OS(O).sub.2N(R.sup.C).sub.2, ON(R.sup.C).sub.2, SC(O)R.sup.C, SC(O)OR.sup.C, SC(O)SR.sup.C, SC(O)N(R.sup.C).sub.2, SC(NR.sup.C)R.sup.C, SC(NR.sup.C)OR.sup.C, SC(NR.sup.C)SR.sup.C, SC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CC(O)R.sup.C, NR.sup.CC(O)OR.sup.C, NR.sup.CC(O)SR.sup.C, NR.sup.CC(O)N(R.sup.C).sub.2, NR.sup.CC(NR.sup.C)R.sup.C, NR.sup.CC(NRS)OR.sup.C, NR.sup.CC(NR.sup.C)SR.sup.C, NR.sup.CC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CS(O)R.sup.C, NR.sup.CS(O)OR.sup.C, NR.sup.CS(O)SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, NR.sup.CS(O).sub.2R.sup.C, NR.sup.CS(O).sub.2OR.sup.C, NR.sup.CS(O).sub.2SR.sup.C, NR.sup.CS(O).sub.2N(R.sup.C).sub.2, Si(R.sup.C).sub.3, Si(R.sup.C).sub.2OR.sup.C, Si(R.sup.C)(OR.sup.C).sub.2, Si(OR.sup.C).sub.3, OSi(R.sup.C).sub.3, OSi(R.sup.C).sub.2OR.sup.C, OSi(R.sup.C)(OR.sup.C).sub.2, or OSi(OR.sup.C).sub.3; [0298] each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and [0299] each instance of R.sup.C is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.C attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; [0300] or R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0301] or R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0302] or R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0303] or R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0304] or R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0305] provided that the compound is not of the formula:

##STR00747##

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

[0306] In some embodiments, the compound is of the formula:

##STR00748##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0307] R.sup.28 is optionally substituted aryl or optionally substituted heteroaryl.

[0308] In some embodiments, the compound is of the formula:

##STR00749##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0309] R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted, monocyclic 5- to 7-membered N-heterocyclic ring.

[0310] In some embodiments, the compound is of the formula:

##STR00750##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0311] R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic 4- to 6-membered carbocyclic ring. In some embodiments,

##STR00751##

respectively. In some embodiments,

##STR00752##

respectively.

[0312] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein optionally two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic C.sub.4-7 carbocyclic ring.

[0313] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.C, SCN, SR.sup.C, SSR.sup.C, N.sub.3, NO, N(R.sup.C).sub.2, NO.sub.2, C(O)R.sup.C, C(O)OR.sup.C, C(O)SR.sup.C, C(O)N(R.sup.C).sub.2, C(NR.sup.C)R.sup.C, C(NR.sup.C)OR.sup.C, C(NR.sup.C)SR.sup.C, C(NR.sup.C)N(R.sup.C).sub.2, S(O)R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, S(O)N(R.sup.C).sub.2, S(O).sub.2R.sup.C, S(O).sub.2OR.sup.C, S(O).sub.2SR.sup.C, S(O).sub.2N(R.sup.C).sub.2, OC(O)R.sup.C, OC(O)OR.sup.C, OC(O)SR.sup.C, OC(O)N(R.sup.C).sub.2, OC(NR.sup.C)R.sup.C, OC(NR.sup.C)OR.sup.C, OC(NR.sup.C)SR.sup.C, OC(NR.sup.C)N(R.sup.C).sub.2, OS(O)R.sup.C, OS(O)OR.sup.C, OS(O)SR.sup.C, OS(O)N(R.sup.C).sub.2, OS(O).sub.2R.sup.C, OS(O).sub.2OR.sup.C, OS(O)SR.sup.C, OS(O).sub.2N(R.sup.C).sub.2, ON(R.sup.C).sub.2, SC(O)R.sup.C, SC(O)OR.sup.C, SC(O)SR.sup.C, SC(O)N(R.sup.C).sub.2, SC(NR.sup.C)R.sup.C, SC(NR.sup.C)OR.sup.C, SC(NR.sup.C)SR.sup.C, SC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CC(O)R.sup.C, NR.sup.CC(O)OR.sup.C, NR.sup.CC(O)SR.sup.C, NR.sup.CC(O)N(R.sup.C).sub.2, NR.sup.CC(NR.sup.C)R.sup.C, NR.sup.CC(NR.sup.C)OR.sup.C, NR.sup.CC(NR.sup.C)SR.sup.C, NR.sup.CC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CS(O)R.sup.C, NR.sup.CS(O)OR.sup.C, NR.sup.CS(O)SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, NR.sup.CS(O).sub.2R.sup.C, NR.sup.CS(O).sub.2OR.sup.C, NR.sup.CS(O).sub.2SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, Si(R.sup.C).sub.3, Si(R.sup.C).sub.2OR.sup.C, Si(R.sup.C)(OR.sup.C).sub.2, Si(OR.sup.C).sub.3, OSi(R.sup.C).sub.3, OSi(R.sup.C).sub.2OR.sup.C, OSi(R.sup.C)(OR.sup.C).sub.2, or OSi(OR.sup.C).sub.3.

[0314] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.C, SR.sup.C, or N(R.sup.C).sub.2. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of C.sub.1-10 haloalkyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of C.sub.1-4 haloalkyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of CF.sub.3. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted C.sub.1-C.sub.6 alkyl or halogen. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of fluorine, CH.sub.3, or CF.sub.3.

[0315] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of halogen. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of bromine, chlorine, or fluorine. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of bromine or chlorine. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of chlorine or fluorine. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of bromine. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of chlorine. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of fluorine.

[0316] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of OR.sup.C, SR.sup.C, or N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of OH. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of SH. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of NH.sub.2. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of CN, SCN, SSR.sup.C, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of C(O)R.sup.C, C(O)OR.sup.C, C(O)SR.sup.C, or C(O)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of C(NR.sup.C)OR.sup.C, C(NR.sup.C)OR.sup.C, C(NR.sup.C)SR.sup.C, or C(NR.sup.C)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of S(O)R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, S(O)N(R.sup.C).sub.2, S(O).sub.2R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, or S(O).sub.2N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of OC(O)R.sup.C, OC(O)OR.sup.C, OC(O)SR.sup.C, OC(O)N(R.sup.C).sub.2, OC(NR.sup.C)R.sup.C, OC(NR.sup.C)OR.sup.C, OC(NR.sup.C)SR.sup.C, OC(NR.sup.C)N(R.sup.C).sub.2, OS(O)R.sup.C, OS(O)OR.sup.C, OS(O)SR.sup.C, OS(O)N(R.sup.C).sub.2, OS(O).sub.2R.sup.C, OS(O).sub.2OR.sup.C, OS(O).sub.2SR.sup.C, OS(O).sub.2N(R.sup.C).sub.2, or ON(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of SC(O)R.sup.C, SC(O)OR.sup.C, SC(O)SR.sup.C, SC(O)N(R.sup.9).sub.2, SC(NR.sup.C)R.sup.C, SC(NR.sup.C)OR.sup.C, SC(NR.sup.C)SR.sup.C, or SC(NR.sup.C)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of NR.sup.CC(O)R.sup.C, NR.sup.CC(O)OR.sup.C, NR.sup.CC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CS(O)R.sup.C, NR.sup.CS(O)OR.sup.C, NR.sup.CS(O)SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, NR.sup.CS(O).sub.2R.sup.C, NR.sup.CS(O).sub.2OR.sup.C, NR.sup.CS(O).sub.2SR.sup.C, or NR.sup.CS(O).sub.2N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of Si(R.sup.C), Si(R.sup.C).sub.2OR.sup.C, Si(R.sup.C)(OR.sup.C).sub.2, Si(OR.sup.C).sub.3, OSi(R.sup.C).sub.3, OSi(R.sup.C).sub.2OR.sup.C, OSi(R.sup.C)(OR.sup.C).sub.2, or OSi(OR.sup.C).sub.3 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0317] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of saturated carbocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0318] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 3- to 14-membered heterocyclyl comprising at least one O and/or S atoms but no N atoms. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 3- to 14-membered heterocyclyl comprising at least one N atoms and optionally at least one O and/S atoms. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising at least one O and/or S atoms but no N atoms. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising at least one N atoms and optionally at least one O and/or S atoms. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of saturated heterocyclyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0319] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic aryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted bicyclic aryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted phenyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted naphthyl.

[0320] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocylic ring substituted with at least one instance of optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0321] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a monocyclic carbocyclic ring substituted with at least one instances of halogen, OMe, OBn, CN, optionally substituted C.sub.1-4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, C(O) NHMe, C(O) NMe.sub.2, C(O)OMe, O, or S(O).sub.2Me.

[0322] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, C.sub.3-4 carbocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, C.sub.5-7 carbocyclic ring.

[0323] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, 3- to 4-membered heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form a substituted monocyclic carbocyclic ring, wherein two substituents on the monocyclic carbocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring.

[0324] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted monocyclic heterocyclic ring, wherein optionally two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted monocyclic heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted, 4- to 7-membered monocyclic heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted, 5- to 6-membered monocyclic heterocyclic ring. In some embodiments, the monocyclic heterocyclic ring comprises O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form optionally substituted tetrahydropyranyl. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted piperidine ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form

##STR00753##

[0325] R.sup.28 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group. In some embodiments, R.sup.28 is hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, optionally substituted C.sub.1-10 heteroalkynyl, optionally substituted C.sub.3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C.sub.6-14 aryl, optionally substituted 5-14-membered heteroaryl, or a sulfur protecting group.

[0326] In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted monocyclic heterocyclic ring, wherein two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted monocyclic heterocyclic ring, wherein two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form an optionally substituted monocyclic heterocyclic ring, wherein two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional optionally substituted, monocyclic, heterocyclic ring. In some embodiments, two substituents on the monocyclic heterocyclic ring are taken together with their intervening atom(s) to form an additional 4- to 7-membered optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.21 and R.sup.22 are taken together with their intervening atom to form

##STR00754##

[0327] R.sup.29 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In some embodiments, R.sup.29 is hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, optionally substituted C.sub.1-10 heteroalkynyl, optionally substituted C.sub.3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C.sub.6-14 aryl, optionally substituted 5-14-membered heteroaryl, or a nitrogen protecting group.

[0328] In some embodiments, R.sup.23 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.C, SR.sup.C, or N(R.sup.C).sub.2. In some embodiments, R.sup.23 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.23 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.23 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.23 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.23 is CF.sub.3. In some embodiments, R.sup.23 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.23 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.23 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.23 is hydrogen or halogen. In some embodiments, R.sup.23 is hydrogen or fluorine. In some embodiments, R.sup.23 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.23 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.23 is hydrogen.

[0329] In some embodiments, R.sup.23 is halogen. In some embodiments, R.sup.23 is bromine, chlorine, or fluorine. In some embodiments, R.sup.23 is bromine or chlorine. In some embodiments, R.sup.23 is chlorine or fluorine. In some embodiments, R.sup.23 is bromine. In some embodiments, R.sup.23 is chlorine. In some embodiments, R.sup.23 is fluorine.

[0330] In some embodiments, R.sup.23 is OR.sup.C, SR.sup.C, or N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is OH. In some embodiments, R.sup.23 is SH. In some embodiments, R.sup.23 is NH.sub.2. In some embodiments, R.sup.23 is CN, SCN, SSR.sup.C, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.23 is C(O)R.sup.C, C(O)OR.sup.C, C(O)SR.sup.C, or C(O)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is C(NR.sup.C)R.sup.C, C(NR.sup.C)OR.sup.C, C(NR.sup.C)SR.sup.C, or C(NR.sup.C)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is S(O)R.sup.C, S(O)OR.sup.C, S(O)SR.sup.C, S(O)N(R.sup.C).sub.2, S(O)R.sup.C, S(O).sub.2OR.sup.C, S(O).sub.2SR.sup.C, or S(O).sub.2N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is OC(O)R.sup.C, OC(O)OR.sup.C, OC(O)SR.sup.C, OC(O)N(R.sup.C).sub.2, OC(NR.sup.C)R.sup.C, OC(NR.sup.C)OR.sup.C, OC(NR.sup.C)SR.sup.C, OC(NR.sup.C)N(R.sup.C).sub.2, OS(O)R.sup.C, OS(O)OR.sup.C, OS(O)SR.sup.C, OS(O)N(R.sup.C).sub.2, OS(O).sub.2R.sup.C, OS(O).sub.2OR.sup.C, OS(O).sub.2SR.sup.C, OS(O).sub.2N(R.sup.C).sub.2, or ON(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is SC(O)R.sup.C, SC(O)OR.sup.C, SC(O)SR.sup.C, SC(O)N(R.sup.C).sub.2, SC(NR.sup.C)R.sup.C, SC(NR.sup.C)OR.sup.C, SC(NR.sup.C)SR.sup.C, or SC(NR.sup.C)N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is NR.sup.CC(O)R.sup.C, NR.sup.CC(O)OR.sup.C, NR.sup.CC(O)SR.sup.C, NR.sup.CC(O)N(R.sup.C).sub.2, NR.sup.CC(NR.sup.C)R.sup.C, NR.sup.CC(NR.sup.C)OR.sup.C, NR.sup.CC(NR.sup.C)SR.sup.C, NR.sup.CC(NR.sup.C)N(R.sup.C).sub.2, NR.sup.CS(O)R.sup.C, NR.sup.CS(O)OR.sup.C, NR.sup.CS(O)SR.sup.C, NR.sup.CS(O)N(R.sup.C).sub.2, NR.sup.CS(O).sub.2R.sup.C, NR.sup.CS(O).sub.2OR.sup.C, NR.sup.CS(O).sub.2SR.sup.C, or NR.sup.CS(O).sub.2N(R.sup.C).sub.2 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.23 is Si(R.sup.C).sub.3, Si(R.sup.C).sub.2OR.sup.C, Si(R.sup.C)(OR.sup.C).sub.2, Si(OR.sup.C).sub.3, OSi(R.sup.C).sub.3, OSi(R.sup.C).sub.2OR.sup.C, OSi(R.sup.C)(OR.sup.C).sub.2, or OSi(OR.sup.C).sub.3 (e.g., wherein R.sup.C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0331] In some embodiments, R.sup.23 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.23 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.23 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.23 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.23 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.23 is saturated carbocyclyl. In some embodiments, R.sup.23 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0332] In some embodiments, R.sup.23 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.23 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.23 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.23 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.23 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.23 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.23 is saturated heterocyclyl. In some embodiments, R.sup.23 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0333] In some embodiments, R.sup.23 is optionally substituted monocyclic aryl. In some embodiments, R.sup.23 is optionally substituted bicyclic aryl. In some embodiments, R.sup.23 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.23 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.23 is optionally substituted phenyl. In some embodiments, R.sup.23 is optionally substituted naphthyl.

[0334] In some embodiments, R.sup.23 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.23 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.23 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.23 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.23 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0335] In some embodiments, at least one instance of R.sup.C is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.C is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.C is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.C is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.C is 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. In some embodiments, two instances of R.sup.C attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0336] In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen, fluorine, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen or halogen. In some embodiments, each of R.sup.24a and R.sup.24b is independently hydrogen or fluorine. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is hydrogen. In some embodiments, each of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, and R.sup.26b is hydrogen. In some embodiments, at least one of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is unsubstituted methyl. In some embodiments, at least one of R.sup.24a, R.sup.24b, R.sup.25a, R.sup.25b, R.sup.26a, and R.sup.26b is fluorine.

[0337] In some embodiments, each of R.sup.24a and R.sup.24b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.24a and R.sup.24b is fluorine.

[0338] In some embodiments, each of R.sup.25a and R.sup.25b is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl. In some embodiments, R.sup.25a and R.sup.25b are CH.sub.3.

[0339] In some embodiments, each of R.sup.26a and R.sup.26b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.26a and R.sup.26b is fluorine.

[0340] In some embodiments, R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.24a and R.sup.24b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0341] In some embodiments, R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.24b and R.sup.25a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0342] In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.25a and R.sup.25b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0343] In some embodiments, R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.25b and R.sup.26a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0344] In some embodiments, R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.26a and R.sup.26b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0345] In some embodiments, Formula III-A or III-B is any one of the formulae shown in Table 5:

TABLE-US-00007 TABLE 5 [00755]embedded image 884111 [00756]embedded image 901477 [00757]embedded image 893309 [00758]embedded image 884112 [00759]embedded image 901478 [00760]embedded image 889572 [00761]embedded image 912078 [00762]embedded image 912079 [00763]embedded image 893316 [00764]embedded image 913128 [00765]embedded image 913127 [00766]embedded image 913129 [00767]embedded image 909206 [00768]embedded image 926861 [00769]embedded image 948437 [00770]embedded image 948439 [00771]embedded image 947306 [00772]embedded image 948037 [00773]embedded image 889573 [00774]embedded image 912075 [00775]embedded image 912094 [00776]embedded image 912113 [00777]embedded image 909209 [00778]embedded image 912170 [00779]embedded image 946078 [00780]embedded image 932653 [00781]embedded image 942301 [00782]embedded image 949323 [00783]embedded image 884013 [00784]embedded image 889577 [00785]embedded image 884023 [00786]embedded image 889583 [00787]embedded image 893314 [00788]embedded image 946080 [00789]embedded image 912217 [00790]embedded image 874319 [00791]embedded image 929446 [00792]embedded image 947813 [00793]embedded image 874320 [00794]embedded image 924309 [00795]embedded image 917145 [00796]embedded image 884014 [00797]embedded image 924298 [00798]embedded image 884016 [00799]embedded image 897755 [00800]embedded image 945477 [00801]embedded image 884024 [00802]embedded image 889575 [00803]embedded image 912106 [00804]embedded image 826763 [00805]embedded image 907328 [00806]embedded image 889584 [00807]embedded image 907329 [00808]embedded image 945395 [00809]embedded image 913184 [00810]embedded image 874536 [00811]embedded image 899559 [00812]embedded image 924311 [00813]embedded image 877314 [00814]embedded image 826649 [00815]embedded image 884113 [00816]embedded image 883846 [00817]embedded image 826765 [00818]embedded image 947301 [00819]embedded image 913214 [00820]embedded image 889568 [00821]embedded image 949640 [00822]embedded image 883833 [00823]embedded image 897756 [00824]embedded image 913185 [00825]embedded image 945394 [00826]embedded image 947732 [00827]embedded image 874537 [00828]embedded image 943895 [00829]embedded image 899560 [00830]embedded image 943958 [00831]embedded image 912076 [00832]embedded image 943956 [00833]embedded image 948222 [00834]embedded image 874529 [00835]embedded image 883794 [00836]embedded image 889574 [00837]embedded image 913185 [00838]embedded image 883834 [00839]embedded image 913002 [00840]embedded image 893319 [00841]embedded image 913215 [00842]embedded image 901475 [00843]embedded image 913213 [00844]embedded image 948217 [00845]embedded image 883836 [00846]embedded image 947257 [00847]embedded image 911083 [00848]embedded image 901476 [00849]embedded image 917160 [00850]embedded image 907326 [00851]embedded image 952434 [00852]embedded image 907327 [00853]embedded image 945483 [00854]embedded image 912073 [00855]embedded image 884120 [00856]embedded image 912173 [00857]embedded image 945396 [00858]embedded image 949322 [00859]embedded image 917129 [00860]embedded image 993935 [00861]embedded image 948320 [00862]embedded image 884114 [00863]embedded image 945658 [00864]embedded image 889569 [00865]embedded image 948039 [00866]embedded image 913442 [00867]embedded image 913263 [00868]embedded image 912112 [00869]embedded image 901458 [00870]embedded image 949320 [00871]embedded image 826713 [00872]embedded image 884022 [00873]embedded image 947251 [00874]embedded image 947262 [00875]embedded image 913216 [00876]embedded image 945478 [00877]embedded image 909210 [00878]embedded image 896013 [00879]embedded image 918315 [00880]embedded image 913056 [00881]embedded image 945679 [00882]embedded image 924306 [00883]embedded image 926823 [00884]embedded image 949318 [00885]embedded image 924299 [00886]embedded image 950477 [00887]embedded image 889576 [00888]embedded image 877313 [00889]embedded image 826648 [00890]embedded image 913138 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[01197]embedded image 947484 [01198]embedded image 951861 [01199]embedded image 893310 [01200]embedded image 901470 [01201]embedded image 947464 [01202]embedded image 947614 [01203]embedded image 951701 [01204]embedded image 951787 [01205]embedded image 901465 [01206]embedded image 917144 [01207]embedded image 947485 [01208]embedded image 913259 [01209]embedded image 913262 [01210]embedded image 945712 [01211]embedded image 913058 [01212]embedded image 945668 [01213]embedded image 948440 [01214]embedded image 951863 [01215]embedded image 947461 [01216]embedded image 943487 [01217]embedded image 947476 [01218]embedded image 951723 [01219]embedded image 909207 [01220]embedded image 947255 [01221]embedded image 947264 [01222]embedded image 951714 [01223]embedded image 947838 [01224]embedded image 947260 [01225]embedded image 945718

[0346] In some embodiments, Formula III-A or III-B is any one of the formulae shown in Table 5A

TABLE-US-00008 TABLE 5A [01226]embedded image 90285 [01227]embedded image 90709 [01228]embedded image 90991 [01229]embedded image 92737 [01230]embedded image 93429 [01231]embedded image 107828 [01232]embedded image 107829 [01233]embedded image 109152

[0347] In some embodiments, Formula III-A or III-B is any one of the formulae shown in Table 6:

TABLE-US-00009 TABLE 6 [01234]embedded image 912105 [01235]embedded image 901472 [01236]embedded image 901473 [01237]embedded image 877295 [01238]embedded image 912168 [01239]embedded image 826714 [01240]embedded image 841867 [01241]embedded image 880765 [01242]embedded image 889571 [01243]embedded image 893313 [01244]embedded image 893315 [01245]embedded image 911958 [01246]embedded image 912077 [01247]embedded image 912107 [01248]embedded image 913265 [01249]embedded image 924310 [01250]embedded image 929436 [01251]embedded image 929438 [01252]embedded image 929439 [01253]embedded image 929441 [01254]embedded image 929448 [01255]embedded image 932633 [01256]embedded image 932650 [01257]embedded image 932651 [01258]embedded image 932652 [01259]embedded image 932654 [01260]embedded image 943544 [01261]embedded image 943545 [01262]embedded image 943914

[0348] In some embodiments, Formula III-A or III-B is any one of the formulae shown in Table 6A:

TABLE-US-00010 TABLE 6A [01263]embedded image 90330 or [01264]embedded image 92315

[0349] In some embodiments, Formula III-A or III-B is not any one of the formulae shown in Table 6. In some embodiments, Formula III-A or III-B is not any one of the formulae shown in Table 6A.

[0350] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula IV-A or IV-B.

##STR01265##

wherein:

[0351] R.sup.31 is

##STR01266##

optionally substituted naphthyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted bicyclic heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; [0352] R.sup.32 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; [0353] each of R.sup.33 and R.sup.38 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(RDB, OS(R.sup.D)OR.sup.D, OS(R.sup.D)(OR.sup.D).sub.2, or OS(OR.sup.D).sub.3; [0354] each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0355] each instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; [0356] or R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0357] or R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0358] or R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0359] or R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; and [0360] or R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0361] q1 is 0, 1, 2, 3, or 4; and [0362] R.sup.37 is Br, I, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3; [0363] provided that R.sup.37 is not-C(CH.sub.3).sub.3, CF.sub.3, CN, or C(O) NH.sub.2.

[0364] In some embodiments, each of Formulae IV-A and IV-B is not

##STR01267##

[0365] In some embodiments, the compound is of the formula:

##STR01268##

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

[0366] In some embodiments, the compound is of the formula:

##STR01269##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0367] R.sup.37 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0368] In some embodiments, the compound is of the formula:

##STR01270##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: [0369] R.sup.31 is optionally substituted naphthyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted bicyclic heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0370] In some embodiments,

##STR01271##

respectively. In some embodiments,

##STR01272##

respectively.

[0371] In some embodiments, R.sup.31 is

##STR01273##

optionally substituted naphthyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted 2-pyridinyl, optionally substituted 4-pyridinyl, optionally substituted 4-pyrimidinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted bicyclic heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0372] In some embodiments, R.sup.31 is optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted 2-pyridinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, or optionally substituted tetrazinyl. In some embodiments, R.sup.31 is optionally substituted furanyl, optionally substituted thiophenyl, or optionally substituted pyrrolyl. In some embodiments, R.sup.31 is optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, or optionally substituted isothiazolyl. In some embodiments, R.sup.31 is optionally substituted triazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, R.sup.31 is tetrazolyl. In some embodiments, R.sup.31 is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, or optionally substituted tetrazinyl. In some embodiments, R.sup.31 is optionally substituted 2-pyridinyl, optionally substituted 4-pyridinyl, optionally substituted 4-pyrimidinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, or optionally substituted tetrazinyl. In some embodiments, R.sup.31 is optionally substituted 2-pyridinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, or optionally substituted tetrazinyl.

[0373] In some embodiments, R.sup.31 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.31 is optionally substituted bicyclic 8- to 14-membered heteroaryl.

[0374] In some embodiments, R.sup.31 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.31 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.31 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.31 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.31 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.31 is saturated carbocyclyl. In some embodiments, R.sup.31 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0375] In some embodiments, R.sup.31 is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R.sup.31 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.31 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.31 is optionally substituted 3-6 to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.31 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.31 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.31 is saturated heterocyclyl. In some embodiments, R.sup.31 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0376] In some embodiments, R.sup.31 is

##STR01274##

or optionally substituted naphthyl. In some embodiments, R.sup.31 is optionally substituted naphthyl. In some embodiments, R.sup.31 is

##STR01275##

In some embodiments, R.sup.31 is

##STR01276##

In some embodiments, R.sup.31 is

##STR01277##

In some embodiments, R.sup.31 is

##STR01278##

In some embodiments, R.sup.31 is

##STR01279##

In some embodiments, R.sup.31 is

##STR01280##

[0377] q1 is 0, 1, 2, 3, or 4. In some embodiments, q1 is 0, 1, 2, or 3. In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is 0 or 1. In some embodiments, q1 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, q1 is 3. In some embodiments, q1 is 4.

[0378] In some embodiments, at least one instance of R.sup.38 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, at least one instance of R.sup.38 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one instance of R.sup.38 is C.sub.1-10 haloalkyl. In some embodiments, at least one instance of R.sup.38 is C.sub.1-4 haloalkyl. In some embodiments, at least one instance of R.sup.38 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, at least one instance of R.sup.38 is CF.sub.3.

[0379] In some embodiments, at least one instance of R.sup.38 is halogen. In some embodiments, at least one instance of R.sup.38 is bromine, chlorine, or fluorine. In some embodiments, at least one instance of R.sup.38 is bromine or chlorine. In some embodiments, at least one instance of R.sup.38 is chlorine or fluorine. In some embodiments, at least one instance of R.sup.38 is bromine. In some embodiments, at least one instance of R.sup.38 is chlorine. In some embodiments, at least one instance of R.sup.38 is fluorine.

[0380] In some embodiments, at least one instance of R.sup.38 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is OH. In some embodiments, at least one instance of R.sup.38 is SH. In some embodiments, at least one instance of R.sup.38 is NH.sub.2. In some embodiments, at least one instance of R.sup.38 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, at least one instance of R.sup.38 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)RP, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.38 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OS(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0381] In some embodiments, at least one instance of R.sup.38 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, at least one instance of R.sup.38 is saturated carbocyclyl. In some embodiments, at least one instance of R.sup.38 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0382] In some embodiments, at least one instance of R.sup.38 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.38 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, at least one instance of R.sup.38 is saturated heterocyclyl. In some embodiments, at least one instance of R.sup.38 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0383] In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic aryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted bicyclic aryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted phenyl. In some embodiments, at least one instance of R.sup.38 is optionally substituted naphthyl.

[0384] In some embodiments, at least one instance of R.sup.38 is optionally substituted monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted bicyclic heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.38 is optionally substituted heteroaryl comprising one or more N atoms.

[0385] In some embodiments, R.sup.37 is Br, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.D, SR.sup.D, N(R.sup.D).sub.2, S(O).sub.2R.sup.D, NR.sup.DC(O)R.sup.D, or NR.sup.DS(O).sub.2SR.sup.D. In some embodiments, R.sup.37 is Br, I, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, R.sup.37 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, R.sup.37 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl.

[0386] In some embodiments, R.sup.37 is Br or I. In some embodiments, R.sup.37 is Br. In some embodiments, R.sup.37 is I.

[0387] In some embodiments, R.sup.37 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is OH. In some embodiments, R.sup.37 is SH. In some embodiments, R.sup.37 is NH.sub.2. In some embodiments, R.sup.37 is SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.37 is SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.37 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)RP, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O)OR.sup.D, OS(O).sub.2SR.sup.D, OS(O) ZN(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.37 is Si(R.sup.D).sub.3, Si(R.sup.D)OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2 or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0388] In some embodiments, R.sup.37 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.37 is optionally substituted carbocyclyl. In some embodiments, R.sup.37 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.37 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.37 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.37 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.37 is saturated carbocyclyl. In some embodiments, R.sup.37 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0389] In some embodiments, R.sup.37 is optionally substituted heterocyclyl. In some embodiments, R.sup.37 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.37 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.37 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.37 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.37 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.37 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.37 is saturated heterocyclyl. In some embodiments, R.sup.37 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0390] In some embodiments, R.sup.37 is optionally substituted monocyclic aryl. In some embodiments, R.sup.37 is optionally substituted bicyclic aryl. In some embodiments, R.sup.37 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.37 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.37 is optionally substituted phenyl. In some embodiments, R.sup.37 is optionally substituted naphthyl.

[0391] In some embodiments, R.sup.37 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.37 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.37 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.37 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.37 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.37 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R.sup.37 is optionally substituted pyridinyl, optionally substituted isoquinolinyl, optionally substituted quinolinyl, or optionally substituted pyrazolyl. In some embodiments, R.sup.37 is optionally substituted pyridinyl or optionally substituted pyrazolyl.

[0392] In some embodiments, R.sup.32 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R.sup.32 is optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-4 alkenyl, or optionally substituted C.sub.1-4 alkynyl. In some embodiments, R.sup.32 is optionally substituted alkyl. In some embodiments, R.sup.32 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.32 is unsubstituted C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.32 is unsubstituted methyl. In some embodiments, R.sup.32 is unsubstituted ethyl.

[0393] In some embodiments, R.sup.33 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, R.sup.33 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.33 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.33 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.33 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.33 is CF.sub.3. In some embodiments, R.sup.33 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.33 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.33 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.33 is hydrogen or halogen. In some embodiments, R.sup.33 is hydrogen or fluorine. In some embodiments, R.sup.33 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.33 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.33 is hydrogen.

[0394] In some embodiments, R.sup.33 is halogen. In some embodiments, R.sup.33 is bromine, chlorine, or fluorine. In some embodiments, R.sup.33 is bromine or chlorine. In some embodiments, R.sup.33 is chlorine or fluorine. In some embodiments, R.sup.33 is bromine. In some embodiments, R.sup.33 is chlorine. In some embodiments, R.sup.33 is fluorine.

[0395] In some embodiments, R.sup.33 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is OH. In some embodiments, R.sup.33 is SH. In some embodiments, R.sup.33 is NH.sub.2. In some embodiments, R.sup.33 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.33 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D), (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.33 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.3 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OS(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0396] In some embodiments, R.sup.33 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.33 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.33 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.33 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.33 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.33 is saturated carbocyclyl. In some embodiments, R.sup.33 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0397] In some embodiments, R.sup.33 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.33 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.33 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.33 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.33 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.33 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.33 is saturated heterocyclyl. In some embodiments, R.sup.33 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0398] In some embodiments, R.sup.33 is optionally substituted monocyclic aryl. In some embodiments, R.sup.33 is optionally substituted bicyclic aryl. In some embodiments, R.sup.33 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.33 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.33 is optionally substituted phenyl. In some embodiments, R.sup.33 is optionally substituted naphthyl.

[0399] In some embodiments, R.sup.33 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.33 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.33 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.33 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.33 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0400] In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.D is 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. In some embodiments, two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0401] In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen, fluorine, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen or halogen. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen or fluorine. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is hydrogen. In some embodiments, each of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is hydrogen. In some embodiments, at least one of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35bb, R.sup.36a, and R.sup.36b is unsubstituted methyl. In some embodiments, at least one of R.sup.34a, R.sup.34b, R.sup.35a, R.sup.35b, R.sup.36a, and R.sup.36b is fluorine.

[0402] In some embodiments, each of R.sup.34a and R.sup.34b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.34a and R.sup.34b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.34a and R.sup.34b is halogen. In some embodiments, at least one of R.sup.34a and R.sup.34b is fluorine. In some embodiments, at least one of R.sup.34a and R.sup.34b is C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.34a and R.sup.34b is hydrogen. In some embodiments, R.sup.34a and R.sup.34b are hydrogen.

[0403] In some embodiments, each of R.sup.35a and R.sup.35b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.35a and R.sup.35b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.35a and R.sup.35b is halogen. In some embodiments, at least one of R.sup.35a and R.sup.35b is fluorine. In some embodiments, at least one of R.sup.35a and R.sup.35b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.35a and R.sup.35b is CH.sub.3. In some embodiments, R.sup.35a and R.sup.35b are optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.35a and R.sup.35b are CH.sub.3, In some embodiments, at least one of R.sup.35a and R.sup.35b is hydrogen. In some embodiments, R.sup.35a and R.sup.35b are hydrogen.

[0404] In some embodiments, each of R.sup.36a and R.sup.36b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.36a and R.sup.36b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.36a and R.sup.36b is halogen. In some embodiments, at least one of R.sup.36a and R.sup.36b is fluorine. In some embodiments, at least one of R.sup.36a and R.sup.36b is C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.36a and R.sup.36b is hydrogen. In some embodiments, R.sup.36a and R.sup.36b are hydrogen.

[0405] In some embodiments, R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.34a and R.sup.34b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0406] In some embodiments, R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.34b and R.sup.35a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0407] In some embodiments, R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-15 carbocyclic ring. In some embodiments, R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 15-membered heterocyclic ring. In some embodiments, R.sup.35a and R.sup.35b are taken together with their intervening atom to form an optionally subsituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0408] In some embodiments, R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.35b and R.sup.36a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0409] In some embodiments, R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-15 carbocyclic ring. In some embodiments, R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 15-membered heterocyclic ring. In some embodiments, R.sup.36a and R.sup.36b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0410] In some embodiments, Formula IV-A or IV-B is

##STR01281##

[0411] In some embodiments, Formula IV-A or IV-B is any one of the formulae shown in Table 7:

TABLE-US-00011 TABLE 7 [01282]embedded image 806604 [01283]embedded image 810362 [01284]embedded image 810379 [01285]embedded image 801313 [01286]embedded image 810365 [01287]embedded image 945713 [01288]embedded image 947867 [01289]embedded image 945532 [01290]embedded image 912171 [01291]embedded image 942642 [01292]embedded image 945328 [01293]embedded image 945546 [01294]embedded image 948545 [01295]embedded image 913047 [01296]embedded image 943990 [01297]embedded image 917291 [01298]embedded image 945481 [01299]embedded image 945704 [01300]embedded image 947384 [01301]embedded image 911992 [01302]embedded image 913043 [01303]embedded image 810366 [01304]embedded image 884117 [01305]embedded image 913035 [01306]embedded image 945531 [01307]embedded image 948546 [01308]embedded image 943913 [01309]embedded image 946099 [01310]embedded image 947333 [01311]embedded image 947658 [01312]embedded image 811565 [01313]embedded image 816885 [01314]embedded image 917293 [01315]embedded image 945527 [01316]embedded image 945710 [01317]embedded image 947511 [01318]embedded image 816800 [01319]embedded image 913032 [01320]embedded image 947324 [01321]embedded image 947326 [01322]embedded image 947372 [01323]embedded image 911989 [01324]embedded image 945619 [01325]embedded image 811561 [01326]embedded image 945958 [01327]embedded image 949268 [01328]embedded image 918327 [01329]embedded image 944035 [01330]embedded image 945728 [01331]embedded image 959342 [01332]embedded image 947665 [01333]embedded image 819560 [01334]embedded image 819639 [01335]embedded image 913046 [01336]embedded image 929452 [01337]embedded image 810489 [01338]embedded image 913041 [01339]embedded image 924543 [01340]embedded image 811558 [01341]embedded image 945482 [01342]embedded image 826651 [01343]embedded image 883872 [01344]embedded image 945618 [01345]embedded image 945726 [01346]embedded image 811563 [01347]embedded image 917151 [01348]embedded image 929445 [01349]embedded image 927339 [01350]embedded image 944036 [01351]embedded image 949514 [01352]embedded image 945545 [01353]embedded image 957510 [01354]embedded image 875608 [01355]embedded image 943546 [01356]embedded image 947816 [01357]embedded image 874315 [01358]embedded image 946101 [01359]embedded image 949391 [01360]embedded image 912004 [01361]embedded image 865170 [01362]embedded image 911972 [01363]embedded image 837803 [01364]embedded image 826719 [01365]embedded image 947412 [01366]embedded image 929449 [01367]embedded image 945486 [01368]embedded image 789561 [01369]embedded image 9121272 [01370]embedded image 929453 [01371]embedded image 945612 [01372]embedded image 913034 [01373]embedded image 948779 [01374]embedded image 943515 [01375]embedded image 810375 [01376]embedded image 927341 [01377]embedded image 913256 [01378]embedded image 947383 [01379]embedded image 949399 [01380]embedded image 946092 [01381]embedded image 816886 [01382]embedded image 947499 [01383]embedded image 917148 [01384]embedded image 893324 [01385]embedded image 945471 [01386]embedded image 913039 [01387]embedded image 943547 [01388]embedded image 949113 [01389]embedded image 946102 [01390]embedded image 911976 [01391]embedded image 950330 [01392]embedded image 889582 [01393]embedded image 947818 [01394]embedded image 946096 [01395]embedded image 957509 [01396]embedded image 946003 [01397]embedded image 912090 [01398]embedded image 865196 [01399]embedded image 947872 [01400]embedded image 949131 [01401]embedded image 913051 [01402]embedded image 865195 [01403]embedded image 912088 [01404]embedded image 819576 [01405]embedded image 913049 [01406]embedded image 909215 [01407]embedded image 790734 [01408]embedded image 874261 [01409]embedded image 902969 [01410]embedded image 911991 [01411]embedded image 946094 [01412]embedded image 950331 [01413]embedded image 874533 [01414]embedded image 913134 [01415]embedded image 943517 [01416]embedded image 865194 [01417]embedded image 837753 [01418]embedded image 883875 [01419]embedded image 946090 [01420]embedded image 874299 [01421]embedded image 945939 [01422]embedded image 913141 [01423]embedded image 947824 [01424]embedded image 947365 [01425]embedded image 945544 [01426]embedded image 909203 [01427]embedded image 913033 [01428]embedded image 816799 [01429]embedded image 913038 [01430]embedded image 917079 [01431]embedded image 826716 [01432]embedded image 932643 [01433]embedded image 943995 [01434]embedded image 912167 [01435]embedded image 913048 [01436]embedded image 885237 [01437]embedded image 885402 [01438]embedded image 947571 [01439]embedded image 924312 [01440]embedded image 828850 [01441]embedded image 947337 [01442]embedded image 913016 [01443]embedded image 945729 [01444]embedded image 913054 [01445]embedded image 885355 [01446]embedded image 947490 [01447]embedded image 945463 [01448]embedded image 889604 [01449]embedded image 915630 [01450]embedded image 913019 [01451]embedded image 943918 [01452]embedded image 945479 [01453]embedded image 801318 [01454]embedded image 865172 [01455]embedded image 946100 [01456]embedded image 913024 [01457]embedded image 943991 [01458]embedded image 885099 [01459]embedded image 947364 [01460]embedded image 801446 [01461]embedded image 909202 [01462]embedded image 930569 [01463]embedded image 946055 [01464]embedded image 884118 [01465]embedded image 823724 [01466]embedded image 913040 [01467]embedded image 947657 [01468]embedded image 915401 [01469]embedded image 947656 [01470]embedded image 917289 [01471]embedded image 917087 [01472]embedded image 943519 [01473]embedded image 945329 [01474]embedded image 946103 [01475]embedded image 889565 [01476]embedded image 792342 [01477]embedded image 811567 [01478]embedded image 819575 [01479]embedded image 853910 [01480]embedded image 789513 [01481]embedded image 885367 [01482]embedded image 885382 [01483]embedded image 945466 [01484]embedded image 917149 [01485]embedded image 810452 [01486]embedded image 948057 [01487]embedded image 945620 [01488]embedded image 917292 [01489]embedded image 915340 [01490]embedded image 948061 [01491]embedded image 957504 [01492]embedded image 874316 [01493]embedded image 947548 [01494]embedded image 947334 [01495]embedded image 945600 [01496]embedded image 801447 [01497]embedded image 947570 [01498]embedded image 932645 [01499]embedded image 885088 [01500]embedded image 945601 [01501]embedded image 917089 [01502]embedded image 801320 [01503]embedded image 810363 [01504]embedded image 924504 [01505]embedded image 884115 [01506]embedded image 947328 [01507]embedded image 913044 [01508]embedded image 789514 [01509]embedded image 912089 [01510]embedded image 913022 [01511]embedded image 913017 [01512]embedded image 932626 [01513]embedded image 926304 [01514]embedded image 913350 [01515]embedded image 885217 [01516]embedded image 948088 [01517]embedded image 885188 [01518]embedded image 801317 [01519]embedded image 918326 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[0412] In some embodiments, Formula IV-A or IV-B is any one of the formulae shown in Table 7A:

TABLE-US-00012 TABLE 7A [01892]embedded image 108954 [01893]embedded image 108956 [01894]embedded image 114687 [01895]embedded image 125976 [01896]embedded image 125977 [01897]embedded image 126012 [01898]embedded image 126013 [01899]embedded image 126014 [01900]embedded image 126190 [01901]embedded image 126191 [01902]embedded image 126192 [01903]embedded image 126193 [01904]embedded image 126366 [01905]embedded image 126393 [01906]embedded image 126394 [01907]embedded image 126395 [01908]embedded image 126397 [01909]embedded image 126398 [01910]embedded image 126399 or [01911]embedded image 126400

[0413] In some embodiments, Formula IV-A or IV-B is any one of the formulae shown in Table 8:

TABLE-US-00013 TABLE 8 [01912]embedded image 945485 [01913]embedded image 957508 [01914]embedded image 959344 [01915]embedded image 810453 [01916]embedded image 823726 [01917]embedded image 932637 [01918]embedded image 932638 [01919]embedded image 947411 [01920]embedded image 950325 [01921]embedded image 950332 [01922]embedded image 801366 [01923]embedded image 801369 [01924]embedded image 801412 [01925]embedded image 810359 [01926]embedded image 810364 [01927]embedded image 810371 [01928]embedded image 810509 [01929]embedded image 889632 [01930]embedded image 909213 [01931]embedded image 909223 [01932]embedded image 912091 [01933]embedded image 913042 [01934]embedded image 913223 [01935]embedded image 917210 [01936]embedded image 918322 [01937]embedded image 924520 [01938]embedded image 927340 [01939]embedded image 927345 [01940]embedded image 929443 [01941]embedded image 929451 [01942]embedded image 929455 [01943]embedded image 932635 [01944]embedded image 932644 [01945]embedded image 932646 [01946]embedded image 932656 [01947]embedded image 932662 [01948]embedded image 932665 [01949]embedded image 932667 [01950]embedded image 943915 [01951]embedded image 943989 [01952]embedded image 943993 [01953]embedded image 944034 [01954]embedded image 945484 [01955]embedded image 945615 [01956]embedded image 945616 [01957]embedded image 946000 [01958]embedded image 946002 [01959]embedded image 946098 [01960]embedded image 949132

[0414] In some embodiments, Formula IV-A or IV-B is any one of the formulae shown in Table 8A

TABLE-US-00014 TABLE 8A [01961]embedded image 126015 [01962]embedded image 126367 or [01963]embedded image 126396

[0415] In some embodiments, Formula IV-A or IV-B is not any one of the formulae shown in Table 8. In some embodiments, Formula IV-A or IV-B is not any one of the formulae shown in Table 8A.

[0416] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula V-A or V-B:

##STR01964##

wherein: [0417] R.sup.41 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0418] R.sup.42 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; [0419] or R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; [0420] R.sup.43 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.E, SCN, SR.sup.E, SSR.sup.E, N.sub.3, NO, N(R.sup.E).sub.2, NO.sub.2, C(O)R.sup.E, C(O)OR.sup.E, C(O)SR.sup.E, C(O)N(R.sup.E).sub.2, C(NR.sup.E)R.sup.E, C(NR.sup.E)OR.sup.E, C(NR.sup.E)SR.sup.E, C(NR.sup.E)N(R.sup.E).sub.2, S(O)R.sup.E, S(O)OR.sup.E, S(O)SR.sup.E, S(O)N(R.sup.E).sub.2, S(O).sub.2R.sup.E, S(O).sub.2OR.sup.E, S(O).sub.2SR.sup.E, S(O).sub.2N(R.sup.E).sub.2, OC(O)R.sup.E, OC(O)OR.sup.E, OC(O)SR.sup.E, OC(O)N(R.sup.E).sub.2, OC(NR.sup.E)R.sup.E, OC(NR.sup.E)OR.sup.E, OC(NR.sup.E)SR.sup.E, OC(NR.sup.E)N(R.sup.E).sub.2, OS(O)R.sup.E, OS(O)OR.sup.E, OS(O)SR.sup.E, OS(O)N(R.sup.E).sub.2, OS(O).sub.2R.sup.E, OS(O).sub.2OR.sup.E, OS(O).sub.2SR.sup.E, OS(O).sub.2N(R.sup.E).sub.2, ON(R.sup.E).sub.2, SC(O)R.sup.E, SC(O)OR.sup.E, SC(O)SR.sup.E, SC(O)N(R.sup.E).sub.2, SC(NR.sup.E)R.sup.E, SC(NR.sup.E)OR.sup.E, SC(NR.sup.E)SR.sup.E, SC(NR.sup.E)N(R.sup.E).sub.2, NR.sup.EC(O)R.sup.E, NR.sup.EC(O)OR.sup.E, NR.sup.EC(O)SR.sup.E, NR.sup.EC(O)N(R.sup.E).sub.2, NR.sup.EC(NR.sup.E)R.sup.E, NR.sup.EC(NR.sup.E)OR.sup.E, NR.sup.EC(NR.sup.E)SR.sup.E, NR.sup.EC(NR.sup.E)N(R.sup.E).sub.2, NR.sup.ES(O)R.sup.E, NR.sup.ES(O)OR.sup.E, NR.sup.ES(O)SR.sup.E, NR.sup.ES(O)N(R.sup.E).sub.2, NR.sup.ES(O).sub.2R.sup.E, NR.sup.ES(O).sub.2OR.sup.E, NR.sup.ES(O).sub.2SR.sup.E, NR.sup.ES(O).sub.2N(R.sup.E).sub.2, Si(R.sup.E).sub.2, Si(R.sup.E).sub.2OR.sup.E, Si(R.sup.E)(OR.sup.E).sub.2, Si(OR.sup.E).sub.3, OSi(R.sup.E).sub.3, OSi(R.sup.E).sub.2OR.sup.E, OSi(R.sup.E)(OR.sup.E).sub.2, or OSi(OR.sup.E).sub.3; [0421] each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or OR.sup.E; and [0422] each instance of R.sup.E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.E attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; [0423] or R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0424] or R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0425] or R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0426] or R.sup.45b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0427] or R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0428] provided that at least one of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b is not hydrogen.

[0429] In some embodiments, the compound is of the formula:

##STR01965##

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

[0430] In some embodiments, the compound is of the formula:

##STR01966##

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

[0431] In some embodiments, the compound is of the formula:

##STR01967##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0432] at least one of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b is halogen.

[0433] In some embodiments, the compound is of the formula:

##STR01968##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0434] at least two of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b are optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

[0435] In some embodiments,

##STR01969##

respectively. In some embodiments,

##STR01970##

respectively.

[0436] In some embodiments, R.sup.41 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.41 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl.

[0437] In some embodiments, R.sup.41 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.41 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.41 is saturated carbocyclyl. In some embodiments, R.sup.41 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0438] In some embodiments, R.sup.41 is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R.sup.41 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.41 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.41 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.41 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.41 is saturated heterocyclyl. In some embodiments, R.sup.41 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0439] In some embodiments, R.sup.41 is optionally substituted aryl. In some embodiments, R.sup.41 is optionally substituted monocyclic aryl. In some embodiments, R.sup.41 is optionally substituted bicyclic aryl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.41 is optionally substituted phenyl. In some embodiments, R.sup.41 is optionally substituted naphthyl.

[0440] In some embodiments, R.sup.41 is optionally substituted heteroaryl. In some embodiments, R.sup.41 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.41 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.41 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.41 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.41 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.41 is optionally substituted 9- to 10-membered bicyclic heteroaryl.

[0441] In some embodiments, R.sup.41 is optionally substituted aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted phenyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted naphthyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0442] In some embodiments, R.sup.41 is optionally substituted aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted phenyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted naphthyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0443] In some embodiments, R.sup.41 is optionally substituted heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.41 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0444] In some embodiments, R.sup.41 is optionally substituted heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.41 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0445] In some embodiments, R.sup.41 is

##STR01971##

[0446] Each instance of R.sup.47 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3.

[0447] r1 is 0, 1, 2, 3, 4, or 5. In some embodiments, r1 is 0, 1, 2, 3, or 4. In some embodiments, r1 is 0, 1, 2, or 3. In some embodiments, r1 is 0, 1, or 2. In some embodiments, r1 is 0 or 1. In some embodiments, r1 is 0. In some embodiments, r1 is 1. In some embodiments, r1 is 2. In some embodiments, r1 is 3. In some embodiments, r1 is 4. In some embodiments, r1 is 5.

[0448] In some embodiments, R.sup.41 is

##STR01972##

In some embodiments, R.sup.41 is

##STR01973##

In some embodiments, R.sup.41 is

##STR01974##

In some embodiments, R.sup.41 is

##STR01975##

In some embodiments, R.sup.41 is

##STR01976##

In some embodiments, R.sup.41 is

##STR01977##

In some embodiments, R.sup.41 is

##STR01978##

In some embodiments, R.sup.41 is

##STR01979##

In some embodiments, R.sup.41 is

##STR01980##

In some embodiments, R.sup.41 is

##STR01981##

[0449] In some embodiments, at least one instance of R.sup.47 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, at least one instance of R.sup.47 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one instance of R.sup.47 is C.sub.1-10 haloalkyl. In some embodiments, at least one instance of R.sup.47 is C.sub.1-4 haloalkyl. In some embodiments, at least one instance of R.sup.47 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, at least one instance of R.sup.47 is CF.sub.3.

[0450] In some embodiments, at least one instance of R.sup.47 is halogen. In some embodiments, at least one instance of R.sup.47 is bromine, chlorine, or fluorine. In some embodiments, at least one instance of R.sup.47 is bromine or chlorine. In some embodiments, at least one instance of R.sup.47 is chlorine or fluorine. In some embodiments, at least one instance of R.sup.47 is bromine. In some embodiments, at least one instance of R.sup.47 is chlorine. In some embodiments, at least one instance of R.sup.47 is fluorine.

[0451] In some embodiments, at least one instance of R.sup.47 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is OH. In some embodiments, at least one instance of R.sup.47 is SH. In some embodiments, at least one instance of R.sup.47 is NH.sub.2. In some embodiments, at least one instance of R.sup.47 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, at least one instance of R.sup.47 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.2).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein RP is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2RP, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.47 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0452] In some embodiments, at least one instance of R.sup.47 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, at least one instance of R.sup.47 is saturated carbocyclyl. In some embodiments, at least one instance of R.sup.47 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0453] In some embodiments, at least one instance of R.sup.47 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.47 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, at least one instance of R.sup.47 is saturated heterocyclyl. In some embodiments, at least one instance of R.sup.47 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0454] In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic aryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted bicyclic aryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted phenyl. In some embodiments, at least one instance of R.sup.47 is optionally substituted naphthyl.

[0455] In some embodiments, at least one instance of R.sup.47 is optionally substituted monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted bicyclic heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.47 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, at least one instance of R.sup.47 is optionally substituted pyridinyl, optionally substituted imidazolyl, or optionally substituted pyrazolyl.

[0456] In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.D is 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. In some embodiments, two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0457] In some embodiments, R.sup.42 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R.sup.42 is optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-4 alkenyl, or optionally substituted C.sub.1-4 alkynyl. In some embodiments, R.sup.42 is optionally substituted alkyl. In some embodiments, R.sup.42 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.42 is unsubstituted C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.42 is unsubstituted methyl. In some embodiments, R.sup.42 is unsubstituted ethyl.

[0458] In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered carbocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.41 and R.sup.42 are taken together with their intervening atom to form an optionally substituted cyclohexyl, piperidinyl, or tetrahydropyranyl.

[0459] In some embodiments, R.sup.43 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.E, SR.sup.E, or N(R.sup.E).sub.2. In some embodiments, R.sup.43 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.43 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.43 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.43 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.43 is CF.sub.3. In some embodiments, R.sup.43 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.43 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.43 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.43 is hydrogen or halogen. In some embodiments, R.sup.43 is hydrogen or fluorine. In some embodiments, R.sup.43 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.43 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.43 is hydrogen.

[0460] In some embodiments, R.sup.43 is halogen. In some embodiments, R.sup.43 is bromine, chlorine, or fluorine. In some embodiments, R.sup.43 is bromine or chlorine. In some embodiments, R.sup.43 is chlorine or fluorine. In some embodiments, R.sup.43 is bromine. In some embodiments, R.sup.43 is chlorine. In some embodiments. R.sup.43 is fluorine.

[0461] In some embodiments, R.sup.43 is OR.sup.E, SR.sup.E, or N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is OH. In some embodiments, R.sup.43 is SH. In some embodiments, R.sup.43 is NH.sub.2. In some embodiments, R.sup.43 is CN, SCN, SSR.sup.E, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.43 is C(O)R.sup.E, C(O)OR.sup.E, C(O)SR.sup.E, or C(O)N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is C(NR.sup.E)R.sup.E, C(NR.sup.E)OR.sup.E, C(NR.sup.E)SR.sup.E, or C(NR.sup.E)N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is S(O)R.sup.E, S(O)OR.sup.E, S(O)SR.sup.E, S(O)N(R.sup.E).sub.2, S(O).sub.2R.sup.E, S(O).sub.2OR.sup.E, S(O).sub.2SR.sup.E, or S(O).sub.2N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is OC(O)R.sup.E, OC(O)OR.sup.E, OC(O)SR.sup.E, OC(O)N(R.sup.E).sub.2, OC(NR.sup.E)R.sup.E, OC(NR.sup.E)OR.sup.E, OC(NR.sup.E)SR.sup.E, OC(NR.sup.E)N(R.sup.E).sub.2, OS(O)R.sup.E, OS(O)OR.sup.E, OS(O)SR.sup.E, OS(O)N(R.sup.E).sub.2, OS(O).sub.2R.sup.E, OS(O).sub.2OR.sup.E, OS(O).sub.2SR.sup.E, OS(O).sub.2N(R.sup.E).sub.2, or ON(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is SC(O)R.sup.E, SC(O)OR.sup.E, SC(O)SR.sup.E, SC(O)N(R.sup.E).sub.2, SC(NR.sup.E)R.sup.E, SC(NR.sup.E)OR.sup.E, SC(NR.sup.E)SR.sup.E, or SC(NR.sup.E)N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is NR.sup.EC(O)R.sup.E, NR.sup.EC(O)OR.sup.E, NR.sup.EC(O)SR.sup.E, NR.sup.EC(O)N(R.sup.E).sub.2, NR.sup.EC(NR.sup.E)R.sup.E, NR.sup.EC(NR.sup.E)OR.sup.E, NR.sup.EC(NR.sup.E)SR.sup.E, NR.sup.EC(NR.sup.E)N(R.sup.E).sub.2, NR.sup.ES(O)R.sup.E, NR.sup.ES(O)OR.sup.E, NR.sup.ES(O)SR.sup.E, NR.sup.ES(O)N(R.sup.E).sub.2, NR.sup.ES(O).sub.2R.sup.E, NR.sup.ES(O).sub.2OR.sup.E, NR.sup.ES(O).sub.2SR.sup.E, or NR.sup.ES(O).sub.2N(R.sup.E).sub.2 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.43 is Si(R.sup.E).sub.3, Si(R.sup.E).sub.2OR.sup.E, Si(R.sup.E)(OR.sup.E).sub.2, Si(OR.sup.E).sub.3, OSi(R.sup.E).sub.3, OSi(R.sup.E).sub.2OR.sup.E, OSi(R.sup.E)(OR.sup.E).sub.2, or OSi(OR.sup.E).sub.3 (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0462] In some embodiments, R.sup.43 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.43 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.43 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.43 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.43 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.43 is saturated carbocyclyl. In some embodiments, R.sup.43 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0463] In some embodiments, R.sup.43 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.43 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.43 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.43 is optionally substituted 3-12 to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.43 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.43 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.43 is saturated heterocyclyl. In some embodiments, R.sup.43 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0464] In some embodiments, R.sup.43 is optionally substituted monocyclic aryl. In some embodiments, R.sup.43 is optionally substituted bicyclic aryl. In some embodiments, R.sup.43 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.43 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.43 is optionally substituted phenyl. In some embodiments, R.sup.43 is optionally substituted naphthyl.

[0465] In some embodiments, R.sup.43 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.43 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.43 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.43 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.43 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0466] In some embodiments, at least one instance of R.sup.E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.E is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.E is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.E is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.E is 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. In some embodiments, two instances of R.sup.E attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0467] In some embodiments,

##STR01982##

wherein R.sup.44a is hydrogen, and R.sup.44b is not hydrogen. In some embodiments,

##STR01983##

wherein R.sup.44a is hydrogen, and R.sup.44b is not hydrogen.

[0468] In some embodiments,

##STR01984##

wherein R.sup.46a is hydrogen, and R.sup.46b is not hydrogen. In some embodiments,

##STR01985##

wherein R.sup.46a is hydrogen, and R.sup.46b is not hydrogen.

[0469] In some embodiments, one of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b are not hydrogen. In some embodiments, two of R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b are not hydrogen. In some embodiments, three of R.sup.44a, R.sup.44b, R.sup.45b, and R.sup.46b are not hydrogen. In some embodiments, R.sup.44a, R.sup.44b, R.sup.46a, and R.sup.46b are not hydrogen. In some embodiments, R.sup.44a is not hydrogen. In some embodiments, R.sup.44b is not hydrogen. In some embodiments, R.sup.46a is not hydrogen. In some embodiments, R.sup.46b is not hydrogen.

[0470] In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or OR.sup.E. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.45b, and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.45b, and R.sup.46b is independently hydrogen, fluorine, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen or halogen. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a and R.sup.46b is independently hydrogen or fluorine. In some embodiments, each of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is hydrogen. In some embodiments, at least one of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is unsubstituted methyl. In some embodiments, at least one of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is fluorine. In some embodiments, at least one of R.sup.44a, R.sup.44b, R.sup.45a, R.sup.45b, R.sup.46a, and R.sup.46b is OR.sup.E (e.g., wherein R.sup.E is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0471] In some embodiments, each of R.sup.44a and R.sup.44b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.44a and R.sup.44b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.44a and R.sup.44b is hydrogen. In some embodiments, one of R.sup.44a and R.sup.44b is hydrogen. In some embodiments, R.sup.44a and R.sup.44b are hydrogen. In some embodiments, at least one of R.sup.44a and R.sup.44b is halogen. In some embodiments, one of R.sup.44a and R.sup.44b is halogen. In some embodiments, at least one of R.sup.44a and R.sup.44b is fluorine. In some embodiments, one of R.sup.44a and R.sup.44b is fluorine. In some embodiments, at least one of R.sup.44a and R.sup.44b is optionally substituted C.sub.1-4 alkyl. In some embodiments, one of R.sup.44a and R.sup.44b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.44a and R.sup.44b is CH.sub.3. In some embodiments, one of R.sup.44a and R.sup.44b is CH.sub.3.

[0472] In some embodiments, each of R.sup.45a and R.sup.45b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.45a and R.sup.45b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.45a and R.sup.45b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.45a and R.sup.45b is CH.sub.3. In some embodiments, at least one of R.sup.45a and R.sup.45b is hydrogen. In some embodiments, R.sup.45a and R.sup.45b are CH.sub.3. In some embodiments, R.sup.45a and R.sup.45b are hydrogen.

[0473] In some embodiments, each of R.sup.45b and R.sup.46b is independently hydrogen, halogen, optionally substituted alkyl, or OR.sup.E. In some embodiments, each of R.sup.45b and R.sup.46b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.46a and R.sup.46b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.46a and R.sup.46b is hydrogen. In some embodiments, one of R.sup.46a and R.sup.46b is hydrogen. In some embodiments, R.sup.46a and R.sup.46b are hydrogen. In some embodiments, at least one of R.sup.46a and R.sup.46b is halogen. In some embodiments, one of R.sup.46a and R.sup.46b is halogen. In some embodiments, at least one of R.sup.46a and R.sup.46b is fluorine. In some embodiments, one of R.sup.45b and R.sup.46b is fluorine. In some embodiments, at least one of R.sup.46a and R.sup.46b is optionally substituted C.sub.1-4 alkyl. In some embodiments, one of R.sup.46a and R.sup.46b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.46a and R.sup.46b is CH.sub.3. In some embodiments, one of R.sup.46a and R.sup.46b is CH.sub.3. In some embodiments, R.sup.46a and R.sup.46b are CH.sub.3. In some embodiments, one of R.sup.46a and R.sup.46b is CH.sub.3. In some embodiments, at least one of R.sup.45b and R.sup.46b is OR.sup.E. In some embodiments, one of R.sup.46a and R.sup.46b is OR.sup.E. In some embodiments, at least one of R.sup.46a and R.sup.4bb is OH. In some embodiments, one of R.sup.46a and R.sup.46b is OH.

[0474] In some embodiments, R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.44a and R.sup.44b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0475] In some embodiments, R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.44b and R.sup.45a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0476] In some embodiments, R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.45a and R.sup.45b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0477] In some embodiments, R.sup.43b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.45b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.45b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.45b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.45b and R.sup.46a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0478] In some embodiments, R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.46a and R.sup.46b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0479] In some embodiments, Formula V-A or V-B is

##STR01986##

[0480] In some embodiments, Formula V-A and V-B is any one of the formulae shown in Table 9:

TABLE-US-00015 TABLE 9 [01987]embedded image 948545 [01988]embedded image 948546 [01989]embedded image 959342 [01990]embedded image 865199 [01991]embedded image 957510 [01992]embedded image 946101 [01993]embedded image 837803 [01994]embedded image 945486 [01995]embedded image 946102 [01996]embedded image 957509 [01997]embedded image 946056 [01998]embedded image 837753 [01999]embedded image 835310 [02000]embedded image 865198 [02001]embedded image 957403 [02002]embedded image 909217 [02003]embedded image 947657 [02004]embedded image 957197 [02005]embedded image 957405 [02006]embedded image 947656 [02007]embedded image 946103 [02008]embedded image 957504 [02009]embedded image 826766 [02010]embedded image 909216 [02011]embedded image 957200 [02012]embedded image 957505 [02013]embedded image 865201 [02014]embedded image 893316 [02015]embedded image 826768 [02016]embedded image 948548 [02017]embedded image 947653 [02018]embedded image 945475 [02019]embedded image 959341 [02020]embedded image 837683 [02021]embedded image 945476 [02022]embedded image 835314 [02023]embedded image 947652 [02024]embedded image 819622 [02025]embedded image 957506 [02026]embedded image 826764 [02027]embedded image 947655 [02028]embedded image 957511 [02029]embedded image 946104 [02030]embedded image 947650 [02031]embedded image 948547 [02032]embedded image 835315 [02033]embedded image 957507 [02034]embedded image 963155 [02035]embedded image 959343 [02036]embedded image 837646 [02037]embedded image 947651 [02038]embedded image 883833 [02039]embedded image 883834 [02040]embedded image 883836 [02041]embedded image 883835 [02042]embedded image 912072 [02043]embedded image 917136 [02044]embedded image 951839 [02045]embedded image 917134 [02046]embedded image 918284 [02047]embedded image 951705 [02048]embedded image 951705 [02049]embedded image 951846 [02050]embedded image 917135 [02051]embedded image 951711 [02052]embedded image 951711 [02053]embedded image 918285 [02054]embedded image 951708 [02055]embedded image 951709 [02056]embedded image 918282 [02057]embedded image 917133 [02058]embedded image 918283 [02059]embedded image 951713 [02060]embedded image 951703 [02061]embedded image 950814 [02062]embedded image 951701

[0481] In some embodiments, Formula V-A and V-B is any one of the formulae shown in Table 10:

TABLE-US-00016 TABLE 10 [02063]embedded image 945485 [02064]embedded image 957508 [02065]embedded image 959344 [02066]embedded image 826767 [02067]embedded image 826769 [02068]embedded image 835312 [02069]embedded image 835313 [02070]embedded image 865202 [02071]embedded image 909218 [02072]embedded image 909219 [02073]embedded image 957196 [02074]embedded image 957199 [02075]embedded image 957404 [02076]embedded image 957406

[0482] In some embodiments, Formula V-A and V-B is not any one of the formulae shown in Table 10.

[0483] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula VI-A or VI-B:

##STR02077##

wherein: [0484] R.sup.51 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0485] R.sup.52 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; [0486] or R.sup.31 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; [0487] R.sup.53 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.F, SCN, SR.sup.F, SSR.sup.F, N.sub.3, NO, N(R.sup.F).sub.2, NO.sub.2, C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, C(O)N(R.sup.F).sub.2, C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, C(NR.sup.F)N(R.sup.F).sub.2, S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, S(O).sub.2N(R.sup.F).sub.2, OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, ON(R.sup.F).sub.2, SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, SC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, NR.sup.FS(O).sub.2N(R.sup.F).sub.2, Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, OSi(R.sup.F).sub.3, Osi(R.sup.F).sub.2OR.sup.F, Osi(R.sup.F)(OR.sup.F).sub.2, or Osi(OR.sup.F).sub.3; [0488] each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0489] each instance of R.sup.F is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.F attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and [0490] R.sup.55a and R.sup.55b are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.F, SCN, SR.sup.F, SSR.sup.F, N.sub.3, NO, N(R.sup.F).sub.2, NO.sub.2C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, C(O)N(R.sup.F).sub.2, C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, C(NR.sup.F)N(R.sup.F).sub.2, S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, S(O).sub.2N(R.sup.F).sub.2, OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, ON(R.sup.F).sub.2, SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, SC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, NR.sup.FS(O).sub.2N(R.sup.F).sub.2, Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, Osi(R.sup.F).sub.2, Osi(R.sup.E).sub.2OR.sup.E, Osi(R.sup.F)(OR.sup.F).sub.2, or Osi(OR.sup.F).sub.3; [0491] or R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0492] or R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0493] or R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring; [0494] or R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0495] or R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; [0496] provided that at least one of R.sup.55a and R.sup.55b is not-CH.sub.3.

[0497] In some embodiments, the compound is of the formula:

##STR02078##

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

[0498] In some embodiments, the compound is of the formula:

##STR02079##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof,
wherein: [0499] R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring.

[0500] In some embodiments, the compound is of the formula:

##STR02080##

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

[0501] In some embodiments,

##STR02081##

respectively. In some embodiments,

##STR02082##

respectively.

[0502] In some embodiments, R.sup.51 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.51 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, or optionally substituted C.sub.1-10 alkynyl.

[0503] In some embodiments, R.sup.51 is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R.sup.51 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.51 is saturated carbocyclyl. In some embodiments, R.sup.51 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0504] In some embodiments, R.sup.51 is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R.sup.51 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.51 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.51 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.51 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.51 is saturated heterocyclyl. In some embodiments, R.sup.51 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0505] In some embodiments, R.sup.51 is optionally substituted aryl. In some embodiments, R.sup.51 is optionally substituted monocyclic aryl. In some embodiments, R.sup.51 is optionally substituted bicyclic aryl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.51 is optionally substituted phenyl. In some embodiments, R.sup.51 is optionally substituted naphthyl.

[0506] In some embodiments, R.sup.51 is optionally substituted heteroaryl. In some embodiments, R.sup.51 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.51 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.51 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.51 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.51 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R.sup.51 is optionally substituted 9- to 10-membered bicyclic heteroaryl.

[0507] In some embodiments, R.sup.51 is optionally substituted aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted phenyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted naphthyl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0508] In some embodiments, R.sup.51 is optionally substituted aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-14 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted C.sub.6-10 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted phenyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted naphthyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0509] In some embodiments, R.sup.51 is optionally substituted heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.51 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic C.sub.3-7 carbocyclyl.

[0510] In some embodiments, R.sup.51 is optionally substituted heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.51 is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0511] In some embodiments, R.sup.51 is

##STR02083##

[0512] Each instance of R.sup.57 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.D, SCN, SR.sup.D, SSR.sup.D, N.sub.3, NO, N(R.sup.D).sub.2, NO.sub.2, C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, C(O)N(R.sup.D).sub.2, C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, C(NR.sup.D)N(R.sup.D).sub.2, S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O)R.sup.D), S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, S(O).sub.2N(R.sup.D).sub.2, OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)R.sup.D, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, ON(R.sup.D).sub.2, SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, SC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, NR.sup.DS(O).sub.2N(R.sup.D).sub.2, Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3.

[0513] s1 is 0, 1, 2, 3, 4, or 5. In some embodiments, s1 is 0, 1, 2, 3, or 4. In some embodiments, s1 is 0, 1, 2, or 3. In some embodiments, s1 is 0, 1, or 2. In some embodiments, s1 is 0 or 1. In some embodiments, s1 is 0. In some embodiments, s1 is 1. In some embodiments, s1 is 2. In some embodiments, s1 is 3. In some embodiments, s1 is 4. In some embodiments, s1 is 5.

[0514] In some embodiments, R.sup.51 is

##STR02084##

In some embodiments, R.sup.51 is

##STR02085##

In some embodiments, R.sup.51 is

##STR02086##

In some embodiments, R.sup.51 is

##STR02087##

In some embodiments, R.sup.51 is

##STR02088##

In some embodiments, R.sup.51 is

##STR02089##

In some embodiments, R.sup.51 is

##STR02090##

In some embodiments, R.sup.51 is

##STR02091##

In some embodiments, R.sup.51 is

##STR02092##

In some embodiments, R.sup.51 is

##STR02093##

[0515] In some embodiments, at least one instance of R.sup.57 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2. In some embodiments, at least one instance of R.sup.57 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, at least one instance of R.sup.57 is C.sub.1-10 haloalkyl. In some embodiments, at least one instance of R.sup.57 is C.sub.1-4 haloalkyl. In some embodiments, at least one instance of R.sup.57 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, at least one instance of R.sup.57 is CF.sub.3.

[0516] In some embodiments, at least one instance of R.sup.57 is halogen. In some embodiments, at least one instance of R.sup.57 is bromine, chlorine, or fluorine. In some embodiments, at least one instance of R.sup.57 is bromine or chlorine. In some embodiments, at least one instance of R.sup.57 is chlorine or fluorine. In some embodiments, at least one instance of R.sup.57 is bromine. In some embodiments, at least one instance of R.sup.57 is chlorine. In some embodiments, at least one instance of R.sup.57 is fluorine.

[0517] In some embodiments, at least one instance of R.sup.57 is OR.sup.D, SR.sup.D, or N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is OH. In some embodiments, at least one instance of R.sup.57 is SH. In some embodiments, at least one instance of R.sup.57 is NH.sub.2. In some embodiments, at least one instance of R.sup.57 is CN, SCN, SSR.sup.D, N.sub.3, NO, or NO.sub.2. In some embodiments, at least one instance of R.sup.57 is C(O)R.sup.D, C(O)OR.sup.D, C(O)SR.sup.D, or C(O)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is C(NR.sup.D)R.sup.D, C(NR.sup.D)OR.sup.D, C(NR.sup.D)SR.sup.D, or C(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is S(O)R.sup.D, S(O)OR.sup.D, S(O)SR.sup.D, S(O)N(R.sup.D).sub.2, S(O).sub.2R.sup.D, S(O).sub.2OR.sup.D, S(O).sub.2SR.sup.D, or S(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is OC(O)R.sup.D, OC(O)OR.sup.D, OC(O)SR.sup.D, OC(O)N(R.sup.D).sub.2, OC(NR.sup.D)R.sup.D, OC(NR.sup.D)OR.sup.D, OC(NR.sup.D)SR.sup.D, OC(NR.sup.D)N(R.sup.D).sub.2, OS(O)RP, OS(O)OR.sup.D, OS(O)SR.sup.D, OS(O)N(R.sup.D).sub.2, OS(O).sub.2R.sup.D, OS(O).sub.2OR.sup.D, OS(O).sub.2SR.sup.D, OS(O).sub.2N(R.sup.D).sub.2, or ON(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is SC(O)R.sup.D, SC(O)OR.sup.D, SC(O)SR.sup.D, SC(O)N(R.sup.D).sub.2, SC(NR.sup.D)R.sup.D, SC(NR.sup.D)OR.sup.D, SC(NR.sup.D)SR.sup.D, or SC(NR.sup.D)N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is NR.sup.DC(O)R.sup.D, NR.sup.DC(O)OR.sup.D, NR.sup.DC(O)SR.sup.D, NR.sup.DC(O)N(R.sup.D).sub.2, NR.sup.DC(NR.sup.D)R.sup.D, NR.sup.DC(NR.sup.D)OR.sup.D, NR.sup.DC(NR.sup.D)SR.sup.D, NR.sup.DC(NR.sup.D)N(R.sup.D).sub.2, NR.sup.DS(O)R.sup.D, NR.sup.DS(O)OR.sup.D, NR.sup.DS(O)SR.sup.D, NR.sup.DS(O)N(R.sup.D).sub.2, NR.sup.DS(O).sub.2R.sup.D, NR.sup.DS(O).sub.2OR.sup.D, NR.sup.DS(O).sub.2SR.sup.D, or NR.sup.DS(O).sub.2N(R.sup.D).sub.2 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R.sup.57 is Si(R.sup.D).sub.3, Si(R.sup.D).sub.2OR.sup.D, Si(R.sup.D)(OR.sup.D).sub.2, Si(OR.sup.D).sub.3, OSi(R.sup.D).sub.3, OSi(R.sup.D).sub.2OR.sup.D, OSi(R.sup.D)(OR.sup.D).sub.2, or OSi(OR.sup.D).sub.3 (e.g., wherein R.sup.D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0518] In some embodiments, at least one instance of R.sup.57 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, at least one instance of R.sup.57 is saturated carbocyclyl. In some embodiments, at least one instance of R.sup.57 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0519] In some embodiments, at least one instance of R.sup.57 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.57 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, at least one instance of R.sup.57 is saturated heterocyclyl. In some embodiments, at least one instance of R.sup.57 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0520] In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic aryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted bicyclic aryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted C.sub.6-10 aryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted phenyl. In some embodiments, at least one instance of R.sup.57 is optionally substituted naphthyl.

[0521] In some embodiments, at least one instance of R.sup.57 is optionally substituted monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted bicyclic heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, at least one instance of R.sup.57 is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, at least one instance of R.sup.57 is optionally substituted pyridinyl or optionally substituted pyrazolyl.

[0522] In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.D is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted Cujo alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of RP is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.D is 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. In some embodiments, two instances of R.sup.D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0523] In some embodiments, R.sup.52 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R.sup.52 is optionally substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-4 alkenyl, or optionally substituted C.sub.1-4 alkynyl. In some embodiments, R.sup.52 is optionally substituted alkyl. In some embodiments, R.sup.52 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.52 is unsubstituted C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.52 is unsubstituted methyl. In some embodiments, R.sup.52 is unsubstituted ethyl.

[0524] In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered carbocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.51 and R.sup.52 are taken together with their intervening atom to form an optionally substituted tetrahydropyranyl.

[0525] In some embodiments, R.sup.53 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.F, SR.sup.F, or N(R.sup.F).sub.2. In some embodiments, R.sup.53 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.53 is C.sub.1-10 haloalkyl. In some embodiments, R.sup.53 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.53 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.53 is CF.sub.3. In some embodiments, R.sup.53 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.53 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.53 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.53 is hydrogen or halogen. In some embodiments, R.sup.53 is hydrogen or fluorine. In some embodiments, R.sup.53 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.53 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.53 is hydrogen.

[0526] In some embodiments, R.sup.53 is halogen. In some embodiments, R.sup.53 is bromine, chlorine, or fluorine. In some embodiments, R.sup.53 is bromine or chlorine. In some embodiments, R.sup.53 is chlorine or fluorine. In some embodiments, R.sup.53 is bromine. In some embodiments, R.sup.53 is chlorine. In some embodiments, R.sup.53 is fluorine.

[0527] In some embodiments, R.sup.53 is OR.sup.F, SR.sup.E, or N(R.sup.E).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is OH. In some embodiments, R.sup.53 is SH. In some embodiments, R.sup.53 is NH.sub.2. In some embodiments, R.sup.53 is CN, SCN, SSR.sup.F, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.53 is C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, or C(O)N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, or C(NR.sup.F)N(R.sup.E).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, or S(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, or ON(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, or SC(NR.sup.F)N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, or NR.sup.FS(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.53 is Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, OSi(R.sup.F).sub.3, OSi(R.sup.F).sub.2OR.sup.F, OSi(R.sup.F)(OR.sup.F).sub.2, or OSi(OR.sup.F).sub.3 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0528] In some embodiments, R.sup.53 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments. R.sup.53 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.53 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.53 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.53 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.53 is saturated carbocyclyl. In some embodiments, R.sup.53 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0529] In some embodiments, R.sup.53 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.53 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.53 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.53 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.53 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.53 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.53 is saturated heterocyclyl. In some embodiments, R.sup.53 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0530] In some embodiments, R.sup.33 is optionally substituted monocyclic aryl. In some embodiments, R.sup.53 is optionally substituted bicyclic aryl. In some embodiments, R.sup.53 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.53 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.53 is optionally substituted phenyl. In some embodiments, R.sup.53 is optionally substituted naphthyl.

[0531] In some embodiments, R.sup.53 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.53 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.53 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.53 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.53 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0532] In some embodiments, at least one instance of R.sup.F is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.F is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.F is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.F is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.F is 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. In some embodiments, two instances of R.sup.F attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0533] In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen, fluorine, or optionally substituted C.sub.1-4 alkyl. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen or halogen. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen or fluorine. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is independently hydrogen or optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is hydrogen. In some embodiments, each of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is hydrogen. In some embodiments, at least one of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is unsubstituted methyl. In some embodiments, at least one of R.sup.54a, R.sup.54b, R.sup.56a, and R.sup.56b is fluorine.

[0534] In some embodiments, each of R.sup.54a and R.sup.54b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.54a and R.sup.545 is hydrogen. In some embodiments, one of R.sup.54a and R.sup.54b is hydrogen. In some embodiments, R.sup.54a and R.sup.54b are hydrogen. In some embodiments, at least one of R.sup.54a and R.sup.54b is optionally substituted C.sub.1-4 alkyl. In some embodiments, one of R.sup.54a and R.sup.54b is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.54a and R.sup.54b are optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.54a and R.sup.54b is CH.sub.3. In some embodiments, one of R.sup.54a and R.sup.54b is CH.sub.3. In some embodiments, one of R.sup.54a and R.sup.54b are CH.sub.3.

[0535] In some embodiments, each of R.sup.56a and R.sup.56b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R.sup.56a and R.sup.56b is hydrogen. In some embodiments, one of R.sup.56a and R.sup.56b is hydrogen. In some embodiments, R.sup.56a and R.sup.56b are hydrogen. In some embodiments, at least one of R.sup.56a and R.sup.56b is optionally substituted C.sub.1-4 alkyl. In some embodiments, one of R.sup.56a and R.sup.56b is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.56a and R.sup.56b are optionally substituted C.sub.1-4 alkyl. In some embodiments, at least one of R.sup.56a and R.sup.56b is CH.sub.3. In some embodiments, one of R.sup.56a and R.sup.56b is CH.sub.3. In some embodiments, R.sup.56a and R.sup.56b are CH.sub.3.

[0536] In some embodiments,

##STR02094##

In some embodiments,

##STR02095##

[0537] In some embodiments, R.sup.55a is not-CH.sub.3. In some embodiments, R.sup.55b is not-CH.sub.3. In some embodiments, R.sup.55a and R.sup.55b are not-CH.sub.3.

[0538] In some embodiments, R.sup.55a and R.sup.55b are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted aryl. In some embodiments, one of R.sup.55a and R.sup.55b is hydrogen. In some embodiments, R.sup.55a and R.sup.55b are both hydrogen.

[0539] In some embodiments, R.sup.55a is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.F, SR.sup.F, or N(R.sup.F).sub.2. In some embodiments, R.sup.55a is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.55a is C.sub.1-10 haloalkyl. In some embodiments, R.sup.55a is C.sub.1-4 haloalkyl. In some embodiments, R.sup.55a is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.55a is CF.sub.3. In some embodiments, R.sup.55a is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.55a is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.55a is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.55a is hydrogen or halogen. In some embodiments, R.sup.35a is hydrogen or fluorine. In some embodiments, R.sup.55a is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.55a is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.55a is hydrogen.

[0540] In some embodiments, R.sup.55a is halogen. In some embodiments, R.sup.55a is bromine, chlorine, or fluorine. In some embodiments, R.sup.55a is bromine or chlorine. In some embodiments, R.sup.55a is chlorine or fluorine. In some embodiments, R.sup.55a is bromine. In some embodiments, R.sup.55a is chlorine. In some embodiments, R.sup.55a is fluorine.

[0541] In some embodiments, R.sup.55a is OR.sup.F, SR.sup.F, or N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is OH. In some embodiments, R.sup.55a is SH. In some embodiments, R.sup.55a is NH.sub.2. In some embodiments, R.sup.55a is CN, SCN, SSR.sup.F, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.55a is C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, or C(O)N(R.sup.E).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, or C(NR.sup.F)N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, or S(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.F).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, or ON(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, or SC(NR.sup.F)N(R.sup.E).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55a is NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, or NR.sup.FS(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.35a is Si(R.sup.F).sub.3, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.3, OSi(R.sup.F).sub.3, OSi(R.sup.F).sub.2OR.sup.F, OSi(R.sup.F)(OR.sup.F).sub.2, or OSi(OR.sup.F).sub.3 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0542] In some embodiments, R.sup.55a is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.55a is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.55a is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.55a is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.55a is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.55a is saturated carbocyclyl. In some embodiments, R.sup.55a is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0543] In some embodiments, R.sup.55a is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.55a is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.55a is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.55a is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.55a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.55a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.55a is saturated heterocyclyl. In some embodiments, R.sup.55a is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0544] In some embodiments, R.sup.55a is optionally substituted monocyclic aryl. In some embodiments, R.sup.55a is optionally substituted bicyclic aryl. In some embodiments, R.sup.55a is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.55a is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.55a is optionally substituted phenyl. In some embodiments, R.sup.55a is optionally substituted naphthyl.

[0545] In some embodiments, R.sup.55a is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.55a is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.55a is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.55a is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.55a is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0546] In some embodiments, R.sup.55b is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.F, SR.sup.F, or N(R.sup.F).sub.2. In some embodiments, R.sup.55b is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.55b is C.sub.1-10 haloalkyl. In some embodiments, R.sup.55b is C.sub.1-4 haloalkyl. In some embodiments, R.sup.55b is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.55b is CF.sub.3. In some embodiments, R.sup.55b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.55b is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.55b is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.55b is hydrogen or halogen. In some embodiments, R.sup.55b is hydrogen or fluorine. In some embodiments, R.sup.55b is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.55b is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.55b is hydrogen.

[0547] In some embodiments, R.sup.55b is halogen. In some embodiments, R.sup.55b is bromine, chlorine, or fluorine. In some embodiments, R.sup.55b is bromine or chlorine. In some embodiments, R.sup.55b is chlorine or fluorine. In some embodiments, R.sup.55b is bromine. In some embodiments, R.sup.55b is chlorine. In some embodiments, R.sup.55b is fluorine.

[0548] In some embodiments, R.sup.55b is OR.sup.F, SR.sup.F, or N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is OH. In some embodiments, R.sup.55b is SH. In some embodiments, R.sup.55b is NH.sub.2. In some embodiments, R.sup.55b is CN, SCN, SSR.sup.F, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.55b is C(O)R.sup.F, C(O)OR.sup.F, C(O)SR.sup.F, or C(O)N(R.sup.F).sub.3 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is C(NR.sup.F)R.sup.F, C(NR.sup.F)OR.sup.F, C(NR.sup.F)SR.sup.F, or C(NR.sup.F)N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is S(O)R.sup.F, S(O)OR.sup.F, S(O)SR.sup.F, S(O)N(R.sup.F).sub.2, S(O).sub.2R.sup.F, S(O).sub.2OR.sup.F, S(O).sub.2SR.sup.F, or S(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is OC(O)R.sup.F, OC(O)OR.sup.F, OC(O)SR.sup.F, OC(O)N(R.sup.F).sub.2, OC(NR.sup.F)R.sup.F, OC(NR.sup.F)OR.sup.F, OC(NR.sup.F)SR.sup.F, OC(NR.sup.F)N(R.sup.F).sub.2, OS(O)R.sup.F, OS(O)OR.sup.F, OS(O)SR.sup.F, OS(O)N(R.sup.E).sub.2, OS(O).sub.2R.sup.F, OS(O).sub.2OR.sup.F, OS(O).sub.2SR.sup.F, OS(O).sub.2N(R.sup.F).sub.2, or ON(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is SC(O)R.sup.F, SC(O)OR.sup.F, SC(O)SR.sup.F, SC(O)N(R.sup.F).sub.2, SC(NR.sup.F)R.sup.F, SC(NR.sup.F)OR.sup.F, SC(NR.sup.F)SR.sup.F, or SC(NR.sup.F)N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is NR.sup.FC(O)R.sup.F, NR.sup.FC(O)OR.sup.F, NR.sup.FC(O)SR.sup.F, NR.sup.FC(O)N(R.sup.F).sub.2, NR.sup.FC(NR.sup.F)R.sup.F, NR.sup.FC(NR.sup.F)OR.sup.F, NR.sup.FC(NR.sup.F)SR.sup.F, NR.sup.FC(NR.sup.F)N(R.sup.F).sub.2, NR.sup.FS(O)R.sup.F, NR.sup.FS(O)OR.sup.F, NR.sup.FS(O)SR.sup.F, NR.sup.FS(O)N(R.sup.F).sub.2, NR.sup.FS(O).sub.2R.sup.F, NR.sup.FS(O).sub.2OR.sup.F, NR.sup.FS(O).sub.2SR.sup.F, or NR.sup.FS(O).sub.2N(R.sup.F).sub.2 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.55b is Si(R.sup.F).sub.2, Si(R.sup.F).sub.2OR.sup.F, Si(R.sup.F)(OR.sup.F).sub.2, Si(OR.sup.F).sub.2, OSi(R.sup.F).sub.3, OSi(R.sup.F).sub.2OR.sup.F, OSi(R.sup.F)(OR.sup.F).sub.2, or OSi(OR.sup.F).sub.3 (e.g., wherein R.sup.F is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0549] In some embodiments, R.sup.55b is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.55b is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.55b is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.55b is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.55b is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.55b is saturated carbocyclyl. In some embodiments, R.sup.35b is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0550] In some embodiments, R.sup.55b is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.55b is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.55b is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.55b is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.55b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.55b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.55b is saturated heterocyclyl. In some embodiments, R.sup.55b is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0551] In some embodiments, R.sup.55b is optionally substituted monocyclic aryl. In some embodiments, R.sup.55b is optionally substituted bicyclic aryl. In some embodiments, R.sup.35b is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.55b is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.55b is optionally substituted phenyl. In some embodiments, R.sup.55b is optionally substituted naphthyl.

[0552] In some embodiments, R.sup.55b is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.55b is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.55b is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.55b is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.55b is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0553] In some embodiments, R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.54a and R.sup.54b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0554] In some embodiments, R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.54b and R.sup.55a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0555] In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 6- to 7-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 6-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 7-membered heterocyclic ring. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl ring, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl.

[0556] In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted tetrahydrofuranyl or optionally substituted tetrahydropyranyl. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted tetrahydrofuranyl. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted tetrahydropyranyl.

[0557] In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring comprising one or more N atoms. In some embodiments, R.sup.55a and R.sup.35b are taken together with their intervening atom to form optionally substituted pyrrolidinyl or optionally substituted piperidinyl. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted pyrrolidinyl. In some embodiments, R.sup.55a and R.sup.55b are taken together with their intervening atom to form optionally substituted piperidinyl.

[0558] In some embodiments, R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.56b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.55b and R.sup.56a are taken together with their intervening atom to form an optionally subsituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0559] In some embodiments, R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-14 carbocyclic ring. In some embodiments, R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, C.sub.3-7 carbocyclic ring. In some embodiments, R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R.sup.56a and R.sup.56b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring.

[0560] In some embodiments, Formula VI-A or VI-B is any one of the formulae shown in Table 11:

TABLE-US-00017 TABLE 11 [02096]embedded image 949753 [02097]embedded image 865199 [02098]embedded image 950161 [02099]embedded image 884111 [02100]embedded image 874315 [02101]embedded image 947412 [02102]embedded image 791265 [02103]embedded image 950160 [02104]embedded image 791264 [02105]embedded image 950330 [02106]embedded image 950331 [02107]embedded image 816884 [02108]embedded image 806608 [02109]embedded image 949760 [02110]embedded image 816875 [02111]embedded image 835310 [02112]embedded image 806609 [02113]embedded image 901477 [02114]embedded image 828849 [02115]embedded image 789013 [02116]embedded image 865198 [02117]embedded image 828850 [02118]embedded image 816796 [02119]embedded image 819569 [02120]embedded image 893309 [02121]embedded image 884112 [02122]embedded image 789334 [02123]embedded image 901478 [02124]embedded image 889572 [02125]embedded image 912078 [02126]embedded image 909217 [02127]embedded image 823724 [02128]embedded image 912079 [02129]embedded image 789332 [02130]embedded image 810452 [02131]embedded image 816873 [02132]embedded image 874316 [02133]embedded image 789010 [02134]embedded image 816878 [02135]embedded image 816881 [02136]embedded image 819565 [02137]embedded image 816879 [02138]embedded image 819568 [02139]embedded image 909216 [02140]embedded image 816752 [02141]embedded image 865201 [02142]embedded image 893316 [02143]embedded image 947407 [02144]embedded image 932657 [02145]embedded image 950326 [02146]embedded image 950333 [02147]embedded image 826653 [02148]embedded image 932658 [02149]embedded image 810486 [02150]embedded image 823720 [02151]embedded image 810487 [02152]embedded image 826652 [02153]embedded image 801397 [02154]embedded image 947406 [02155]embedded image 856947 [02156]embedded image 950324 [02157]embedded image 823721 [02158]embedded image 874318 [02159]embedded image 950329 [02160]embedded image 810451 [02161]embedded image 874317 [02162]embedded image 810450 [02163]embedded image 826715 [02164]embedded image 828848 [02165]embedded image 828847 [02166]embedded image 901458 [02167]embedded image 901476 [02168]embedded image 901475 [02169]embedded image 889573

[0561] In some embodiments, Formula VI-A or VI-B is any one of the formulae shown in Table 12:

TABLE-US-00018 TABLE 12 [02170]embedded image 865202 [02171]embedded image 909218 [02172]embedded image 909219 [02173]embedded image 810453 [02174]embedded image 823726 [02175]embedded image 932637 [02176]embedded image 932638 [02177]embedded image 947411 [02178]embedded image 950325 [02179]embedded image 950332 [02180]embedded image 789009 [02181]embedded image 789011 [02182]embedded image 789331 [02183]embedded image 789333 [02184]embedded image 791262 [02185]embedded image 791263 [02186]embedded image 806607 [02187]embedded image 806611 [02188]embedded image 810484 [02189]embedded image 810485 [02190]embedded image 816872 [02191]embedded image 816874 [02192]embedded image 816876 [02193]embedded image 816877 [02194]embedded image 816880 [02195]embedded image 816882 [02196]embedded image 819570 [02197]embedded image 819571 [02198]embedded image 826654 [02199]embedded image 826655 [02200]embedded image 949754 [02201]embedded image 949759 [02202]embedded image 950164 [02203]embedded image 950165.

[0562] In some embodiments, Formula VI-A or VI-B is not any one of the formulae shown in Table 12.

[0563] In another aspect, provided herein is a compound of any one of the formulae shown in Table 13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;

TABLE-US-00019 TABLE 13 [02204]embedded image 816839 [02205]embedded image 792339 [02206]embedded image 791256 [02207]embedded image 806632 [02208]embedded image 801351 [02209]embedded image 819563 [02210]embedded image 810505 [02211]embedded image 819562 [02212]embedded image 874313 [02213]embedded image 801406 [02214]embedded image 786065 [02215]embedded image 884019 [02216]embedded image 786061 [02217]embedded image 862028 [02218]embedded image 883978 [02219]embedded image 874509 [02220]embedded image 913441 [02221]embedded image 786072 [02222]embedded image 790666 [02223]embedded image 897752 [02224]embedded image 826650 [02225]embedded image 816797 [02226]embedded image 816837 [02227]embedded image 811596 [02228]embedded image 874323 [02229]embedded image 789461 [02230]embedded image 810460 [02231]embedded image 930565 [02232]embedded image 790619 [02233]embedded image 806605 [02234]embedded image 789504 [02235]embedded image 789497 [02236]embedded image 810464 [02237]embedded image 772965 [02238]embedded image 806568 [02239]embedded image 801309 [02240]embedded image 816840 [02241]embedded image 945550 [02242]embedded image 810590 [02243]embedded image 810591 [02244]embedded image 784440 [02245]embedded image 945552 [02246]embedded image 801357 [02247]embedded image 789583 [02248]embedded image 801310 [02249]embedded image 789505 [02250]embedded image 947873 [02251]embedded image 790755 [02252]embedded image 810368 [02253]embedded image 785735 [02254]embedded image 810495 [02255]embedded image 801315 [02256]embedded image 801352 [02257]embedded image 806938 [02258]embedded image 874324 [02259]embedded image 789584 [02260]embedded image 841868 [02261]embedded image 816838 [02262]embedded image 789457 [02263]embedded image 828845 [02264]embedded image 785739 [02265]embedded image 810377 [02266]embedded image 811595 [02267]embedded image 789337 [02268]embedded image 782425 [02269]embedded image 789460 [02270]embedded image 856949 [02271]embedded image 789524 [02272]embedded image 789330 [02273]embedded image 782424 [02274]embedded image 792341 [02275]embedded image 917226 [02276]embedded image 811555 [02277]embedded image 913219 [02278]embedded image 806633 [02279]embedded image 790615 [02280]embedded image 874511 [02281]embedded image 791257 [02282]embedded image 792338 [02283]embedded image 819573 [02284]embedded image 930566 [02285]embedded image 810376 [02286]embedded image 806603 [02287]embedded image 785737 [02288]embedded image 816795 [02289]embedded image 789562 [02290]embedded image 913136 [02291]embedded image 801356 [02292]embedded image 790745 [02293]embedded image 816798 [02294]embedded image 789336 [02295]embedded image 801358 [02296]embedded image 801321 [02297]embedded image 811556 [02298]embedded image 945549 [02299]embedded image 883866 [02300]embedded image 790612 [02301]embedded image 792343 [02302]embedded image 945551 [02303]embedded image 789459 [02304]embedded image 945548 [02305]embedded image 806569 [02306]embedded image 785762 [02307]embedded image 810367 [02308]embedded image 802358 [02309]embedded image 789564 [02310]embedded image 806939 [02311]embedded image 947868 [02312]embedded image 790617 [02313]embedded image 790754 [02314]embedded image 789566 [02315]embedded image 810466 [02316]embedded image 874510 [02317]embedded image 801311 [02318]embedded image 801314 [02319]embedded image 792340 [02320]embedded image 801308 [02321]embedded image 945547

[0564] In another aspect, provided herein is a compound of any one of the formulae shown in Table 13A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof:

TABLE-US-00020 TABLE 13A [02322]embedded image 117093, [02323]embedded image 119047, [02324]embedded image 119048, [02325]embedded image 125978, [02326]embedded image 125979, [02327]embedded image 127429 [02328]embedded image 127430.

[0565] In another aspect, provided herein is a compound of any one of the formulae shown in Table 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof:

TABLE-US-00021 TABLE 14 [02329]embedded image 913137 [02330]embedded image 790632 [02331]embedded image 790611 [02332]embedded image 789458 [02333]embedded image 789563 [02334]embedded image 790616 [02335]embedded image 819572 [02336]embedded image 856948 [02337]embedded image 841866 [02338]embedded image 877294 [02339]embedded image 884020 [02340]embedded image 889570 [02341]embedded image 877288 [02342]embedded image 806940 [02343]embedded image 811512 [02344]embedded image 913355

[0566] In another aspect, provided herein is a compound of the formula:

##STR02345##

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

[0567] A compound of the present disclosure or a compound provided herein refers to a compound of Formula I-A, I-B, II-A, II-B, III-A, III-B, IV-A, IV-B, V-A, V-B, VI-A, or VI-B, or shown in Table 13, Table 13A, or Table 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0568] In some embodiments, a compound of the present disclosure is a compound of Formula I-A or I-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula I-A or I-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula I-A or I-B, or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, a compound of the present disclosure is a compound of Formula II-A or II-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula II-A or II-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula II-A or II-B, or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, a compound of the present disclosure is a compound of Formula III-A or III-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula III-A or III-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula III-A or III-B, or a pharmaceutically acceptable salt thereof.

[0571] In some embodiments, a compound of the present disclosure is a compound of Formula IV-A or IV-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula IV-A or IV-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula IV-A or IV-B, or a pharmaceutically acceptable salt thereof.

[0572] In some embodiments, a compound of the present disclosure is a compound of Formula V-A or V-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula V-A or V-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula V-A or V-B, or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, a compound of the present disclosure is a compound of Formula VI-A or VI-B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula VI-A or VI-B, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound of Formula VI-A or VI-B, or a pharmaceutically acceptable salt thereof.

[0574] In some embodiments, a compound of the present disclosure is a compound shown in Table 13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 13, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 13, or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, a compound of the present disclosure is a compound shown in Table 13A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 13A, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 13A, or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, a compound of the present disclosure is a compound shown in Table 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 14, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, a compound of the present disclosure is a compound shown in Table 14, or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions, Kits, and Administration

[0577] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound provided herein and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents.

[0578] Pharmaceutical compositions can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the active ingredient) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0579] In some embodiments, pharmaceutical compositions are prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A unit dose is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0580] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0581] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition.

[0582] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0583] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0584] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0585] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0586] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0587] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0588] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0589] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0590] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0591] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0592] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0593] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0594] Exemplary natural oils include almond, apricot kernal, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0595] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0596] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0597] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0598] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, in some embodiments, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0599] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0600] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0601] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0602] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0603] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0604] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0605] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

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

[0606] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0607] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0608] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, May have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0609] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0610] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0611] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0612] In some embodiments, the compounds and compositions provided herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0613] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. In some embodiments, an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any 22 dose of multiple doses) described herein includes independently between 0.1 g and 1 g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0614] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art. In some embodiments, the amount to be administered to, for example, a child or an adolescent is lower or the same as that administered to an adult.

[0615] In some embodiments, a compound or composition, as described herein, is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). In some embodiments, the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity and/or production of a GSK3 in a subject, cell, tissue, or biological sample), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, cell, tissue, or biological sample. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0616] In some embodiments, the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents. In some embodiments, the one or more additional pharmaceutical agents are useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease. In some embodiments, each additional pharmaceutical agent is administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0617] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein are administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0618] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs) comprising a compound or pharmaceutical composition provided herein; and instructions for using the compound or pharmaceutical composition provided herein. In some embodiments, the kit comprises a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0619] In certain embodiments, the kit includes a first container comprising a compound or pharmaceutical composition provided herein. In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) and/or production of a GSK3 in a subject, cell, tissue, or biological sample.

[0620] In certain embodiments, a kit provided herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) and/or production of a GSK3 in a subject, cell, or tissue. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Methods of Treatment and Uses

[0621] Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for many diseases, however the development of small molecule inhibitors has been hindered by significant safety concerns related to -catenin activation and the lack of structural information for the GSK3 paralog.

[0622] Originally identified as a protein kinase involved in the regulation of glycogen metabolism, GSK3 is now known to be a multi-functional protein with key roles in diverse biological processes including cell proliferation, differentiation, apoptosis, embryonic development, and insulin response (Cole A R, 2012; Racaud-Sultan C, Vergnolle N, 2021; Henriksen E J and Dokken B B, 2006). In addition, GSK3 is also of considerable interest as a therapeutic target because of its involvement in core pathophysiologies underlying multiple diseases including Alzheimer's Disease (AD), Fragile X Syndrome, diabetes, and several types of cancer (Bhat R V et al . . . , 2004; Beurel et al . . . , 2015; O'Leary O and Nolan Y, 2015; McCubrey J A et al . . . , 2014).

[0623] GSK3 has been of particular focus in AD because preclinical data demonstrates that modulation of this kinase has beneficial effects on both hallmark pathological processes in AD: hyperphosphorylation of tau protein and production of amyloid-beta peptides (Phiel, C J et al . . . , 2003; Plattner, F et al., 2006; Ly, P et al . . . , 2013). Based on the therapeutic potential of targeting GSK3 in AD, several GSK3 inhibitors have advanced into clinical trials (Georgievska B et al . . . , 2013; del Ser T et al . . . , 2013), but these compounds have had limited clinical success due to lack of efficacy and/or significant safety concerns. Safety concerns around GSK3 stem from evidence demonstrating a key role for this kinase in regulating the Wnt--catenin pathway (Behrens J et al . . . , 1998) and multiple reports have demonstrated that long-term inhibition of GSK3 can induce aberrant proliferation and hyperplasia in several tissues in vivo (Meijer et al., 2004; Sato N et al . . . , 2004; Coghlan et al . . . , 2000; Bhat R et al . . . , 2003).

[0624] GSK3 exists as two paralogs, GSK3 and GSK3, which are encoded from separate genes and are thought to have arisen evolutionarily through gene duplication. The GSK3 paralogs are similar in sequence with 95% identity in the ATP binding site (67% amino acid identity overall) and exhibit a high degree of overlap in both tissue expression patterns and in their phosphorylation substrates (Woodgett, J R 1991; Yao H B et al., 2002; Soutar et al . . . , 2010; Kaidanovich-Beilin O, Woodgett J R 2011). Interestingly, recent studies have highlighted distinct functional roles for GSK3 in several biological processes (Beurel et al . . . , 2015). Notably, loss of GSK3 causes embryonic lethality in mice whereas loss of GSK3 results in relatively modest defects (Kim, W Y et al . . . , 2009; Morgansmith, M et al . . . , 2014). In the context of AD, most of the focus has traditionally been on GSK3 (Hooper C et al . . . , 2008). However, in a study using a mouse model that combines amyloid and tau pathologies, Hurtado et al. (2012) reported that knockdown of either GSK or GSK3 ameliorated tau hyper-phosphorylation, yet only knockdown of GSK3 additionally reduced amyloid pathology. More recently, selective loss or inhibition of GSK3, but not GSK3, has been shown to rescue deficits in a mouse model of Fragile x (McCamphill P K et al . . . , 2020) and suppress tumorigenesis in models of acute myeloid leukemia (Wang Y et al . . . , 2019). With respect to safety risks, studies have shown that selective reduction or ablation of either GSK3 paralog circumvents -catenin stabilization (Doble B W et al . . . , 2007) and that selective genetic suppression of GSK impairs leukemia progression in mouse models of AML without increasing -catenin levels (Banerji V et al . . . , 2012).

[0625] The challenge in discovery of selective GSK3 inhibitors is predominantly due to the high degree of homology in the ATP binding site where the primary difference is an Asp to Glu switch located in the hinge region (Wagner F F et al . . . , 2018). This difference is further complicated by the positioning of corresponding amino acid side chains located outside of the ATP binding site and therefore directed away from potential interactions with ATP competitive inhibitors. Previously a series of oxadiazole inhibitors were identified that were able to achieve 3-fold GSK3 selectivity for the - paralog (Lo Monte et al., 2013) and there have also been reports of imide-based (Palomo V et al . . . , 2012) and thioxoimidazolidine kinase inhibitors that exhibit paralog selectivity up to 7-fold (Wang Y et al . . . , 2019). Interestingly, a series of aminopyrazole inhibitors with up to 8-fold selectivity were recently reported by Wagner et al.. (2018) and their development was based on the crystal structure of a GSK3 D133E mutant thought to mimic key differences between the two paralogs within the ATP binding site. Further results from this study also identified differential hydrogen bonding networks outside of the hinge Asp/Glu switch.

[0626] A compound useful in a provided method is: [0627] a compound provided herein; or [0628] a compound of the formula:

##STR02346##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, [0629] each instance of the atoms marked with * is independently optionally substituted; [0630] custom-character is a single or double bond; [0631] R.sup.13 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, OR.sup.B, SCN, SR.sup.B, SSR.sup.B, N.sub.3, NO, N(R.sup.B).sub.2, NO.sub.2, C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, C(O)N(R.sup.B).sub.2, C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, C(NR.sup.B)N(R.sup.B).sub.2, S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, S(O).sub.2N(R.sup.B).sub.2, OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.BOC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, ON(R.sup.B).sub.2, SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, SC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, NR.sup.BS(O).sub.2N(R.sup.B).sub.2, Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3; [0632] each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and [0633] each instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0634] In some embodiments, custom-character is a single bond. In some embodiments, custom-character is a double bond.

[0635] In some embodiments, R.sup.13 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, OR.sup.B, SR.sup.B, or N(R.sup.B).sub.2. In some embodiments, R.sup.13 is optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, or optionally substituted C.sub.1-10 heteroalkynyl. In some embodiments, R.sup.13 is Cie haloalkyl. In some embodiments, R.sup.13 is C.sub.1-4 haloalkyl. In some embodiments, R.sup.13 is C.sub.1-4 fluoroalkyl (e.g., C.sub.1-4 perfluoroalkyl). In some embodiments, R.sup.13 is CF.sub.3. In some embodiments, R.sup.13 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or halogen. In some embodiments, R.sup.13 is hydrogen, fluorine, CH.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3. In some embodiments, R.sup.13 is hydrogen, fluorine, CH.sub.3, or CF.sub.3. In some embodiments, R.sup.13 is hydrogen or halogen. In some embodiments, R.sup.13 is hydrogen or fluorine. In some embodiments, R.sup.13 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.13 is hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-6 haloalkyl. In some embodiments, R.sup.13 is hydrogen.

[0636] In some embodiments, R.sup.13 is halogen. In some embodiments, R.sup.13 is bromine, chlorine, or fluorine. In some embodiments, R.sup.13 is bromine or chlorine. In some embodiments, R.sup.13 is chlorine or fluorine. In some embodiments, R.sup.13 is bromine. In some embodiments, R.sup.13 is chlorine. In some embodiments, R.sup.13 is fluorine.

[0637] In some embodiments, R.sup.13 is OR.sup.B, SR.sup.B, or N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is OH. In some embodiments, R.sup.13 is SH. In some embodiments, R.sup.13 is NH.sub.2. In some embodiments, R.sup.13 is CN, SCN, SSR.sup.B, N.sub.3, NO, or NO.sub.2. In some embodiments, R.sup.13 is C(O)R.sup.B, C(O)OR.sup.B, C(O)SR.sup.B, or C(O)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is C(NR.sup.B)R.sup.B, C(NR.sup.B)OR.sup.B, C(NR.sup.B)SR.sup.B, or C(NR.sup.B)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is S(O)R.sup.B, S(O)OR.sup.B, S(O)SR.sup.B, S(O)N(R.sup.B).sub.2, S(O).sub.2R.sup.B, S(O).sub.2OR.sup.B, S(O).sub.2SR.sup.B, or S(O).sub.2N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is OC(O)R.sup.B, OC(O)OR.sup.B, OC(O)SR.sup.B, OC(O)N(R.sup.B).sub.2, OC(NR.sup.B)R.sup.B, OC(NR.sup.B)OR.sup.B, OC(NR.sup.B)SR.sup.B, OC(NR.sup.B)N(R.sup.B).sub.2, OS(O)R.sup.B, OS(O)OR.sup.B, OS(O)SR.sup.B, OS(O)N(R.sup.B).sub.2, OS(O).sub.2R.sup.B, OS(O).sub.2OR.sup.B, OS(O).sub.2SR.sup.B, OS(O).sub.2N(R.sup.B).sub.2, or ON(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is SC(O)R.sup.B, SC(O)OR.sup.B, SC(O)SR.sup.B, SC(O)N(R.sup.B)).sub.2, SC(NR.sup.B)R.sup.B, SC(NR.sup.B)OR.sup.B, SC(NR.sup.B)SR.sup.B, or SC(NR.sup.B)N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is NR.sup.BC(O)R.sup.B, NR.sup.BC(O)OR.sup.B, NR.sup.BC(O)SR.sup.B, NR.sup.BC(O)N(R.sup.B).sub.2, NR.sup.BC(NR.sup.B)R.sup.B, NR.sup.BC(NR.sup.B)OR.sup.B, NR.sup.BC(NR.sup.B)SR.sup.B, NR.sup.BC(NR.sup.B)N(R.sup.B).sub.2, NR.sup.BS(O)R.sup.B, NR.sup.BS(O)OR.sup.B, NR.sup.BS(O)SR.sup.B, NR.sup.BS(O)N(R.sup.B).sub.2, NR.sup.BS(O).sub.2R.sup.B, NR.sup.BS(O).sub.2OR.sup.B, NR.sup.BS(O).sub.2SR.sup.B, or NR.sup.BS(O).sub.2N(R.sup.B).sub.2 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R.sup.13 is Si(R.sup.B).sub.3, Si(R.sup.B).sub.2OR.sup.B, Si(R.sup.B)(OR.sup.B).sub.2, Si(OR.sup.B).sub.3, OSi(R.sup.B).sub.3, OSi(R.sup.B).sub.2OR.sup.B, OSi(R.sup.B)(OR.sup.B).sub.2, or OSi(OR.sup.B).sub.3 (e.g., wherein R.sup.B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0638] In some embodiments, R.sup.13 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.13 is optionally substituted C.sub.3-14 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.3-7 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.3-4 carbocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic C.sub.5-7 carbocyclyl. In some embodiments, R.sup.13 is saturated carbocyclyl. In some embodiments, R.sup.13 is carbocyclyl comprising only one unsaturated bond (e.g., CC bond) in the carbocyclic ring system.

[0639] In some embodiments, R.sup.13 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R.sup.13 is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R.sup.13 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.13 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R.sup.13 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R.sup.13 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R.sup.13 is saturated heterocyclyl. In some embodiments, R.sup.13 is heterocyclyl comprising only one unsaturated bond (e.g., CC bond) in the heterocyclic ring system.

[0640] In some embodiments, R.sup.13 is optionally substituted monocyclic aryl. In some embodiments, R.sup.13 is optionally substituted bicyclic aryl. In some embodiments, R.sup.13 is optionally substituted C.sub.6-14 aryl. In some embodiments, R.sup.13 is optionally substituted C.sub.6-10 aryl. In some embodiments, R.sup.13 is optionally substituted phenyl. In some embodiments, R.sup.13 is optionally substituted naphthyl.

[0641] In some embodiments, R.sup.13 is optionally substituted monocyclic heteroaryl. In some embodiments, R.sup.13 is optionally substituted bicyclic heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.13 is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0642] In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R.sup.B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.3-14 carbocyclyl, or optionally substituted C.sub.6-14 aryl. In some embodiments, at least one instance of R.sup.B is independently hydrogen, optionally substituted C.sub.1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R.sup.B is 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. In some embodiments, two instances of R.sup.E attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0643] In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R.sup.14a, R.sup.14b, R.sup.17a, and R.sup.17b is independently hydrogen, halogen, or optionally substituted C.sub.1-4 alkyl.

[0644] In some embodiments, each of R.sup.14a and R.sup.14b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.14a and R.sup.14b is independently hydrogen, halogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted Cujo heteroalkenyl, optionally substituted C.sub.1-10 heteroalkynyl, optionally substituted C.sub.3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C.sub.6-14 aryl, or optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one of R.sup.14a and R.sup.14b is hydrogen.

[0645] In some embodiments, each of R.sup.17a and R.sup.17b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each of R.sup.17a and R.sup.17b is independently hydrogen, halogen, optionally substituted C.sub.1-10 alkyl, optionally substituted C.sub.1-10 alkenyl, optionally substituted C.sub.1-10 alkynyl, optionally substituted C.sub.1-10 heteroalkyl, optionally substituted C.sub.1-10 heteroalkenyl, optionally substituted C.sub.1-10 heteroalkynyl, optionally substituted C.sub.3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C.sub.6-14 aryl, or optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one of R.sup.17a and R.sup.17b is hydrogen.

[0646] Compounds useful in a provided method and pharmaceutical compositions provided herein may be useful for the inhibition of a GSK3. Without being bound by any particular theory, the compounds useful in a provided method and the pharmaceutical compositions provided herein being useful as described herein may be at least in part due to their inhibition of the activity and/or production of a GSK3. Compared to known GSK3 inhibitors, the compounds useful in a provided method and the pharmaceutical compositions provided herein may increase the potency, efficacy, and/or selectivity in inhibiting the activity and/or production of a GSK3 in a subject, cell, or tissue. Compared to known GSK3 inhibitors, the compounds useful in a provided method and the pharmaceutical compositions provided herein may increase bioavailability, safety, and/or therapeutic window, reduce toxicity and/or resistance, and/or increase subject compliance, in a subject. In certain embodiments, the compounds useful in a provided method are selective GSK3 inhibitors (e.g., GSK3 inhibitors that selectively inhibit a GSK3 over one or more other kinases). In certain embodiments, the compounds useful in a provided method are selective GSK3 inhibitors (e.g., GSK3 inhibitors that selectively inhibit GSK3 over GSK3 and optionally one or more other kinases). In certain embodiments, the compounds useful in a provided method are selective GSK3 inhibitors (e.g., GSK3 inhibitors that selectively inhibit GSK3 over GSK3 and optionally one or more other kinases).

[0647] In some embodiments, the GSK3 is glycogen synthase kinase 3 (GSK3). In some embodiments, the compound provided herein is more selective for inhibiting the activity and/or production of GSK3 than glycogen synthase kinase 3 (GSK3) in an in vitro assay. In some embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is determined by the relative K.sub.d values for GSK3 and GSK. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is determined by the quotient of the IC.sub.50 value of the compound in inhibiting GSK38 over the IC.sub.50 value of the compound in inhibiting GSK3. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 1.1, at least 1.3, at least 1.5, at least 1.7, at least 2, at least 3, at least 4, at least 6, at least 8, at least 10, at least 12, at least 15, at least 17, at least 20, at least 30, at least 50, at least 100, at least 1,000, or at least 10,000. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 8. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 10. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 12. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 15. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 17. In certain embodiments, the selectivity of the compound provided herein for GSK30 over GSK3 is at least 20. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 30. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 50. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 100. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is between 10 and 1,000, inclusive.

[0648] In some embodiments, the GSK3 is glycogen synthase kinase 3 (GSK3). In some embodiments, the compound provided herein is more selective for inhibiting the activity and/or production of GSK3 than glycogen synthase kinase 3 (GSK3) in an in vitro assay. In some embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is determined by the relative K.sub.d values for GSK3 and GSK. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is determined by the quotient of the IC.sub.50 value of the compound in inhibiting GSK3 over the IC.sub.50 value of the compound in inhibiting GSK3. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 1.1, at least 1.3, at least 1.5, at least 1.7, at least 2, at least 3, at least 4, at least 6, at least 8, at least 10, at least 12, at least 15, at least 17, at least 20, at least 30, at least 50, at least 100, at least 1,000, or at least 10,000. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 8. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 10. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 12. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 15. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 17. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 20. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 30. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 50. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is at least 100. In certain embodiments, the selectivity of the compound provided herein for GSK3 over GSK3 is between 10 and 1,000, inclusive.

[0649] In another aspect, provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein. In another aspect, provided herein is a use a compound useful in a provided method or pharmaceutical composition provided herein for the manufacture of a medicament for treating a disease in a subject in need thereof. In another aspect, provided herein is a compound useful in a provided method or pharmaceutical composition provided herein for use in treating a disease in a subject in need thereof.

[0650] In another aspect, provided herein is a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein. In another aspect, provided herein is a use of a compound useful in a provided method or pharmaceutical composition provided herein for the manufacture of a medicament for preventing a disease in a subject in need thereof. In another aspect, provided herein is a compound useful in a provided method or pharmaceutical composition provided herein for use in preventing a disease in a subject in need thereof.

[0651] In some embodiments the effective amount is further effective in inhibiting the activity and/or production of a GSK3. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a GSK3 in a subject, cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting the production of a GSK3 in a subject, cell, tissue, or biological sample.

[0652] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0653] In some embodiments, the term refers to a reduction of the level of production, e.g., GSK3 protein production, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of production. In some embodiments, the term refers to a reduction of the level of production, e.g., GSK3 protein production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of production.

[0654] In some embodiments, the disease is associated with aberrantly high activity and/or production of catenin beta-1. In some embodiments, the disease is associated with a mutation and/or overexpression of the CTNNB1 gene. In some embodiments, the disease is a mental or behavioral disease. In some embodiments, the disease is fragile X syndrome. In some embodiments, the disease is autism. In some embodiments, the disease is schizophrenia. In some embodiments, the disease is bipolar disorder. In some embodiments, the disease is attention deficit hyperactivity disorder. In some embodiments, the disease is a neurological disease. In some embodiments, the disease is seizure. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is Huntington's disease. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is amyotrophic lateral sclerosis. In some embodiments, the disease is a cancer. In some embodiments, the disease is a hematological malignancy. In some embodiments, the disease is leukemia. In some embodiments, the disease is acute myeloid leukemia. In some embodiments, the disease is acute lymphoblastic leukemia. In some embodiments, the disease is colon cancer. In some embodiments, the disease is pancreatic cancer. In some embodiments, the disease is a metabolic disease. in some embodiments, the disease is diabetes. In some embodiments, the disease is Type II diabetes. In some embodiments, the disease is obesity.

[0655] In another aspect, provided herein is a method of inhibiting the activity and/or production of a glycogen synthase kinase 3 (GSK3) in a subject in need thereof, the method comprising administering to the subject an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein.

[0656] In another aspect, provided herein is a method of inhibiting the activity and/or production of a glycogen synthase kinase 3 (GSK3) in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein.

[0657] In certain embodiments, the cell, tissue, or biological sample is in vitro. In certain embodiments, the cell, tissue, or biological sample is in vivo.

[0658] In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years and older. In some embodiments, the subject is a human aged <2 years. In some embodiments, the subject is a human aged 2-6 years, inclusive. In some embodiments, the subject is a human aged 6-18 years, inclusive. In some embodiments, the subject is a human aged 18-65 years, inclusive. In some embodiments, the subject is a human aged >65 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In some embodiments, the subject is a research animal.

EXAMPLES

[0659] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

General Methods of Preparing the Compounds Useful in a Provided Method

Example 1. Preparation of Vinylogous Amides

Protocol A:

##STR02347##

[0660] In Synthesis Protocol A (Scheme 1a), ketone (1.0 equivalent) and amine (1.0 equivalent) were dissolved in toluene (0.1-0.5 M). p-Toluenesulfonic acid (0.1 equivalent) was added, and the mixture was heated at 110 C. The reaction mixture was cooled, and toluene was evaporated. The crude reaction mixture was purified by column chromatography on silica to afford intermediate 1.

[0661] The resulting intermediate 1 (1.0 equivalent) was then dissolved in toluene and 1,3-diketone (1.0 equivalent) followed by p-toluenesulfonic acid (0.1 equivalent) were added. The mixture was heated at 110 C. for 30 minutes to afford the uncyclized intermediate 2 quantitatively. Toluene was evaporated to remove the water generated in the enamine formation reaction.

[0662] Fresh toluene was added and the mixture was heated at 110 C. After complete conversion of the uncyclized intermediate 2, toluene was evaporated and the crude mixture was purified by column chromatography on silica to afford the cyclized product.

Protocol B:

[0663] In Synthesis Protocol B, the uncyclized intermediate 2 was dissolved in toluene, and trifluoroacetic acid (1.0 equivalent) was added. The mixture was heated at 110 C. After complete conversion of the uncyclized intermediate, volatiles were evaporated, and the crude mixture was purified by column chromatography on silica to afford the cyclized product.

Protocol C:

[0664] In Synthesis Protocol C, the uncyclized intermediate 2 was dissolved in trifluoroacetic acid (0.5M), and the mixture was heated at 73 C. After complete conversion of the uncyclized intermediate, volatiles were evaporated, and the crude mixture was purified by column chromatography on silica to afford the cyclized product.

Protocol D:

[0665] In Synthesis Protocol D, the uncyclized intermediate 2 was dissolved in trifluoroacetic acid (0.5M), and the mixture was heated at 140 C. in the microwave. After complete conversion of the uncyclized intermediate, volatiles were evaporated, and the crude mixture was purified by column chromatography on silica to afford the cyclized product.

Example 2. Preparation of Compound 913006

##STR02348##

(E)-4-(1-(3-(trifluoromethyl)phenyl) prop-1-en-1-yl)-1H-pyrazol-3-amine (Intermediate 3)

[0666] 1-(3-(trifluoromethyl)phenyl) propan-1-one (25.0 g, 1 Eq. 123.7 mmol) and 1H-pyrazol-3-amine (10.3 g, 1 Eq, 124 mmol) were suspended in toluene (400 mL). p-Toluenesulfonic acid monohydrate (2.35 g, 0.1 Eq. 12.4 mmol) was added, and the mixture was stirred for two days under Dean-Stark conditions. After .sup.1H-NMR showed full conversion, the mixture was cooled to room temperature and concentrated in vacuo to give 36.8 g (quantitative) of a brown oil (Intermediate 3) that was used as such in the next step. 4-ethyl-7,7-dimethyl-4-(3-(trifluoromethyl)phenyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b][1,6]naphthyridin-5-one (TBME-adduct) (913006)

[0667] The reaction was carried out in 4 identical batches, which were combined after the reaction.

[0668] (E)-4-(1-(3-(trifluoromethyl)phenyl) prop-1-en-1-yl)-1H-pyrazol-3-amine (Intermediate 3) (33.1 g, 1 Eq, 124 mmol) and 6,6-dimethylpiperidine-2,4-dione (17.5 g, 1 Eq, 124 mmol) were dissolved in TFA (254 g, 172 mL, 18 Eq, 2.23 mol). The mixture was stirred at 110 C. in a pressure tube in a sand bath for 4 days.

[0669] After .sup.1H-NMR showed almost full conversion towards the product, the mixture was cooled to room temperature. The mixture was concentrated in vacuo. The mixture was basified with 2N NaOH (aq.) The formed solids were filtered off and washed with H.sub.2O and TBME and dried in vacuo. The product was obtained as a light yellow solid (10.6 g). The filtrate was concentrated in vacuo. The solids were filtered off and washed with TBME to give a second crop (5.73 g). The two crops were combined and dried in vacuo to give 14.9 g (31%) of 3.

Example 3. Preparation of Compound 826648

##STR02349##

[0670] 7,7-dimethyl-2,2,3,5,6,7,8,9-octahydrospiro[pyran-4,4-pyrazolo[3,4-b]quinolin]-5 (6H)-one (826648). A solution of 5,5-dimethylcyclohexane-1,3-dione (506 mg, 3.61 mmol, 1 eq.), tetrahydro-4H-pyran-4-one (361 mg, 3.61 mmol, 1 eq.), and 1H-pyrazol-3-amine (300 mg, 3.61 mmol, 1 eq.) in ethanol (5.0 mL) was stirred at 80 C. for 18 h in a sealed tube. A suspension was formed, and the reaction mixture was filtered. The collected filter cake was washed with EtOAc (2 mL) and PE (20 mL) to provide 826648 (322 mg, 31% yield) as a white solid. LCMS: 288.0 [M+H].sup.+.

Example 4. Preparation of Fluorinated Compounds

[0671] Intermediates were synthesized according to the following scheme.

##STR02350##

Preparation of 4-(1-(3-bromophenyl) prop-1-en-1-yl)-1H-pyrazol-3-amine (mixture of E/Z isomers)

[0672] 1H-pyrazol-3-amine (3.50 g, 42.1 mmol), 1-(3-bromophenyl) propan-1-one (8.98 g, 42.1 mmol) and 4-methylbenzenesulfonic acid hydrate (801 mg, 4.21 mmol) were combined then toluene (50.0 mL) was added. The mixture was stirred at 125 C. for 18 hours under N.sub.2 atmosphere. The mixture was then concentrated and the residue was purified by flash chromatography (CH.sub.2Cl.sub.2:MeOH=100:0 to 99:1 to 98:2) to supply 4-(1-(3-bromophenyl) prop-1-en-1-yl)-1H-pyrazol-3-amine (10.0 g, 35.95 mmol, 85% yield, 98% purity) as a mixture of isomers and as a pale-yellow solid. LCMS m/z=279.9 (M+H)+.

Preparation of 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one

[0673] 4-(1-(3-bromophenyl) prop-1-en-1-yl)-1H-pyrazol-3-amine (10.0 g, 35.95 mmol) and 5,5-dimethylcyclohexane-1,3-dione (5.04 g, 35.95 mmol) were dissolved in trifluoroethanol (71.9 mL) and TFA (4.10 g, 35.95 mmol, 2.75 mL) was then added. The mixture was split into four microwave vials. The vials were then heated to 150 C. in a microwave for 1.5 hours then cooled to room temperature. The samples were combined and the mixture was concentrated and purified by column chromatography (5-50% EtOAc/EtOH:Heptanes) to provide 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (4.11 g, 10.27 mmol, 29% yield). LCMS m/z=402.1 (M+H)+.

Preparation of 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one

[0674] A solution of 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (4.40 g, 10.99 mmol) in THF (110 mL) was cooled to 0 C. and sodium hydride (923 mg, 38.5 mmol, 60% in mineral oil) was added portionwise. After the addition, the mixture was stirred at 0 C. for 1 hour. SEM-chloride (7.33 g, 43.96 mmol, 7.80 mL) was then added dropwise and the resulting mixture was stirred at 0 C. for 2 hour then warmed to room temperature and stirred overnight. The mixture was poured into 50 mL of ice-water slowly, then extracted with EtOAc (30 mL2). The combined organic layers were dried over MgSO.sub.4 and concentrated. The residue was purified by column chromatography (5-20% EtOAc in heptane) to supply 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (5.40 g, 8.17 mmol, 74% yield) as pale-yellow gum. LCMS m/z=662.3 (M+H)+.

Preparation of 4-(3-bromophenyl)-4-ethyl-8-fluoro-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one

[0675] 4-(3-bromophenyl)-4-ethyl-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (1.52 g, 2.30 mmol) was dissolved in THF (23.0 mL) and cooled in a dry ice-acetone bath to 78 C. [bis(trimethylsilyl)amino]lithium (1 M in toluene, 2.19 mL) was then added and the mixture was stirred for 30 minutes then warmed to 0 C. and stirred for an additional 30 minutes. The mixture was then cooled to 78 C. and NFSI (798 mg, 2.53 mmol) was added. The mixture was allowed to warm to room temperature overnight. The mixture was then quenched upon addition of water and saturated, aqueous NH.sub.4Cl. The mixture was then extracted with ethyl acetate (50 mL3) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was then purified by column chromatography (5 to 25% EtOAc in heptanes) to provide 4-(3-bromophenyl)-4-ethyl-8-fluoro-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (1.15 g, 1.69 mmol, 74% yield) as a mixture of diastereomers. LCMS m/z=680.7 (M+H)+.

Preparation of 4-ethyl-8-fluoro-7,7-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-SH-pyrazolo[3,4-b]quinolin-5-one

[0676] 4-(3-bromophenyl)-4-ethyl-8-fluoro-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (297 mg, 437 mol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (144 mg, 568 mol), Pd (dppf) Cl.sub.2CH.sub.2Cl.sub.2 (17.9 mg, 21.85 mol) and KOAc (85.8 mg, 874 mol) were combined in a vial and dissolved in dioxane (2.19 mL). Nitrogen was bubbled through the solution for 5 min then the vial was sealed and stirred at 100 C. for 18 hours. The mixture was then concentrated and dissolved in EtOAc. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (5 to 60% EtOAc in heptanes) to afford 4-ethyl-8-fluoro-7,7-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (231 mg, 318 mol, 73% yield) as an orange oil. LCMS m/z=726.9 (M+H)+.

Preparation of 4-(3-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl)-4-ethyl-8-fluoro-7,7-dimethyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one

##STR02351##

[0677] 4-(3-bromophenyl)-4-ethyl-8-fluoro-7,7-dimethyl-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (200 mg, 295 mol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (131 mg, 589 mol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (12.5 mg, 14.7 mol), and potassium phosphate tribasic (125 mg, 589 mol) were added to a reaction vial. The vial was then sealed and degassed by evacuating and backfilling with nitrogen. Dioxane (786 uL) and water (393 uL) were then added and the mixture was stirred at 100 C. for 24 hours. The mixture was then cooled to room temperature, concentrated, and used directly in the next step.

[0678] The crude mixture of 4-[3-(1,3-dimethylpyrazol-4-yl)phenyl]-4-ethyl-7,7-dimethyl-2,9-bis(2-trimethylsilylethoxymethyl)-6,8-dihydropyrazolo[3,4-b]quinolin-5-one (204.5 mg, 302.5 mol) was dissolved in TFA (1.51 mL) and CH.sub.2Cl.sub.2 (4.54 mL) and stirred at room temperature for 3 hours under nitrogen. The mixture was then concentrated and purified by column chromatography (5-100% [3:1 EtOAc:EtOH] in heptanes). The residue obtained was then purified by chiral SFC (CHIRALPAK IB 30250 mm, 5 um, Method: 30% MeOH w/0.1% DEA in CO.sub.2 [flow rate: 100 mL/min, ABPR 120bar, MBPR 40 psi, column temp 40 deg C]) to provide four stereoisomers (Rt: Peak 1:2.36 min, Peak 2:2.63, Peak 3:2.89, Peak 4:3.31).

[0679] Peak 1 (947650): 11.3 mg (98.5% purity, 100% ee, 0.5 equiv Diethylamine solvate). LCMS m/z=434.6 (M+H)+. 1H NMR (500 MHZ, METHANOL-d4) ppm 7.57-7.64 (m, 1H), 7.39 (t, J=1.83 Hz, 1H), 7.18-7.31 (m, 2H), 7.11 (d, J=7.33 Hz, 1H), 7.02 (s, 1H), 5.13-5.26 (m, 1H), 3.84 (s, 3H), 3.06-3.14 (m, 1H), 3.03 (q, J=7.33 Hz, 2H), 2.35 (dd, J=16.79, 4.58 Hz, 1H), 2.25-2.29 (m, 3H), 2.03-2.18 (m, 2H), 1.30 (t. J=7.33 Hz, 3H), 1.12-1.20 (m, 6H), 0.80-0.86 (m, 3H).

[0680] Peak 2 (947651): 14.0 mg (95.9% purity, 94.7% ee). LCMS m/z=434.6 (M+H)+. 1H NMR (500 MHz, METHANOL-d4) ppm 7.61 (s, 1H), 7.37-7.48 (m, 1H), 7.27-7.34 (m, 1H), 7.24 (t, J=7.63 Hz, 1H), 7.10-7.15 (m, 1H), 7.01 (s, 1H), 5.01-5.25 (m, 1H), 3.84 (s, 3H), 2.97-3.11 (m, 1H), 2.18-2.33 (m, 5H), 2.08-2.17 (m, 1H), 1.20 (s, 3H), 1.14 (d, J=1.22 Hz, 3H), 0.81 (t, J=7.33 Hz, 3H).

[0681] Peak 3 (947652): 15.2 mg (96.7% purity, 84.3% ee). LCMS m/z=434.6 (M+H)+. 1H NMR (500 MHZ, METHANOL-d4) ppm 7.61 (s, 1H), 7.41 (t, J=1.83 Hz, 1H), 7.28-7.34 (m, 1H), 7.24 (t. J=7.63 Hz, 1H), 7.12 (dt, J=7.63, 1.37 Hz, 1H), 7.01 (s, 1H), 5.08-5.23 (m, 1H), 3.84 (s, 3H), 3.01-3.10 (m, 1H), 2.19-2.33 (m, 5H), 2.07-2.16 (m, 1H), 1.20 (s, 3H), 1.14 (d, J=1.22 Hz, 3H), 0.81 (t, J=7.33 Hz, 3H).

[0682] Peak 4 (947653): 9.7 mg (98.4% purity, 83.8% ee). LCMS m/z=434.6 (M+H)+. 1H NMR (500 MHz, METHANOL-d4) ppm 7.62 (s, 1H), 7.37-7.42 (m, 1H), 7.24-7.29 (m, 1H), 7.20-7.24 (m, 1H), 7.09-7.13 (m, 1H), 7.02 (s, 1H), 5.08-5.26 (m, 1H), 3.84 (s, 3H), 3.05-3.13 (m, 1H), 2.31-2.39 (m, 1H), 2.28 (s, 3H), 2.06-2.18 (m, 2H), 1.10-1.19 (m, 6H), 0.83 (t, J=7.33 Hz, 3H).

Preparation of 4-ethyl-8-fluoro-4-(3-(3-fluoro-5-methoxypyridin-4-yl)phenyl)-7,7-dimethyl-2,4,6,7,8,9-hexahydro-SH-pyrazolo[3,4-b]quinolin-5-one

##STR02352##

[0683] 4-ethyl-8-fluoro-7,7-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,9-bis((2-(trimethylsilyl) ethoxy)methyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (231 mg, 318 mol), 4-bromo-3-fluoro-5-methoxy-pyridine (65.5 mg, 318 mol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13.5 mg, 15.9 mol), and potassium phosphate tribasic (135 mg, 636 mol) were added to a reaction vial. The vial was then sealed and degassed by evacuating and backfilling with nitrogen. Dioxane (848 uL) and water (424 uL) were then added and the mixture was stirred at 100 C. for 24 hours. The mixture was then cooled to room temperature, concentrated, and used directly in the next step. LCMS m/z=725.8 (M+H)+.

[0684] 4-ethyl-8-fluoro-4-[3-(3-fluoro-5-methoxy-4-pyridyl)phenyl]-7,7-dimethyl-2,9-bis(2-trimethylsilylethoxymethyl)-6,8-dihydropyrazolo[3,4-b]quinolin-5-one (230 mg, 317 mol) was dissolved in TFA (1.50 mL) and CH.sub.2Cl.sub.2 (4.50 mL) and stirred at room temperature for 3 hours under nitrogen. The mixture was then concentrated and purified by column chromatography (5-100% [3:1 EtOAc:EtOH] in heptanes). The residue obtained was then purified by chiral SFC (CHIRALPAK IB 30250 mm, 5 um, Method: 30% MeOH w/0.1% DEA in CO.sub.2 [flow rate: 100 mL/min, ABPR 120bar, MBPR 40 psi, column temp 40 deg C]) to provide four stereoisomers (Rt: Peak 1:2.44 min, Peak 2:2.91, Peak 3:3.30, Peak 4:4.04).

[0685] Peak 1 (948545): 9.8 mg (95.7% purity, 100% ee). LCMS m/z=465.5 (M+H)+, 1H NMR (500 MHZ, METHANOL-d4) ppm 8.22 (s, 1H), 8.17 (s, 1H), 7.46 (d, J=8.55 Hz, 1H), 7.39 (s, 1H), 7.31 (t, J=7.94 Hz, 1H), 7.14 (d, J=6.71 Hz, 1H), 7.01 (s, 1H), 5.09-5.22 (m, 1H), 3.85 (s, 3H), 3.00-3.09 (m, 2H), 2.34 (dd, J=16.48, 4.88 Hz, 1H), 2.14 (d, J=16.48 Hz, 1H), 2.06-2.11 (m, 1H), 1.15 (d, J=8.55 Hz, 6H), 0.81 (t, J=7.33 Hz, 3H).

[0686] Peak 2 (948546): 13.1 mg (98% purity, 97.8% ee). LCMS m/z=465.6 (M+H)+. 1H NMR (500 MHz, METHANOL-d4) ppm 8.24 (s, 1H), 8.19 (s, 1H), 7.49 (d, J=7.94 Hz, 1H), 7.43 (d, J=1.83 Hz, 1H), 7.33 (t, J=7.63 Hz, 1H), 7.14-7.19 (m, 1H), 7.02 (s, 1H), 5.11-5.25 (m, 1H), 3.85-3.91 (m, 3H), 2.98-3.09 (m, 1H), 2.21-2.34 (m, 2H), 2.06-2.15 (m, 1H), 1.20 (s, 3H), 1.13 (d, J=1.22 Hz, 3H), 0.81 (t, J=7.33 Hz, 3H).

[0687] Peak 3 (948547): 13.3 mg (96.8% purity, 95.1% ee). LCMS m/z=465.6 (M+H)+1H NMR (500 MHz, METHANOL-d4) ppm 8.22 (s, 1H), 8.18 (s, 1H), 7.48 (d, J=9.16 Hz, 1H), 7.42 (s, 1H), 7.32 (t, J=7.63 Hz, 1H), 7.15 (d, J=6.71 Hz, 1H), 7.00 (s, 1H), 5.09-5.23 (m, 1H), 3.86 (s, 3H), 3.02 (dd, J=12.82, 7.33 Hz, 1H), 2.18-2.31 (m, 2H), 2.09 (dd, J=12.82, 6.71 Hz, 1H), 1.18 (s, 3H), 1.11 (d, J=1.22 Hz, 3H), 0.79 (t, J=7.33 Hz, 3H).

[0688] Peak 4 (948548): 8.7 mg (97% purity, 100% ee). LCMS m/z=465.6 (M+H)+. 1H NMR (500 MHZ, METHANOL-d4) ppm 8.21 (s, 1H), 8.17 (s, 1H), 7.46 (d, J=8.55 Hz, 1H), 7.39 (s, 1H), 7.31 (t, J=7.63 Hz, 1H), 7.14 (d, J=7.33 Hz, 1H), 7.01 (s, 1H), 5.08-5.25 (m, 1H), 3.85 (s, 3H), 3.04 (dd, J=12.51, 7.63 Hz, 1H), 2.34 (dd, J=16.79, 4.58 Hz, 1H), 2.14 (d, J=17.09 Hz, 1H), 2.09 (dd, J=12.82, 7.33 Hz, 1H), 1.15 (d, J=9.77 Hz, 6H), 0.81 (t, J=7.33 Hz, 3H).

Preparation of 4-ethyl-8-fluoro-7,7-dimethyl-4-(3-(trifluoromethyl)phenyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one

##STR02353##

[0689] Step 1: 1H-pyrazol-3-amine (164 mg, 1.98 mmol), 1-[3-(trifluoromethyl)phenyl]propan-1-one (400 mg, 1.98 mmol, 333 uL), and pTSA (37.7 mg, 198 mol) were combined then toluene (4.00 mL) was added and the mixture was heated to 110 C. for 16 hours. The reaction was then cooled to room temperature and concentrated and the crude residue was purified by column chromatography (0 to 30% MeOH in CH.sub.2Cl.sub.2) to give 4-[1-[3-(trifluoromethyl)phenyl]prop-1-enyl]-1H-pyrazol-3-amine (510 mg, 1.91 mmol, 96.4% yield). LCMS: Rt=1.25 min, m/z 268.1.

[0690] Step 2:4-fluoro-5,5-dimethyl-cyclohexane-1,3-dione (79.9 mg, 505 mol) and 4-[(E)-1-[3-(trifluoromethyl)phenyl]prop-1-enyl]-1H-pyrazol-3-amine (135 mg, 505 mol) were combined and dissolved in TFA (1.00 mL) and the mixture was heated to 110 C. for 4 hours. The mixture was then cooled to room temperature and concentrated. The crude residue was purified with preporatory HPLC to give 4-ethyl-8-fluoro-7,7-dimethyl-4-[3-(trifluoromethyl)phenyl]-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one (37.0 mg, 90.8 mol, 18% yield) as a mixture of isomers. LCMS: Rt=1.59 min, m/z 408.2.

[0691] The mixture of isomers was then purified by chiral SFC (CHIRALPAK IB 30250 mm, 5 um, Method: 30% Methanol with 0.1% diethyl amine in CO.sub.2 [flow rate: 100 mL/min, ABPR 120bar, MBPR 40 psi]) to provide four stereoisomers (Rt: Peak 1:2.22 min, Peak 2:2.63, Peak 3: 3.05, Peak 4:3.41).

[0692] Peak 1 (837646): 40.4 mg (95% purity, 100% ee). LCMS: Rt=1.76 min, m/z 408.2. 1H NMR (400 MHZ, CHLOROFORM-d) 7.46-7.71 (m, 2H), 7.30-7.44 (m, 2H), 6.85 (s, 1H), 4.16-4.49 (m, 1H), 3.11 (dd, J=7.53, 12.80 Hz, 1H), 2.36-2.61 (m, 2H), 1.84-2.18 (m, 1H), 1.20 (s, 3H), 1.17 (s, 3H), 0.82 (t, J=7.28 Hz, 3H).

[0693] Peak 2 (837683): 28.2 mg (95% purity, 100% ee). LCMS: Rt=1.73 min, m/z 408.2. 1H NMR (400 MHZ, CHLOROFORM-d) 7.60 (s, 2H), 7.36 (br. s., 2H), 6.90 (s, 1H), 4.26-4.56 (m, 1H), 2.93-3.16 (m, 1H), 2.41-2.59 (m, 2H), 1.95-2.14 (m, 1H), 1.23 (s, 3H), 1.08 (s, 3H), 0.77 (t, J=7.40 Hz, 3H).

[0694] Peak 3 (837753): 13.3 mg (95% purity, 100% ee). LCMS: Rt=1.73 min, m/z 408.2. 1H NMR (400 MHZ, CHLOROFORM-d) 7.60 (s, 2H), 7.36 (br. s., 2H), 6.90 (s, 1H), 4.31-4.61 (m, 1H), 2.95-3.14 (m, 1H), 2.35-2.59 (m, 2H), 1.90-2.19 (m, 1H), 1.23 (s, 3H), 1.08 (s, 3H), 0.77 (t, J=7.28 Hz, 3H).

[0695] Peak 4 (837803): 16.9 mg (95% purity, 100% ee). LCMS: Rt=1.75 min, m/z 408.2. 1H NMR (400 MHZ, CHLOROFORM-d) 7.60 (s, 2H), 7.36 (s, 2H), 6.86 (s, 1H), 4.18-4.52 (m, 1H), 2.98-3.26 (m, 1H), 2.34-2.60 (m, 2H), 1.93-2.14 (m, 1H), 1.20 (s, 3H), 1.17 (s, 3H), 0.82 (t, J=7.28 Hz, 3H).

Example 5. Elucidation of GSK3 Structure Leads to Design Potent, Paralog Selective Small Molecule Inhibitors

[0696] Several GSK3-selective inhibitors were developed and their activity evaluated across several in vitro and in vivo models of tau phosphorylation. The crystal structure for GSK3 both bound to a selective inhibitor and in apo form was obtained. Using this structure, compounds were designed with up to 20-fold selectivity for GSK3 over GSK3 and favorable drug-like properties. A rat model of tau phosphorylation and a chemoproteomic approach demonstrated that acute GSK3 inhibition can lower tau phosphorylation at disease-relevant sites in vivo with a high degree of selectivity over GSK3 and other kinases.

Methods:

Cell Culture and Transfection.

[0697] HEK293 or SH-SY5Y cells were obtained from American Type Culture Collection (ATCC, Manassas, VA) and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 10 units/ml penicillin, and 10 g/ml streptomycin (all reagents were purchased from Gibco, Waltham, MA). Cell cultures were maintained in a humidified 5% (v/v) CO.sub.2/air environment at 37 C. When the cells reached 50-80% confluence, they were transfected with a complex consisting of a 3:1 ratio of FuGENE 6 Transfection Reagent (Promega, Madison, WI) and plasmid DNA. Plasmid DNA was balanced out across reactions using an empty plasmid so that the same amount of DNA was added per well. This transfection complex was prepared following the manufacturers protocol and added directly to the cell media for 24 or 48 hours prior to lysis.

SDS-PAGE and Western Blot.

[0698] Samples were lysed in Pierce RIPA lysis and extraction buffer (Thermo Fisher Scientific, Waltham, MA) supplemented with 1% Halt protease and phosphatase inhibitor cocktail (Thermo Fisher Scientific, Waltham, MA) and centrifuged at 14000g for 20 min at 4 C. to clear the lysate. Protein concentrations were determined using the Direct Detect Infrared Spectrometer (EMD Millipore Corp., Burlington, MA) and 10 g of each sample was denatured in 6SDS sample buffer (Boston Bioproducts, Ashland, MA) for 7 minutes at 90 C. Proteins were loaded into a Criterion 7.5% tris-glycine gel (Bio-Rad, Hercules, CA) and separated by SDS-PAGE at 120V for 135 minutes. The gel was transferred to an IBlot2 nitrocellulose membrane (Invitrogen, Carlsbad, CA), blocked with TBST blocking buffer (Li-cor Biosciences, Lincoln, NE) for 1 hour, and washed three times with TBST. The membrane was probed with primary antibodies (1:1000 dilution) in antibody dilution buffer (1:1 TBST blocking buffer and 1TBST) overnight at 4 C. The blot was then washed in triplicate with TBST and incubated for 1 hour with secondary antibody (1:10,000 dilution of IRDye 800 anti-mouse IgG and IRDye 680 anti-rabbit IgG, Li-cor Biosciences, Lincoln, NE) in antibody dilution buffer. After a final triplicate wash with TBST, the blot was visualized using the Odyssey CLx imaging system (Li-cor Biosciences, Lincoln, NE).

Phospho-Tau: plate-based assays for epitopes Thr231 and AT8.

[0699] 293T cells stably expressing human 2N4R Tau were transfected with appropriate cDNA plasmids. 24 hours following transfection cells were treated with compound in a 10-point dose-response (from 1000 stocks of compound) and lysates harvested 2 hours later with cell extraction buffer (Life Technologies Cat #BN0001) or RIPA Buffer with Halt protease/phosphatase inhibitors added.

[0700] For pThr231 assay: Lysate was diluted 1:100 in assay buffer and Total Tau and pTau T231 was assessed by plate-based ELISA as per manufacturer instructions (MSD Cat #K15121D-1). Total fluorescence was measured using an Envison plate reader.

[0701] For AT8 assay: FRET antibodies (Custom designed Cisbio assay kit; S202/T205 Tb and total Tau D2 FRET antibodies) were added to lysate in a 384 well assay plate at 1:4 ratio (antibody/lysate). After antibody addition, the plate was left at room temperature for 60 minutes incubation time. Plate was read with appropriate wavelength settings using an Envision plate reader (ex320 and em620 and em665).

NanoBRET.

[0702] HEK293T cells were transiently transfected with NanoLuc-GSK3-alpha or NanoLuc-GSK3-beta constructs using FuGene-HD (Promega). Next day, the live cell NanoBRETTM target engagement assay was performed. Cells were treated with serially diluted compound in addition to NanoBRETTM In-cell Kinase Tracer-8 at EC.sub.50 concentration (87 nM for GSK3-alpha and at 120 nM for GSK3-beta) for 2 hours at 37 C.+5% CO.sub.2 incubator. Immediately prior to BRET measurements, NanoBRETTM Nano-Glo Substrate and Extracellular NanoLuc Inhibitor were added on cells and incubated for 2-3 minutes at room temperature. Donor emission at 450 nm and acceptor emission at 610 nm were measured using a EnVision plate reader. Raw BRET ratio values were calculated by dividing the acceptor emission value by the donor emission value for each sample. Raw BRET units were converted to milliBRET units (mBU) by multiplying each raw BRET value by 1000. mBU values for compound treatments were normalized to DMSO treatment. Ki values are calculated using the formula: Ki=(IC.sub.50)/(1+([Tracer]/EC.sub.50)). All experiments were performed as biological triplicates with three technical replications.

-catenin translocation Assay:

[0703] SH-SY5Y cells were seeded into a 96-well CellCarrier Ultra (Perkin Elmer) plate at a density of 1105 cells/ml in complete DMEM. Sixteen hours following plating, media was changed to DMEM with 2% serum, and compound was added with a D300e Digital Dispenser (Tecan) for an incubation time of six hours. After compound incubation, media was removed, and cells were fixed with 4% PFA for 10 minutes at room temperature. Each well was washed three times with PBS-T and then blocked with buffer (1PBS with 5% Normal Goat Serum and 0.3% Triton X-100) for 30 minutes at room temperature. -Catenin primary antibody (Cell Signaling #8480) was added at 1:500 dilution in blocking buffer and the cells were allowed to incubate in primary overnight at 4 C. The following day, primary antibody was removed, each well was washed three times with PBS-T, and secondary antibody (1:2000 anti-rabbit AlexaFluor Plus 488 and 1:10,000 Hoechst 33342) was added and allowed to incubate for 60 minutes at room temperature protected from light. After one-hour, secondary antibody was removed and wells were washed four times with PBS-T before imaging on the Opera Phenix. Sixteen fields per well were imaged with a 20 water lens.

[0704] Images were quantified in the Columbus Image Data Storage and Analysis software. Cells were identified using the Hoechst nuclear stain to identify individual nuclei. Intensity of the nuclear stain was also used to determine cell viability (Viable cells <30% CV of Hoechst Intensity)

Animal Use.

[0705] All experiments were conducted in compliance with the rules set forth by the Biogen Institutional Animal Use and Care Committee in accordance with the guidelines established in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. These protocols were approved by the Biogen IACUC committee.

Rat Developmental Model of Tau Phosphorylation

[0706] Sprague Dawley rats were bred in-house and litters were injected with compound, I.P. at post-natal day 10. Rats were then euthanized at indicated times following drug administration. For tissue collection, animals were euthanized via decapitation, brains were quickly removed, and bisected sagitally. The right cortex, was isolated, placed into 2 mL microtubes along with a single 5 mm stainless steel bead and the left cortex were placed into 2 mL Lysing Matrix A tubes (MP Biomedicals, Santa Ana, CA), Both tubes were immediately snap frozen in liquid nitrogen.

Determination of Free Drug Concentration in the Brain

[0707] Aqueous buffered homogenate was created from cortical tissue via bead beater, at a consistent homogenization factor, which was normalized by tissue weight. Total drug in brain was determined by measuring total exposure in brain in ng/ml (cortical tissue) via LC-MS/MS. This was then corrected to free concentration via an experimentally derived fu,br using rapid equilibrium dialysis with brain homogenate.

In Vivo Target Engagement Assay:

[0708] Chemoproteomics competition was used to evaluate inhibitor selectivity and target engagement in vivo. Frozen cortexes were prepared for homogenization with 1.2 mL of Lysis Buffer (50 mM Tris-HCl, 0.8% NP-40 ((octylphenoxy poly(ethyleneoxy) ethanol)), 5% glycerol, 150 mM NaCl, 1.5 mM MgCl2, 25 mM NaF, 1 mM sodium vanadate, 1 mM DTT, pH 7.5 and supplemented with protease inhibitors). Tissues were homogenized in FastPrep-24 5G instrument at maximum oscillations for 20 seconds. The resulting brain homogenate was clarified by centrifugation for 1 h at 145 000 g, 4 C. The protein concentration of the supernatant was determined by BCA assay and each sample was diluted to final concentration of 5 mg/mL with lysis buffer. Kinome enrichment was performed similarly as described previously (Reinecke et.al. 2019) with minor modifications. In short, in a 96 deep-well filter plate, one milliliter of the brain lysate (5 mg/mL protein concentration) was incubated with 200 uL (50% slurry) of probe functionalized beads for 30 minutes on an end-over-end rotator at 4 C. Beads were thoroughly washed in two steps with lysis buffer containing 0.4% and 0.2% NP-40, respectively, and eluted with 100 L of a 2LDS sample buffer supplemented with 20 mM DTT. Eluates containing the enriched kinome were alkylated with 40 mM iodoacetamide for 30 min in the dark, then separated on 4-12% NuPAGE for approximately 1 cm and stained with colloidal Coomassie. Gel bands were first cut and diced into 1 mm cubes, and then de-stained with 50/50 Acetonitrile/50 mM NH4HCO3 solution, followed by tryptic digestion overnight at 37 C. The tryptic peptides were extracted into 40/60 Acetonitrile/0.1% formic acid solution and dried in speed-vac. The dry peptide mixture was reconstituted in 15 L of 0.1% trifluoro acetic acid and analyzed on ID nanoLC-MS/MS platform using a standardized 140 min method. Peptides were separated on an Easy-Spray column (75 m50 cm, PepMAP C18, 1.9 m) at 250 nL/min, analyzed on a QExactive HF mass spectrometer at data dependent acquisition (DDA) mode with MS1 at 60,000 and MS2 at 15,000 resolution, respectively. Raw data was first QC checked using in-house developed software and was subsequently searched against the Swissprot human database using Andromeda integrated in Maxquant (V 1.6.38) with mass tolerance of 20 ppm (MS1) and 4.5 ppm (MS2). Carbamidomethylation of cysteine residues was set as fixed modifications and (ST) phosphorylation, methionine oxidation, and (NQ) deamidation were set as variable modifications. LFQ values generated in the protein groups file were used to create the selectivity and target engagement graphs. Both selectivity and target engagement data at different doses and multiple time points are reported percentage inhibition compared to the vehicle groups.

Protein Expression, Purification and x-Ray Crystallography:

[0709] GSK3 residues 98-446 were cloned into a his-tag-MBP-TEV-vector and grown in T.ni cells. Six litters of cell pellets were lysed in 50 mM Hepes 7.4, 150 mM NaCl, 1 mM TCEP with protease inhibitors. Cells were lysed using a microfluidizer at 15,000 PSI and centrifuged at 18,000 rcf for 30 minutes. The resulting supernatant was run over a 35 ml MBPTrap HP column and washed with the lysis buffer. The protein was eluted in the lysis buffer containing 20 mM maltose. Eluted protein was treated with 200 ul of TEC (20,000 units) at 4 C. and dialyzed overnight into 50 mM Hepes 7.4, 150 mM NaCl, 1 mM TECP. The cleaved protein was put over an MBPTrap column and the eluent was collected. This was then put over a 16/60 Superdex200 column in 50 mM Hepes 7.4, 150 mM NaCl, 1 mM TCEP. Finally, the protein was then concentrated to 6 mg/ml for crystallography.

Crystallization and Data Collection and Refinement.

[0710] Sitting drop plates were setup with GSK3 at 6 mg/ml complexed with 0.5 mM of the small molecule inhibitor, and 0.5 mM of synthetic Axin peptide. The complex crystallized in 0.1M Bis-TRIS pH 5.0, 0.2M CaCl2, 5% Glycerol and 30% PEG3350. The crystals were cryoprotected in 0.1M Bis-TRIS pH 5.0, 0.2M CaCl2, 25% Glycerol and 30% PEG3350. Data collection was performed at the LRL-CAT beamline at APS on a MAR-CCD detector at 0.97 . The data merged and scaled using Aimless. A structure of GSK3 was used as a search model to do molecular refinement using phaser in Phenix. Refinement was also done using phenix. The statistics for the quality of the data is as seen in Table 15.

TABLE-US-00022 TABLE 15 Data BRD0705 BRD0705 948546 bound 948546 bound Collection/ bound to bound to to GSK3alpha- to GSK3beta- refinement GSK3alpha- GSK3beta-axin axin axin statistics axin complex complex complex complex PDB Code 7SXF 7SXJ 7SXG 7SXH Space Group C2 P2.sub.12.sub.12.sub.1 C 2 P2.sub.12.sub.12.sub.1 Cell Dimensions a, b, c () 119, 55, 66 68, 73, 82 120, 55, 66 68, 72, 79 , , () 90, 97, 90 90, 90, 90 90, 97, 90 90, 90, 90 Resolution () 1.94 50-1.85 2.4 2.1 R.sub.sym.sup.a 0.03 0.03 0.06 0.06 I/ 24.3 29.13 12.26 14.65 Multiplicity 3.5 6.6 3.4 6.5 Total/unique 109474/31641 237493/36167 58008/16932 155896/23943 reflections Completeness (%) 97.7 (91.06) 99.9 (99.9) 96 (98) 99.3 (95.0) Rwork (Rfree) 20/23 17.9/20.2 23/26 21/25 CC.sub.1/2 0.99 (0.97) 0.99 (0.72) 0.99 (0.54) 0.99 (0.6) R.m.s.d. bond 0.006 0.01 0.003 0.003 distance () R.m.s.d bond angle 0.89 1.00 0.55 0.97 (deg) Avg. protein B-value 61.6 47.83 72.99 57.8 (.sup.2) Avg. solvent B-value 53.4 48.22 57.39 53.7 (.sup.2) Ramachandran Values Preferred 97.6 97 97 98.2 Allowed 2.3 3 3 1.8 Disallowed 0 0 0 0 *The value in parentheses is for the highest resolution bin (approximate interval, 0.1 A), .sup.aRsym = f| fhkl .Math. < fhkl > | f fhkl .sup.bRwork = f fhkl| |Fo .Math. |Fc| | / f fhkl|Fo| for all data except 5% which is used for the R.sub.free calculation

Results:

Acute and Selective Inhibition of GSK3 can Reduce Tau Phosphorylation at Disease Relevant Sites

[0711] The hyper-phosphorylation of tau by GSK-3 has been implicated in Alzheimer's Disease (Llorens-Martin M et al . . . , 2014); however, the development of GSK paralog selective tool compounds is important for the field to investigate the relative contributions of GSK3 and/or GSK3 to different disease pathologies. To demonstrate the specific effects of each paralog on tau phosphorylation, HEK293 cells stably expressing human 2N4R tau (HEK-huTau) were transfected with plasmids expressing human GSK3, human GSK3, or kinase dead mutants in which the catalytic lysine was mutated to an alanine. Twenty-four hours after transfection, cells were lysed and run by SDS page to probe for phosphorylation of tau at different epitopes. The results demonstrate that both GSK3 isoforms phosphorylate tau at multiple epitopes including the disease enriched epitopes Thr231 and S202/Thr205 (AT8; FIG. 1A). Interestingly, when these kinases were expressed at approximately equal levels, selectivity of the GSK3 paralogs was not detected for specific phosphorylation epitopes on tau or a difference in total phosphorylation of tau (FIG. 1A, FIG. 8). This data indicates that in the current HEK-huTau cell assay, both GSK3 and GSK3 have comparable substrate affinity for several disease-enriched phospho-epitopes on tau.

[0712] To test the potency and isoform selectivity of GSK3 small molecule inhibitors, HEK-huTau cells were transfected with plasmids containing either human GSK3 or GSK3. Twenty-four hours after transfection, compounds were added at a 10-point dose response curve (at a range of 30 M-3 nM) for a total of 2 hours, and cell lysates were probed for total tau and pThr231 using a plate-based assay. The results demonstrate that this assay is both sensitive to GSK3 activity and that the capture antibody is specific to pThr231 as mutating this Threonine residue to an Alanine abolished assay signal (FIG. 9). As a benchmark GSK3 inhibitor, the Astrazeneca compound AZ1080 (Georgievska et al . . . , 2013) was used. The results show similar potencies for this compound to both GSK3 isoforms (FIG. 1B; GSK3 IC.sub.50=3.18 M; GSK3 IC.sub.50=2.03 M). These results verify previous reports that this compound is not paralog selective. In addition, the reported GSK3 selective compound BRD0705 (Wagner et al . . . , 2018) was profiled. Selectivity of this compound was confirmed for GSK3 (FIG. 1C; GSK3 IC50=3.75 M; GSK3 IC.sub.50=Undetermined due to toxicity of this compound at doses >30 M).

[0713] GSK3 selective compound 837646 was developed using structural analysis of the previously reported GSK3 D133E mutant, characterized, and underwent subsequent screening of functional group substitutions at both the phenyl and cyclohexyl ring. 837646 retains GSK3 paralog selectivity (FIG. 1C; GSK3 IC50=0.15 M; GSK3 IC50=1 M) while dramatically increasing cellular potency (GSK3; BRD0705 IC50=3 M, 837646 IC50=0.15 M). Importantly, for BRD0705 and 837646, the relative cellular potency and paralog selectivity was similar when these compounds were tested for activity at an additional tau phosphorylation site pS202/pThr205 (AT8; FIG. 10) demonstrating the utility of these cell-based assays in future compound screening.

Reported GSK3 Small Molecule Inhibitors Bind at ATP Binding Pocket and have Similar Residence Times

[0714] To further characterize the GSK3 inhibitor 837646, this compound was tested in a live-cell target engagement assay to investigate binding mode and residence time. To assess binding at the ATP pocket, HEK293T cells were transiently transfected with NanoLuc-GSK3 or NanoLuc-GSK3 plasmids and the following day treated for two hours with both inhibitors and the NanoBRET Target Engagement Kinase Tracer-8 (Promega; EC.sub.50 concentration GSK3=87 nM; GSK3=120 nM; FIG. 11). In this assay, compound binding was quantified as loss of BRET signal from baseline due to competitive displacement of the tracer. The results show competitive displacement of the tracer with each of the inhibitors indicating that all compounds tested bind in the ATP pocket (FIG. 2A). Importantly, the rank order for compound potency and isoform selectivity was similar between the NanoBret assay and HEK293 tau phosphorylation assay providing additional confirmation of our previous results.

[0715] To investigate compound residence time, cells transfected with GSK3 NanoLuc plasmids were treated with inhibitors at 10 the previously identified IC.sub.50 and BRET signal was measured every 5 min for a total of 3 hours after tracer addition. Overall, there was no difference in the residence time of compound 837646 at either GSK3 or GSK3 when compared to the previously profiled compounds AZ1080 or BRD0705. Together the data suggest the increase in potency observed with 837646 was not due to differences in binding mode or kinetics.

Combined Inhibition of Both GSK3 Paralogs is Necessary for Nuclear Translocation of -Catenin in SY5Y Cells

[0716] One concern in the clinical development of dual GSK3/B inhibitors is the predicted stabilization and nuclear translocation of -catenin (Yost et al . . . , 1996) whose mutation or overexpression is associated with many cancers (Iwao et al . . . , 1998; Kurnit et al., 2017).

[0717] Importantly, previous experiments have shown that selective genetic knockdown of either GSK3 or GSK3 does not increase -catenin levels (Doble et al . . . , 2007). To determine whether 837646 shows a similar profile, -catenin activation was measured by looking at nuclear translocation following compound addition. As expected, the non-selective compound AZ1080 lead to nuclear translation of -catenin at a potency similar to what was previously reported for the tau phosphorylation assay (HEK-huTau assay GSK3 IC50=3.18 M, GSK3 IC50=2.03 M; SYSY -catenin assay IC50=3 M). The results show that compounds which had selectivity towards the GSK3 isoform (BRD0705 and 837646) had a significant window between their reported potency to effect tau phosphorylation by GSK3 and concentrations which affected -catenin stabilization (BRD0705 >5-fold; 837646 >20-fold). The data demonstrate that inhibition of the GSK3 paralog alone was not sufficient to cause -catenin activation because translocation to the nucleus was only observed with concentrations high enough to inhibit both paralogs (See Table 15). Together, these results demonstrate the identification of a novel GSK3 inhibitor with improved safety profile between inhibition of tau phosphorylation and -catenin activation.

Acute GSK3 Inhibition Reduces Tau Phosphorylation at Disease Relevant Sites In Vivo

[0718] To determine whether a selective GSK3 inhibitor could also lower tau phosphorylation in a more physiological setting, 837646 was administered to rats at post-natal day 10. Previous experiments testing tau kinase inhibitors have demonstrated several advantages of using neonatal rats for in vivo PK/PD studies including the observation that these animals have a high level of basal tau phosphorylation (Halkina T et al . . . , 2021) and that compounds with less-than-ideal physical characteristics are able to cross the blood brain barrier due to the absence of Pgp transporters at this age (Matsuoka et al . . . , 1999). In the current experiment, 837646 was administered at 60, 20 and 10 mg/kg in P10 rats. The animals were sacrificed at several time points following treatment. The results demonstrate a significant lowering of tau phosphorylation at pThr231 beginning 3 hours after drug administration when compared to vehicle treated controls (FIG. 4A; 60 mpk p=0.004; 20 mpk p=0.0227). Interestingly, over 24 hours tau phosphorylation levels in the vehicle treated animals increased by 58% when compared to the previous baseline level (normalized tau phosphorylation at 1 hr and 24 hr in vehicle treated animals was 1 and 1.58 respectively). Animals injected with 837646 at either 20 or 60 mg/kg did not see a similar increase in tau phosphorylation over this time and were significantly different from the vehicle group at the 24 hr timepoint (60 mpk p=0.005; 20 mpk p=0.0139).

[0719] To determine drug exposure, blood and cortical tissue were analyzed at each time point following dosing. Overall, the pharmacokinetic data demonstrates dose responsive compound concentrations with a steady C.sub.max extending 6 hours post injection (FIG. 4B). In addition, similar levels of the compound in both the blood and brain were observed (FIG. 4B), indicating that in neonatal rats, the compound had no issue crossing the blood brain barrier after peripheral injection. Free drug concentration in the brain was estimated based on plasma protein binding data (FIG. 12) and demonstrates a C.sub.max of 715 nM for the 60 mpk dose, three hours after injection (FIG. 13). Together the data show a correlation between drug exposure and effects on tau phosphorylation levels.

[0720] To measure direct target engagement of the compound for both GSK3 and GSK3 competitive chemoproteomics methodology was used. Briefly, brain lysates were incubated with non-selective kinase inhibitors coupled sepharose beads (kinobeads) (Bantscheff et.al., 2007). Enriched proteins were analyzed by liquid chromatography coupled with tandem mass spectrometry. Target engagement was then measured as competitive displacement of 837646 with the non-selective beads. The results demonstrate that 837646 retained its selectivity for GSK3 over GSK3 in vivo (FIGS. 4D and 4E). In particular, three hours after dosing (a timepoint for which a significant decrease in tau phosphorylation at Thr231 was demonstrated), 837646 achieved over 90% target engagement for GSK3 (FIG. 4D) compared to 40% for GSK3 (FIG. 4E). At 24 hr, target engagement of 837646 at GSK3 was still close to 50% for both the 60 mg/kg and 20 mg/kg dose while there was no significant binding detected at this time point to the GSK3 paralog. The data suggest that the extended effect of this compound preventing tau phosphorylation at Thr231 was likely driven solely by GSK3 inhibition.

[0721] To investigate whether the effects of 837646 on tau phosphorylation were solely the result of GSK3 inhibition, additional kinases detected by mass spectrometry for compound engagement in the same brain lysates were profiled. The results show that at the highest dose tested (60 mg/kg) 7 out of 251 unique detected kinases (including GSK3), which had target engagement greater than 70% (FIG. 4F and FIG. 13). Of the 6 off-target kinases detected none have previously been identified to share tau as a direct phosphorylation substrate. These results demonstrate that acute GSK3 inhibition can lead to significant reductions in tau phosphorylation in vivo.

Elucidation of GSK3 Crystal Structure

[0722] The development of GSK3 paralog-selective inhibitors is complicated by the fact that, despite numerous reports over the past 20 years of structural information pertaining to GSK3 (Dajani R et al . . . , 2001), no crystal structures have been reported for GSK3. Previously, Wagner et al. (2018) reported challenges associated with directly obtaining a crystal structure for GSK3 and instead utilized a GSK3 D133E mutant to mimic key differences between the two paralogs within the ATP binding site. From this structure it was speculated that a differential hydrogen-bonding outside of the ATP binding site may lead to alternative pockets allowing for paralog selective inhibitors. A previous report on the crystallization of GSK3 (Dajani et al . . . , 2003) described increased diffraction in the presence of its physiological binding partner Axin.

[0723] A first crystal structure of GSK3, with an inhibitor (BRD0705) bound to the ATP active site was obtained (FIG. 5A). Crystallization of both GSK3 and GSK3 with Axin and BRD0705 led to differences in the hydrogen bonding network surrounding Glu196/Asp133 for each paralog (FIGS. 5A and SB). In particular, Glu196 had an interaction with Lys260 in GSK3, whereas the corresponding interaction was not observed for GSK3. Additionally, the two crystal structures contained subtle differences in the sidechain rotamers located within the ATP binding site surrounding BRD0705 which are represented in FIGS. 5B and 5C.

[0724] Since the primary difference in the two GSK3 active sites is situated at the hinge, substitutions adjacent to the aminopyrazole hinge-binding motif were considered. The crystal structure of BRD070S revealed that the binding pocket would likely tolerate substitution of the 3-position of the aryl ring. Indeed, as shown with 837646, fluorine substitution adjacent to the binge and an aryl trifluoromethyl substitution led to improved potency while maintaining GSK3 paralog selectivity. Next, using this crystal structure, additional compound derivatives were explored to further increase both the potency and selectivity of 837646. In particular, differential substitution of the phenyl ring was evaluated to provide improved paralog selectivity despite its position within the binding pocket. In some compounds, the trifluoromethyl group found in 837646 was replaced with heterocycle or pyridyl substituents, directing a hydrogen bond acceptor towards the catalytic lysine residue. This additional hydrogen bond interaction showed increased affinity of these compounds for either GSK3 paralog.

Intelligent Design Leads to Novel, Potent GSK3 Inhibitors

[0725] To determine whether the structure-based designs led to compound improvements, both 947651 and 948546 were tested in our buTau-HEK assay and their inhibition of tau phosphorylation at pThr231 was measured. Each of these compounds demonstrated a significant improvement in both potency and GSK3 selectivity when compared to the parent compound 837646 (FIG. 6A; 947651 GSK3 IC50=0.061 M, GSK3 IC50=1.4 M, 23-fold selective; 948546 GSK3 IC50=0.096 M; GSK3 IC50=1 M, 11-Fold selective). To measure more proximal target engagement, it was verified that 947651 and 948546 were ATP-competitive and direct GSK3 binders using the previously described nanobret tracer assay (FIG. 6B). Interestingly, both 947651 and 948546 show significantly longer residence times for GSK3 in comparison to 837646 (FIG. 6C). These results suggest that increasing ligand-protein interactions created a tighter interaction in the ATP pocket which subsequently led to slower dissociation. To verify that selective GSK3 inhibition with these compounds does not lead to -catenin stabilization, the potency of these compounds to cause translocation of -catenin to the nucleus in SYSY cells was measured. For each of these compounds, nuclear translocation of -catenin occurred at concentrations in which both GSK3 paralogs are being inhibited (FIG. 14). These GSK3 selective compounds exhibited significant improvements in cellular potency compared to those previously reported in the literature.

Crystal Structure of GSK3 and GSK3 with the Novel 948546.

[0726] The in vitro characterization of 948546 demonstrates both a dramatic increase in compound potency and improvements in GSK30, paralog selectivity. To further validate that this was due to increased interactions of this compound with the GSK3 ATP pocket, crystallization of GSK3 was performed with Axin and 948546. The results show that 948546 interacts with Lys148/85 in both GSK3 paralogs which could account for some of the increased binding affinity. In addition, the crystal structure also demonstrates minor differences in the orientation of the biaryl motif via the lysine interaction between the GSK3 and GSK3. The orientation of this biaryl motif relative to Lys148/85, and subsequent difference in hydrogen bonding enthalpy, may contribute to the observed paralog selectivity but more importantly highlights the binding differences of 948546 relative to BRD0705 and potential secondary effects on affinity. Interestingly, both the GSK3 and GSK3 structures with 948546 show that the central phenyl ring is rotated relative to BRD0705 and that this rotation may be needed for the biaryl ring to interact with Lys148/85. Additionally, the gem-dimethyl substituents on the solvent exposed ring adjacent to the hinge have undergone a pseudo chair-flip between the BRD0705 and 948546 structures and the axial methyl group is directed to the N-lobe rather than the C-lobe. Taken together, these differential conformational biases that are captured in the X-ray structures of 948546 may further contribute to selectivity by reinforcing the interaction of the ethyl moiety with the corresponding lipophilic pocket which was originally identified in BRD0705 Importantly, the structures of 948546 indicate that the ILE125(/62) residue in this lipophilic pocket is shifted relative to the 948546 GSK3 structure as well as both GSK3 structures of BRD0705 and provides an expanded binding site.

Discussion:

[0727] Several GSK3-selective inhibitors were developed and evaluated for their activity in both cellular and animal models of tau phosphorylation. The development of these compounds was aided by the first demonstration of a GSK3 crystal structure, and the results further describe how increasing ligand interactions with the GSK3 binding pocket led to significant improvements in compound potency and target residence time. Using a postnatal rat model and chemoproteomics, it was confirmed that acute, inhibition of GSK3 can suppress tau phosphorylation at epitopes enriched in disease. The selectivity of 948546 was demonstrated across the kinome. The current studies advance prior efforts to develop GSK3 paralog selective inhibitors and demonstrate therapeutically relevant activity both in vitro and in vivo.

[0728] The hyper-phosphorylation of tau has been shown to negatively affect a wide range of cellular processes including microtubule polymerization (Dillon et al . . . , 2020), axonal transport (Rodrguez-Martn T et al . . . , 2013), RNA translational selectivity (Koren et al . . . , 2019), nuclear import/export (Eftekharzadeh et al . . . , 2018), pre-synaptic vesicle motility (Zhou et al . . . , 2017) and post-synaptic excitotoxicity (Ittner et al . . . , 2010). However, the longest human tau isoform contains a total of 85 possible phosphorylation sites (Goedert et al . . . , 1989); making the identification of specific phosphorylation sites as drivers of disease difficult. GSK3 has been shown to phosphorylate tau at 42 different epitopes (Hanger et al . . . , 2011; Martin et al . . . , 2013) and the activity of GSK3 has been shown to correlate with the level of neurofibrillary tangles found in AD brains (Leroy et al . . . , 2002). It was demonstrated in a HEK293 cell system that both GSK3 paralogs phosphorylate tau at several epitopes (T181, S262, S396, Thr231, and AT8) with equal affinity and strength. To test whether acute GSK3 inhibition could also modulate tau phosphorylation in the rat brain a paralog selective inhibitor 837646 was tested at doses up to 60 mg/kg which at C.sub.max engaged GSK3 over 90% while only occupying GSK3 at 40%. The results demonstrate a reduction in tau phosphorylation at Thr231 at all doses tested three hours after compound administration. Phosphorylation at Thr231 was examined because several lines of evidence indicate that phosphorylation at this epitope is an early event in in Alzheimer's Disease (Luna-Munoz et al . . . , 2005; Neddens et al . . . , 2018). In addition, phosphorylated tau at Thr231 is readily detectable in CSF and was found to be significantly higher in patients with dementia due to AD (Santos et al . . . , 2019). Importantly, this suggests the possibility that Thr231 phosphorylation could serve as a distal biomarker of GSK3 target engagement in the clinical development of similar compounds.

[0729] Chemoproteomics-based profiling allows for the simultaneous measuring of both target engagement and selectivity of kinase inhibitors (Reinecke et. al. 2019). In the current study, following administration of 837646, kinobeads were used to enrich for endogenous kinases and followed this with quantitative mass spectrometry to measure the differential enrichment of kinases over time at multiple doses. This approach showed a direct correlation between the free drug levels of our small molecule and target engagement at either the GSK3 or GSK3 active site. The data demonstrate that even at drug C.sub.max (3 hr after injection of 60 mg/kg) the compound has selectivity for the GSK3 paralog. In addition, the results show that the kinobeads were able to label around 251 unique kinases in the rat brain at post-natal day 10. Of the 251 unique kinases identified, 837646 at C.sub.max demonstrated greater than 70% target engagement at only 6 kinases apart from GSK30/GSK3. Together these results demonstrate the selectivity of 837646 between GSK3 paralogs and across the kinome, while at the same time, establishing an expected range of target engagement in the tissue of interest.

[0730] 947651 and 948546 showed significant improvements in cellular potency compared to previously described GSK3 inhibitors (Palomo V et al., 2012; Wagner F F et al . . . , 2018; Wang Y et al . . . , 2019) and, interestingly, significantly slower off rates when compared to their parent compound (Normalized Koff of Parent 837646=1 vs 7651=0.54; 8546=0.46). These data suggest that increased binding interactions within the GSK30 ATP pocket resulted in a tighter interaction with the target and therefore slower dissociation.

[0731] The development of GSK3 selective compounds demonstrates that selective inhibition of GSK3 paralogs can be obtained despite high binding site homology. Originally it was thought that selective inhibition would necessitate interaction with the one residue difference between GSK3 and GSK3 in the hinge region (Asp/Glu) due to all additional paralog specific side chains directed outside of the ATP pocket and therefore likely inaccessible to small molecules. Here it is shown that modification of the previously identified GSK3 inhibitor BRD0705 on the cyclohexyl ring and aryl substitution, led to 837646, which exhibited a significant improvement in cellular potency. This improvement may be due to substitutions adjacent and distal to the hinge binding region and was suggested in multiple assay systems as well as through determination of binding kinetics. This confirmed that despite highly homologous primary sequences for the active sites of the GSK3 paralogs, the projection and interactions of these residues occurs in a differential manner and leads to avenues to obtain selective binding with small molecule inhibitors. Further derivatization of the aryl functionality revealed that the biaryl moieties in 947651 and 948546 further improved in vitro potency and selectivity. Importantly, 948546 interacted with Lys148/85 after obtaining a crystal structure of this inhibitor with both GSK3 paralogs.

[0732] Previous attempts to use GSK3 inhibitors in the clinic have been plagued by various toxicities, driven in part by the simultaneous inhibition of both GSK3 paralogs resulting in -catenin stabilization (Yost et al . . . , 1996). GSK3 selective inhibitors were investigated in the context of tau phosphorylation; however, GSK3 paralog-selective inhibitors have development potential across a multitude of disease indications. Differences in the crystal structures of GSK paralogs were used to drive potency and selectivity to the GSK3. GSK3 has been implicated in the pathology of Fragile X syndrome and two separate studies have demonstrated that GSK3, but not GSK3, is overactive in the Fmr1-/y mouse hippocampus (Min et al . . . , 2019; McCamphill et al . . . , 2020). In series of recently published studies, McCamphill et al . . . , demonstrate that the GSK3 selective inhibitor BRD0705 corrected susceptibility to audiogenic seizures and reversed learning and memory deficits in a Fragile X mouse model (Fmr1-/y). Two compounds show significant improvements in potency when compared to BRD0705, which may increase the therapeutic window in different disease models.

Example 6. GSK3 Inhibition of Compounds Useful in a Provided Method

[0733] TR-FRET Assay: The assay was performed in a white, 384 well, low volume, flat bottom plate (Grenier). After a 30 minute preincubation in assay buffer with the indicated concentration of compound, the kinase activity was initiated by the addition of the substrates. 1 nM GSK3 (GST-full length GSK3 [SignalChem G08-10G]) or 1 nM GSK3b (GST-full length GSK3b: [SignalChem G08-9G]) were then incubated at ambient temperature for 100 minutes in 10 L of 50 mM Tris, pH 7.5, 20 mM MgCl2, 0.05 mM DTT, 100 g/mL BSA and 1% DMSO, with 200 nM biotinylated peptide substrate (biotinylated and S645 phosphorylated glycogen synthase 631-650) and either 4 M ATP (GSK3, Table 16) or 2 M ATP (GSK3b, Table 16) or 1 mM ATP (Table 17). The kinase activity was quenched with 2 L of 250 mM EDTA. A 10 L volume of 40 nM Strepavidin-d2, 2 nM Tb.sup.2+-pSer641 antibody in TR-FRET Detection Buffer (Invitrogen) was then added. After 60 min at room temperature the plate was read on Envision plate reader using Ex: 340 nm, Em: 615 nM and 665 nM. The normalized 665/615 Signal ratio versus log compound concentration was analyzed by XLFIT to yield IC.sub.50 values.

TABLE-US-00023 TABLE 16 GSK3-A GSK3-B GSK3-A GSK3-B TR-FRET TR-FRET TR-FRET TR-FRET BIOCHEMICAL BIOCHEMICAL BIOCHEMICAL BIOCHEMICAL (TR-FRET); (TR-FRET); (TR-FRET); (TR-FRET); Compound GMean; IC.sub.50 GMean; IC.sub.50 Compound GMean; IC.sub.50 GMean; IC.sub.50 number (M) (M) number (M) (M) 772965 C D 947396 A A 782424 B A 947399 B C 782425 B B 947401 A B 784440 B A 947402 A B 785735 B D 947403 A A 785736 A B 947404 A A 785737 A B 947405 A A 785738 A B 947408 A A 785739 B D 947409 C D 785762 A A 947410 A B 789009 D D 947413 C D 789010 B B 947414 A A 789011 D D 947415 C D 789013 B D 947432 A B 789277 A B 947433 D D 789312 A B 947562 A A 789330 B C 947563 A B 789331 D D 947564 B B 789332 B B 947565 A A 789333 D D 947566 C C 789334 B C 947567 A A 789335 B C 947568 A A 789336 A B 947573 B C 789337 B C 947574 A A 789457 B C 947575 A A 789458 D D 947576 A C 789459 A A 947673 A B 789460 B B 947674 A B 789461 C D 947675 A B 789462 B C 947676 A B 789497 C D 947677 A A 789504 C B 947748 A B 789505 B A 947798 A B 789513 B B 947799 A A 789514 B B 947800 A A 789524 B A 947801 A A 789560 A B 947803 A A 789561 C D 947804 A B 789562 A B 947805 B C 789563 D D 947806 A A 789564 A A 947807 A B 789565 A B 947809 B C 789566 A A 947811 A A 789583 B B 947812 A A 789584 B C 947814 A A 790611 D D 947815 C D 790612 A A 947817 A A 790613 A B 947819 A A 790614 D D 947820 B B 790615 A B 947821 A A 790616 D D 947822 B D 790617 A A 947823 B C 790618 C D 947825 B D 790619 C D 947826 A A 790632 D D 947835 A B 790730 A B 947836 A B 790733 A A 947837 A A 790734 B D 947858 A A 790745 A A 947859 A A 790754 A A 947860 A A 790755 B F 947861 A A 791256 F C 947862 A A 791257 A A 947863 A A 791262 D D 947864 A B 791263 D D 947865 A A 791264 B D 947866 A A 791265 C D 947869 A A 791271 A B 947870 A B 791272 A B 947871 A B 791273 A B 947874 B C 792336 B B 947876 A A 792337 F D 947877 A A 792338 A B 947905 A B 792339 F D 947906 A B 792340 A A 947907 C D 792341 B B 947908 C D 792342 B B 947909 B C 792343 A A 947910 A A 801308 A A 947911 A A 801309 C E 947912 B C 801310 B E 948014 B D 801311 A A 948015 A A 801312 A B 948016 D D 801313 E D 948017 A A 801314 A A 948018 A A 801315 B B 948019 C D 801316 A A 948020 B B 801317 B B 948021 B D 801318 B E 948022 A A 801319 A A 948052 A B 801320 B B 948127 B D 801321 A A 948140 A B 801322 A B 948141 C D 801323 A B 948142 A A 801324 A A 948143 A B 801351 E B 948144 A B 801352 B A 948145 B D 801356 A A 948146 C D 801357 B E 948147 A A 801358 A A 948148 C D 801366 D D 948149 A B 801367 A B 948150 A A 801368 A B 948151 B D 801369 D D 948152 A B 801397 A B 948153 D D 801412 D D 948175 A A 801413 A A 948176 A A 801445 A A 948177 A B 801446 B E 948178 A A 801447 B C 948179 A A 801448 A B 948180 A A 802358 A A 948181 B B 806568 C B 948183 C D 806569 A A 948184 A B 806603 A B 948185 A A 806604 E D 948187 A A 806605 C D 948188 C D 806607 D D 948224 A B 806608 B E 948225 C D 806609 B E 948226 A B 806611 D D 948227 C D 806632 E D 948238 A B 806633 A B 948241 A B 806637 A B 948296 B C 806938 B C 948297 A A 806939 A A 948299 A C 810358 A A 948300 A B 810359 D D 948301 A A 810360 A B 948302 A B 810362 E D 948303 A A 810363 B B 948304 A A 810364 D D 948305 A A 810365 E E 948306 A B 810366 A A 948307 A A 810367 A A 948308 D D 810368 B E 948309 C D 810369 A B 948311 B C 810371 D D 948312 A B 810373 A A 948313 A A 810375 C D 948314 A A 810376 A B 948358 A A 810377 B C 948359 A A 810379 E D 948360 C D 810450 A A 948361 A A 810451 A A 948362 D D 810452 B C 948363 C D 810453 D D 948365 C D 810460 C D 948366 C D 810464 C C 948367 B D 810466 A A 948368 A B 810484 D D 948369 D D 810485 D D 948370 A B 810486 A B 948371 A A 810487 A B 948379 A B 810488 A B 948380 B D 810489 C D 948414 D D 810495 B A 948417 B C 810506 A A 948418 A A 810507 A A 948419 A A 810508 A B 948420 A B 810509 D D 948421 A A 810510 A B 948422 B B 810590 B B 948423 A B 810591 B B 948493 D D 811555 B B 948512 A A 811556 A A 948513 A B 811557 A A 948514 C D 811558 C D 948515 A A 811559 A B 948516 A B 811561 C D 948517 A A 811563 C D 948518 D D 811564 A A 948519 D D 811565 A A 948520 B C 811567 B B 948521 A C 811595 B A 948522 B D 811596 C B 948523 A B 816752 A C 948524 C D 816795 A B 948525 A A 816796 B C 948526 C D 816797 C D 948527 A A 816798 A B 948528 A B 816799 B C 948529 A B 816800 A A 948530 B C 816837 C B 948531 B D 816838 B B 948638 D D 816839 D C 948639 A B 816840 C B 948640 A A 816871 A B 948641 D D 816872 D D 948642 B C 816873 B C 948643 D D 816874 D D 948644 A A 816875 B C 948645 B D 816876 D D 948646 C D 816877 D D 948647 D D 816878 B C 948648 D D 816879 B B 948649 D D 816880 D D 948650 D D 816881 B C 948651 D D 816882 D D 948652 B D 816884 B C 948653 A A 816885 A A 948654 D D 816886 C C 948655 A B 819560 C D 948656 D D 819561 A A 948657 D D 819564 A A 948658 D D 819565 B B 948659 D D 819568 B B 948660 A A 819569 B C 948661 A B 819570 D D 948662 C D 819571 D D 948663 D D 819572 D D 948664 C D 819573 A B 948761 A A 819574 A A 948762 A A 819575 B A 948763 A B 819576 B C 948764 A B 819577 A B 948765 A A 819622 A B 948766 A B 819638 A B 948767 A A 819639 C D 948768 A A 819640 D D 948769 B B 819641 D D 948770 B B 823720 A B 948771 A A 823721 A B 948772 B B 823724 B C 948773 C D 823726 D D 948774 A A 826651 C D 948775 A A 826652 A B 948776 B B 826653 A B 948777 A A 826654 D D 948778 A A 826655 D D 948794 A B 826715 A A 948812 A A 826716 B D 948813 C D 826717 A A 948814 D D 826718 A A 948815 A B 826719 C D 948816 D D 826764 A B 948817 D D 826766 B B 948818 D D 826767 D D 948819 C D 826768 A B 948824 C D 826769 D D 948825 B C 828845 B B 948826 C D 828847 A A 948827 A B 828848 A A 948828 A B 828849 B B 948829 D D 828850 B B 948998 A A 835310 B C 948999 A B 835312 D D 949000 B B 835313 D D 949001 B B 835314 A B 949002 C D 835315 A A 949003 B B 837646 A A 949004 A B 837683 A B 949005 A A 837753 B D 949006 A B 837803 C D 949007 C D 840857 A B 949008 C D 841868 B B 949009 D D 853910 B C 949010 A A 854926 A B 949011 A B 856947 A B 949012 A B 856948 D D 949013 A A 856949 B A 949040 A B 865168 A A 949041 C D 865169 A B 949105 A B 865170 C D 949106 C D 865171 A B 949107 D D 865172 B C 949108 A A 865194 B C 949109 A B 865195 B D 949110 C D 865196 B D 949111 B C 865198 B C 949112 A B 865199 C D 949114 C D 865201 A B 949115 A A 865202 D D 949116 D D 874260 A B 949118 A B 874261 B D 949119 C D 874294 A B 949126 A B 874298 A A 949127 C D 874299 B D 949128 A B 874312 A A 949129 D D 874314 A A 949169 A A 874315 C D 949170 A A 874316 B C 949171 A A 874317 A A 949172 A A 874318 A B 949173 A A 874323 C C 949174 A A 874324 B B 949175 A A 874510 A A 949176 C D 874511 A B 949177 A A 874531 A A 949178 B C 874533 B D 949179 B D 875568 A A 949180 A B 875608 C D 949181 A A 877310 A B 949182 A A 877311 A A 949183 A A 883850 A B 949184 C D 883851 A A 949185 A A 883852 A A 949186 B B 883866 A A 949263 D D 883872 C D 949264 D D 883873 A A 949265 C D 883874 A A 949266 A B 883875 B C 949267 B C 883984 A A 949270 A B 883985 A B 949271 B D 883986 A A 949310 A B 883987 A B 949311 B D 883988 A A 949324 A A 883989 A B 949326 A B 883990 A B 949327 C D 883991 A A 949328 C D 883992 A A 949329 C D 883993 A A 949330 A B 883994 A A 949331 A B 883995 A A 949332 C D 883996 A B 949333 A B 883997 A B 949334 C D 883998 A B 949335 D D 883999 A A 949336 A A 884000 A B 949337 B C 884001 A A 949338 A A 884002 A A 949351 A B 884003 A A 949352 A A 884109 A A 949353 A B 884110 A A 949354 B C 884111 C D 949388 C D 884112 B B 949389 C D 884115 B B 949390 C D 884116 A A 949392 C D 884117 A A 949393 C D 884118 B C 949394 A B 885088 B B 949395 C D 885099 B C 949396 D D 885110 A B 949398 A B 885120 A B 949400 C D 885188 B B 949417 A A 885204 A B 949421 B D 885217 B B 949422 A A 885228 A B 949509 D D 885237 B C 949510 D D 885331 A A 949511 D D 885344 A A 949512 C D 885355 B C 949513 D D 885367 B C 949515 D D 885382 B C 949516 C D 885402 B C 949517 C D 889556 A A 949518 B D 889557 A A 949519 D D 889558 A B 949520 A B 889565 B C 949522 A B 889572 B B 949599 B B 889579 A A 949600 D D 889580 A B 949641 D D 889581 A A 949642 B C 889582 B C 949643 D D 889604 B C 949644 B C 889622 B B 949646 D D 889631 B B 949647 B D 889632 D D 949648 A A 889639 A A 949649 A A 893305 A A 949650 A A 893306 A A 949651 A A 893309 B C 949747 A A 893316 A B 949748 A B 893323 A B 949752 D D 893324 C D 949756 D D 901477 B C 949757 A A 901478 B B 949761 A B 901479 A A 949835 A B 901480 A B 949836 C D 902202 A A 949867 A B 902969 B C 949868 B D 902970 A B 949910 A A 902971 A A 949911 B D 909201 A B 949917 A A 909202 B C 949919 A A 909203 B C 950055 A A 909204 A A 950056 B D 909205 A A 950059 A A 909212 A B 950060 A B 909213 D D 950061 B D 909214 A A 950062 A B 909215 B C 950151 A C 909216 B B 950162 B B 909217 B C 950163 A A 909218 D D 950252 A A 909219 D D 950254 A C 909220 A B 950255 B D 909223 D D 950318 A A 911969 A B 950320 A A 911970 A B 950323 A A 911972 C D 950479 A B 911975 A A 950484 A A 911976 B D 950486 B C 911980 A A 950490 B B 911981 A A 950493 B B 911988 A B 950494 A A 911989 C D 950497 A A 911990 A A 950561 A B 911991 B D 950562 A B 911992 A A 950563 A A 911993 A B 950564 A B 912003 A B 950565 A B 912004 C D 950608 B C 912064 A A 950612 A C 912065 A B 950614 A B 912066 A B 950615 A B 912067 A A 950776 A B 912068 A B 950777 A B 912069 A A 950813 A B 912070 A B 950817 D D 912071 A A 950821 B C 912078 B B 950822 B B 912079 B B 950824 A A 912088 B D 950825 D D 912089 B B 950828 A B 912090 B D 950830 A B 912091 D D 951592 D D 912105 D D 951598 B D 912166 A A 951599 B B 912167 B C 951604 A B 912169 A A 951605 C D 912171 A A 951606 A A 912172 C D 951607 A A 913015 A A 951612 A A 913016 B C 951618 B C 913017 B B 951706 A A 913018 A A 951707 B C 913019 B C 951733 A B 913020 A A 951736 A B 913021 A A 951740 A A 913022 B C 951742 B C 913023 A A 951836 B C 913024 B C 951837 B B 913025 A A 951838 B C 913026 B B 951840 A B 913027 A A 951842 B C 913028 A A 951843 B D 913029 A A 951844 A B 913030 A A 951845 B B 913031 A A 951848 A B 913032 A A 951849 A B 913033 B C 951939 A B 913034 C D 951944 C D 913035 A A 951946 B C 913036 A A 951948 A A 913037 A B 951949 A B 913038 B C 951954 D D 913039 C D 952016 B C 913040 B C 952017 A B 913041 C D 952018 B C 913042 D D 952019 A B 913043 A A 952021 A A 913044 B B 952022 B C 913045 A A 952023 B C 913046 C D 952024 B D 913047 A A 952025 A A 913048 B C 952207 B C 913049 B D 952208 B D 913050 A A 952209 A A 913051 B D 952210 A B 913052 A A 952257 A B 913053 A A 952262 D D 913054 B C 952410 A A 913121 A B 952411 C D 913122 B B 952478 C D 913123 A A 952479 D D 913124 B B 952560 A A 913125 A B 952561 B B 913134 B C 952563 C D 913135 A A 952565 A B 913136 A B 952566 B C 913137 D D 952629 A B 913140 A B 952630 A B 913141 B C 952636 D D 913219 A B 952638 D D 913222 A B 952754 A B 913223 D D 952758 A B 913252 B B 952760 D D 913253 A A 952909 A B 913254 A A 952910 A B 913255 A B 952912 B D 913256 C D 952913 A B 913257 A A 957497 D D 913258 A A 957518 A B 913274 A A 861716 C D 913310 A A 948205 A A 913311 A A 949742 B B 913334 A B 949743 A A 913346 A B 949082 A A 913347 A A 949397 A A 913348 A B 949399 C D 913349 A A 949514 C D 913350 B A 949521 A A 913351 A A 949639 B B 913352 A A 949805 B C 915316 A A 949840 B C 915340 B C 950272 A B 915400 A A 950273 D D 915401 B C 950282 A B 915630 B C 950283 C D 917076 A A 950815 B C 917079 B C 950818 B C 917086 A A 950819 B C 917087 B C 950826 D D 917088 A A 950827 D D 917089 B C 951565 A B 917130 A B 951566 C D 917131 A A 951702 A B 917132 A A 951710 D D 917146 A A 952205 C D 917147 A B 952212 A B 917148 C D 952557 A B 917149 B C 952562 C D 917150 A A 952564 A A 917151 C D 952752 A B 917152 A B 952757 C D 917209 A B 952759 A A 917210 D D 826714 D D 917212 A B 841866 D D 917226 B B 841867 D D 917289 B C 877288 D D 917291 A A 877294 D D 917292 B B 880765 D D 917293 A A 884020 D D 918271 A A 889570 D D 918272 B B 889571 D D 918273 A A 893313 D D 918274 A B 893315 D D 918279 A A 901472 D D 918280 A A 901473 D D 918281 A B 911958 D D 918321 A A 912077 D D 918322 D D 912107 D D 918326 B B 913265 D D 918327 C D 924310 D D 919840 A A 929436 D D 924312 B C 929438 D D 924504 B B 929439 D D 924520 D D 929441 D D 924543 C D 929448 D D 926304 B C 932633 D D 926836 A B 932650 D D 926840 A A 932651 D D 926844 A B 932652 D D 927338 A B 932654 D D 927339 C D 943544 D D 927340 D D 943545 D D 927341 C C 943914 D D 927342 A A 810378 E E 927344 A A 909206 A A 927345 D D 913127 A A 927346 A A 913128 A A 927347 A A 913129 A A 927348 A A 889573 A B 929387 A A 912075 C D 929398 A A 912094 C D 929399 A A 912113 C C 929400 A A 909209 C C 929401 A A 912170 C D 929402 A B 946078 C D 929442 A B 932653 C D 929443 D D 949323 C D 929444 A A 884013 C D 929445 C D 889577 C C 929447 A A 884023 C D 929449 C C 889583 C D 929450 A B 893314 C D 929451 D D 819563 C D 929452 C D 946080 C C 929453 C D 810505 C D 929454 A A 874319 C C 929455 D D 819562 C D 930334 A B 874313 C C 930565 C D 929446 C C 930566 A B 947813 C C 930569 B C 874320 C C 932625 A A 924309 C D 932626 B B 917145 C C 932627 A A 884014 C D 932628 A B 924298 C C 932629 A B 884106 C C 932630 A A 945477 C C 932631 A A 884024 C D 932634 A B 786065 C E 932635 D D 889575 B C 932636 A A 912106 B C 932637 D D 826763 B C 932638 D D 907328 B C 932642 A B 889584 B C 932643 B C 907329 B C 932644 D D 945395 B C 932645 B C 913184 B C 932646 D D 874536 B C 932647 A B 884019 B C 932655 A A 899559 B C 932656 D D 924311 B C 932657 A C 877314 B C 932658 A B 826649 B C 932662 D D 884113 B C 932663 A A 826765 B C 932664 A B 883846 B C 932665 D D 786061 B E 932666 A B 913214 B C 932667 D D 889568 B C 942642 A A 949640 B C 943492 A A 883833 B C 943514 A A 913185 B C 943515 C D 945394 B C 943516 A A 874537 B B 943517 B D 943895 B B 943518 A A 899560 B C 943519 B C 912076 B C 943531 A B 874529 B C 943532 A B 883974 B C 943533 A A 889574 B B 943534 A A 913186 B C 943535 A A 883834 B C 943536 A C 893319 B B 943537 A B 913215 B C 943538 A B 901475 B B 943539 A A 913213 B C 943540 A B 883836 B C 943541 A A 947257 B C 943542 A A 901476 B B 943546 C D 917160 B B 943547 C D 952434 B B 943913 A A 945483 B B 943915 D D 912073 B B 943918 B C 884120 B B 943919 A B 912173 B B 943988 B C 883978 B B 943989 D D 945396 B B 943990 A A 949322 B C 943991 B C 883835 B B 943992 A B 884114 B B 943993 D D 945658 B C 943994 A A 889569 B B 943995 B D 913442 B B 943996 A A 913263 B B 944017 A A 912112 B B 944018 A A 901458 B B 944019 A A 949320 B C 944023 A B 826713 B B 944024 A A 884022 B B 944025 A B 947251 B B 944026 A A 947262 B B 944029 A B 913216 B B 944031 A A 945478 B B 944032 A A 909210 B B 944033 A A 896013 B B 944034 D D 918315 B B 944035 C D 945679 B C 944036 C D 949318 B B 945328 A A 924299 B B 945329 B C 950477 B B 945458 A A 889576 B B 945463 B C 877313 B B 945466 B C 826648 B B 945467 A B 874509 B B 945468 A B 884021 B B 945469 A A 918270 B B 945471 C C 883840 B B 945472 A B 945397 B B 945474 A B 912072 B B 945475 A B 924307 B B 945476 A B 924308 B B 945479 B C 883962 B B 945481 A A 883841 B B 945482 C D 952437 B B 945484 D D 893318 B B 945485 D D 945906 B B 945486 C D 947473 B B 945527 A A 913441 B B 945528 A A 893307 A B 945529 A A 946072 A B 945530 A A 909208 A B 945531 A A 918316 A B 945532 A A 909211 A B 945543 A A 946073 A B 945544 B D 874527 A B 945545 C D 924715 A B 945546 A A 912074 A B 945547 C D 897751 A B 945548 A A 932659 A B 945549 A A 889567 A B 945550 B D 932660 A B 945551 A A 918277 A B 945552 B D 917136 A B 945600 B C 945674 A B 945601 B B 952435 A B 945605 A A 889664 A B 945606 A B 874528 A B 945607 A B 926832 A B 945609 A B 951839 A B 945610 A B 917142 A B 945612 C D 945473 A B 945613 A A 917140 A B 945615 D D 883865 A B 945616 D D 947466 A B 945618 C D 947471 A B 945619 C D 913126 A B 945620 B C 945662 A B 945703 A A 927343 A B 945704 A A 932641 A B 945708 A B 893308 A B 945710 A A 917134 A B 945713 A A 918284 A A 945715 A A 883973 A B 945724 A A 874532 A A 945725 A A 947245 A B 945726 C D 786072 A A 945728 C D 948122 A B 945729 B C 883972 A B 945730 A B 884107 A B 945933 A A 932675 A B 945939 B D 790666 A A 945943 A B 945678 A B 945958 C D 884119 A B 945992 A B 932661 A B 945995 A A 951705 A A 945997 A A 883864 A B 945998 A A 951846 A B 946000 D D 874975 A A 946002 D D 942344 A B 946003 B D 948416 A B 946055 B C 897750 A A 946056 B D 893320 A A 946089 A A 897752 A B 946090 B D 932639 A B 946091 A A 917135 A B 946092 C D 917137 A A 946093 A A 932632 A B 946094 B C 947472 A B 946095 A A 874535 A A 946096 B D 926827 A A 946097 A B 947459 A B 946098 D D 947609 A B 946099 A A 951711 A A 946100 B C 912084 A A 946101 C D 917141 A B 946102 C D 943894 A B 946103 B C 893321 A A 946104 A B 947463 A B 947324 A A 947898 A B 947325 A B 918275 A A 947326 A A 945669 A A 947327 A B 948415 A A 947328 B B 826650 A A 947329 A A 947460 A A 947333 A A 949321 A A 947334 B C 877320 A A 947336 A A 918285 A B 947337 B C 943962 A B 947363 A A 947474 A A 947364 B B 948298 A A 947365 B C 951708 A B 947372 A A 884005 A A 947383 C D 917081 A A 947384 A A 947470 A A 947397 A A 951709 A B 947398 A A 942462 A A 947400 A A 889578 A A 947406 A B 918282 A A 947407 A C 947256 A A 947411 D D 947261 A A 947412 C D 951790 A A 947434 A B 917133 A A 947490 B C 943961 A A 947491 A A 945667 A B 947492 A C 947467 A B 947493 A B 947468 A A 947494 A B 951862 A A 947498 A A 912092 A A 947499 C D 913260 A A 947511 A A 913356 A A 947512 A B 947241 A A 947548 B B 947249 A A 947569 A A 950478 A A 947570 B C 917161 A A 947571 B C 942432 A A 947650 A A 945719 A A 947651 A A 947259 A A 947652 A B 948117 A A 947653 A B 918283 A A 947655 A B 945677 A B 947656 B D 947477 A A 947657 B D 951713 A A 947658 A A 952436 A A 947659 A B 917082 A A 947664 A B 926815 A A 947665 C D 932649 A A 947802 A A 943483 A A 947808 A A 945664 A A 947810 A B 947475 A A 947816 C D 947607 A A 947818 B D 947610 A A 947824 B C 947615 A A 947867 A A 917138 A A 947868 A A 932640 A A 947872 B C 947606 A A 947873 B B 947608 A A 948057 B C 951788 A A 948058 A A 951864 A A 948060 A A 884004 A A 948061 B C 913264 A A 948088 B C 932648 A A 948089 A B 945657 A B 948090 A B 945671 A A 948091 A B 945676 A A 948092 A A 947247 A A 948093 A B 947612 A A 948545 A A 947904 A A 948546 A A 951726 A A 948547 A A 918278 A A 948548 A B 943543 A A 948615 A A 947479 A A 948779 C D 947900 A A 948793 A A 949319 A A 949083 A B 865193 A A 949103 A A 880776 A A 949104 A A 945673 A A 949113 C D 945680 A A 949131 B C 947250 A A 949132 D D 947465 A A 949268 C D 947480 A A 949391 C D 947605 A A 949401 A A 947897 A A 949753 C D 947901 A A 949754 D D 901466 A A 949759 D D 901471 A A 949760 B D 918276 A A 950160 C D 943482 A A 950161 C D 943486 A A 950164 D D 943488 A A 950165 D D 943489 A A 950324 A B 945655 A A 950325 D D 945659 A A 950326 A B 945660 A A 950329 A A 945663 A A 950330 B D 945665 A A 950331 B D 945714 A A 950332 D D 947903 A A 950333 A B 948119 A A 957196 D D 950814 A A 957197 B C 951703 A A 957199 D D 951724 A A 957200 B B 874530 A A 957403 B C 901467 A A 957404 D D 913251 A A 957405 B C 917143 A A 957406 D D 942366 A A 957504 B C 943481 A A 957505 A C 945661 A A 957506 A B 945666 A A 957507 A A 947244 A A 957508 D D 947462 A A 957509 B D 947478 A A 957510 C D 947482 A A 957511 A B 947899 A A 959341 A B 948120 A A 959342 C D 948121 A A 959343 A A 901468 A A 959344 D D 901474 A A 929440 A A 943484 A A 963155 A A 947243 A A 947246 A A 947248 A A 791266 D D 947252 A A 791268 D D 947258 A A 791269 B B 947263 A A 791270 B F 947481 A A 901464 B B 947483 A A 912080 B B 947613 A A 912081 B C 947616 A A 943916 A B 889665 A A 943917 A B 893311 A A 943920 C D 901469 A A 943921 C D 913261 A A 913355 D D 917139 A A 911957 A B 943485 A A 912104 A B 945656 A A 913156 B D 945670 A A 913198 A B 945672 A A 913451 A B 945905 A A 913452 D D 947242 A A 913454 A B 947253 A A 913473 A B 947254 A A 913475 C D 947469 A A 913495 D D 947611 A A 917157 D D 947902 A A 917158 B C 948118 A A 917159 A B 948123 A A 917162 A B 951725 A A 917294 B C 893310 A A 917295 B C 901465 A A 918251 D D 901470 A A 918252 A B 913259 A A 918313 B C 913262 A A 929388 A B 917144 A A 929389 C D 929437 A A 930330 A B 945668 A A 930331 A B 945712 A A 930332 C D 947464 A A 930333 D D 947484 A A 945367 B C 947614 A A 945368 D D 951701 A A 945376 D D 951787 A A 945377 B C 951789 A A 945378 A B 951861 A A 945379 B C 909207 A A 945380 D D 943487 A A 945381 D D 945718 A A 948549 A A 947255 A A 948550 A B 947260 A A 948551 A B 947264 A A 948552 B D 947461 A A 806940 D D 947476 A A 801406 C D 951714 A A 811512 D D 951723 A A 862028 B C 951863 A A 823130 A B 877295 D D 825755 A B 912168 D D 826790 A A 913172 D D 826791 B C 948157 D D 857336 A B 926861 A A 857362 D D 947306 A A 870263 B D 948037 A A 883867 D D 948437 A A 883979 A A 948439 A A 883980 A A 924301 C D 883981 D D 912217 C D 883982 D D 897755 C C 897749 B D 947301 B C 911956 A B 897756 B B 912005 B C 947732 B C 912006 D D 943958 B C 912096 A B 943956 B C 912097 B D 948222 B C 912098 A B 913002 B C 912099 D D 948217 B C 912205 D D 911083 B C 912206 A B 907326 B C 912622 B C 907327 B C 912668 D D 917129 B B 913004 D D 948320 B C 913006 A A 948039 B C 913178 B C 913056 B C 913225 B C 924306 B B 913357 B C 926823 B C 913439 A B 913138 B B 914308 A A 911973 B B 914344 B D 913139 B B 914930 A C 948036 B B 914971 A B 948221 B B 917211 A B 926872 B B 917282 A B 917128 B B 917283 D D 947736 A B 917284 B C 947284 A B 919318 A B 947294 A B 926212 A C 883977 A B 926299 C D 945407 A B 926300 A B 947274 A B 926302 C D 948156 A B 927325 A B 947285 A B 927326 B D 947287 A B 927389 A A 948040 A B 927390 B D 944075 A B 929474 A B 947839 A B 929475 D D 947270 A B 943371 A C 947267 A B 943496 A C 947308 A B 943912 A C 947265 A B 943959 A B 947304 A B 943960 A A 948319 A B 943961 A A 947271 A B 943962 A B 947268 A A 943963 A A 947282 A B 943964 A A 917232 A A 943965 B D 947291 A B 943966 A B 948438 A A 943967 D D 947278 A A 944020 A A 947299 A A 944021 A B 913057 A A 944022 A B 943957 A A 944027 A B 947276 A A 944028 A B 893312 A A 944030 A A 947302 A A 944071 C D 947486 A A 944074 A B 947289 A A 945361 A B 947297 A A 945362 C D 947277 A A 945363 C D 947283 A A 945364 D D 947292 A A 945382 A B 947307 A A 945383 A B 947487 A A 945384 C D 947303 A A 945385 D D 947300 A A 945459 A A 948219 A A 945460 A A 917231 A A 945461 A A 947273 A A 945462 A A 947286 A A 945464 A A 947290 A A 945465 A A 947293 A A 945470 A A 947298 A A 945480 C D 926808 A A 945597 A A 947266 A A 945598 A A 947272 A A 945599 A A 947279 A A 945602 C D 947296 A A 945603 A B 874477 A A 945604 A A 943955 A A 945608 A B 947280 A A 945611 D D 947295 A A 945614 A B 947269 A A 945617 C D 947281 A A 945621 C D 947733 A A 945633 D D 947735 A A 945634 C D 874534 A A 945635 A B 947275 A A 945637 A B 947288 A A 945722 A A 947305 A A 945723 B C 948038 A A 945727 D D 913058 A A 945731 A A 947485 A A 945920 A B 948215 A A 945921 C D 948223 A A 945922 A B 948440 A A 945923 D D 947838 A A 945993 A B 943898 A A 945994 A B 943896 A A 945996 B C 947835 A B 945999 A A 947836 A B 946001 A A 943959 A B 946004 B D 947837 A A 947332 A B 943963 A A 947395 A A 943960 A A A: 0.100 M; B: >0.100 = 1.000 M; C: >1.000-5.000 M; D: >5.000 M; E >1.670 M; F >1.700 M

TABLE-US-00024 TABLE 17 GSK3-A GSK3-B GSK3-A GSK3-B (TR-FRET (TR-FRET (TR-FRET (TR-FRET 1 mM ATP); 1 mM ATP); 1 mM ATP); 1 mM ATP); Compound GMean; IC.sub.50 GMean; IC.sub.50 Compound GMean; IC.sub.50 GMean; IC.sub.50 number (M) (M) number (M) (M) 949010 A A 945997 B C 945713 A A 951714 B B 947867 A A 911975 B C 947324 A A 948215 B B 947329 A A 948778 B C 948546 A B 951861 B B 913032 A A 947281 B B 819575 A A 943481 B B 950563 A A 945672 B B 948185 A A 948547 B C 948307 A A 874510 B B 945710 A A 947275 B B 947814 A A 948371 B B 947859 A A 949177 B C 947511 A A 948223 B B 819574 A A 943960 B B 948418 A A 943960 B B 947819 A A 947263 B C 811565 A A 914308 B C 816800 A A 901468 B C 913035 A B 948549 B C 913043 A B 949103 B B 949917 A A 959343 B C 948421 A A 947395 B B 945527 A B 948359 B C 947333 A B 943964 B C 947372 A A 947611 B B 949181 A B 948205 B B 945704 A B 952759 B C 949175 A A 950824 B B 951607 A B 948120 B C 949336 A B 947253 B C 947404 A B 810373 B C 948314 A A 948998 B C 948419 A A 949650 B C 947326 A A 901469 B B 950497 A B 945724 B C 947808 A B 792340 B B 947811 A A 943485 B C 951740 A B 947408 B C 948037 A A 893311 B C 917293 A A 927347 B C 943913 A B 883980 B C 947384 A B 917088 B C 911992 A B 952410 B C 913128 A B 943994 B C 945725 A B 949401 B C 945529 A B 943488 B B 909206 A B 951863 B B 945481 A B 949324 B C 950055 A B 943484 B C 913127 A B 947243 B C 947363 A B 948812 B C 926861 A A 947269 B B 945531 A B 917086 B C 948771 A B 947414 B C 913025 A B 948060 B C 810366 A B 874530 B C 946099 A B 949169 B C 913047 A B 874477 B C 913036 A B 917139 B B 947860 A B 945543 B C 913129 A B 945905 B B 947658 A B 947462 B C 945718 A B 865193 B C 816885 A A 945995 B C 950494 A B 952560 B D 949183 A B 943482 B B 948437 A A 948525 B C 947403 A B 949521 B C 948150 A B 948358 B C 911990 A B 950059 B C 810466 A B 826790 B C 951948 A B 929454 B C 913052 A B 949352 B C 913023 A B 951701 B C 945328 A B 801413 B C 884117 A B 901471 B C 826718 A B 949115 B C 944033 A B 948828 B C 917291 A B 810450 B C 913135 A B 947613 B C 911981 A B 945670 B C 911980 A B 947616 B C 909207 A B 949651 B D 943990 A B 948184 B C 947651 A B 948058 B C 945668 A B 945606 B C 947861 A B 945613 B C 801308 A B 901467 B C 945546 A B 790733 B C 947306 A A 951725 B C 947862 A B 949397 B C 951606 A B 947650 B D 949185 A C 835315 B C 945528 A B 927389 B C 943518 A B 945470 B C 949648 A C 943542 B C 948439 A A 949174 B B 947877 A B 913018 B C 947255 A B 952021 B D 948545 A B 947401 B D 947405 A B 948361 B C 889665 A B 951612 B C 901465 A B 949331 B C 949005 A C 865169 B D 913058 A B 913006 B D 947260 A B 948219 B C 943996 A B 911988 B D 945712 A B 951949 B D 801311 A B 947432 B D 913350 A B 949006 B D 949919 A B 837683 B D 946001 A B 947652 B D 949171 A C 949310 B D 913045 A B 948529 B C 949743 A B 951703 B C 948022 A B 948379 B D 883873 A B 945657 B C 943487 A B 819577 B D 947242 A B 948815 B D 948118 A B 945920 B C 947264 A B 957511 B D 945532 A B 946104 B D 917150 A B 943541 B C 801314 A B 952212 B D 947246 A B 948793 B D 889639 A B 823721 B D 929447 A B 950163 B D 913050 A B 927325 B D 948038 A B 945614 B C 913123 A B 951702 B D 947254 A B 943531 B D 948142 A B 951788 B C 950252 A C 951864 B C 947876 A B 957506 B D 946089 A B 944074 B D 929437 A B 926300 B D 948515 A B 893323 B D 912171 A B 929388 B D 948775 A B 952910 B D 945656 A B 951713 B C 883874 A B 947410 B D 943516 A C 819638 B D 837646 A C 943961 B D 946093 A B 943961 B D 909204 A B 945476 B D 893310 A B 947406 B D 947464 A B 949761 B D 951723 A B 952436 C C 927346 A C 951726 C C 947869 A C 945607 C D 951787 A B 950828 C D 952025 A C 959341 C D 942642 A C 945475 C D 957507 A C 918285 C D 949172 B C 789560 C D 901470 B B 952565 C D 952564 B C 957505 C D 826717 B C 957200 D D 948313 B C 946103 D D 949422 B C 957504 D 947288 B B 837753 D D 948123 B B 837803 D D 948121 B B 913046 D D 949649 B C 913311 D D 884116 B B 917289 D D 949757 B C 917292 D D 913030 B B 945471 D D 948512 B C 945482 D D 944032 B C 947499 D D 790754 B C 957197 D D 951789 B B 949108 D D 947336 B C 949112 D D 811557 B C 952566 D D 874534 B B 108005 B B 108006 D D 108791 C B 126193 D 108794 D D 126366 C B 108954 C B 126367 D D 108956 D C 126393 C B 114531 D C 126394 D 114532 D 126395 C B 114679 A B 126396 D D 114687 B A 126397 C A 114744 D D 126398 D 117092 D D 126399 D 117093 C B 126400 C B 119047 C B 127429 D C 119048 C B 127430 C B 125976 C B 90285 D C 125977 D 90330 D D 125978 C B 90709 D 125979 D C 90991 D 126012 C B 92315 D D 126013 D 92737 D C 126014 B B 93429 D C 126015 D D 107828 A B 126190 C B 107829 C B 126191 D B 109152 B B A: 0.100 M; B: >0.100 = 1.000 M; C: >1.000-5.000 M; D: >5.000 M; E >1.670 M; F >1.700 M

TABLE-US-00025 TABLE 18 GSK3b (10 GSK3b (100 GSK3a (10 GSK3a (100 M ATP) M ATP) M ATP) M ATP) Average Average Average Average Compound IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 number (M) (M) (M) (M) 90285 0.003 0.055 0.051 0.956 90709 0.038 1.738 1.791 13.719 90991 0.113 3.403 3.012 17.541 92737 0.066 0.438 93429 0.134 0.36

Example 7. Additional Physical, Chemical, Biochemical, and Biological Assays of Exemplary Compounds

Microsomal Stability (MIC)

[0734] Stability of compound in liver microsomes was tested in duplicate by incubating compound at 1 M for 60 minutes at 37 C. Compound level at 60 minutes was compared to level at 0 minutes, and percent remaining was calculated. Assay Parameters

[0735] Available species: human and mouse (CD-1). Compound requirements: 5 L of a 10 mM DMSO solution. Incubation time: 60 minutes at 37 C. Test Concentration: 1 M.

Assay Controls

[0736] Microsomes with NADPH without compound-matrix interference. Microsomes plus compound without NADPHnon-enzymatic instability.

MDR1/MDCK Assay

[0737] The MDR1/MDCK assay is run at Absorption Systems. This assay is used to determine the blood-brain barrier (BBB) penetration potential of a test compound using MDR1-MDCK cell monolayers. Catalog number EA203. Exemplary results are shown in Table 19.

Deliverables

[0738] The percent recovery of the test compound from the Transwell wells containing MDR1-MDCK cell monolayers [0739] The apparent permeability (P.sub.app) in both directions [0740] The efflux ratio (P.sub.app B to A)/(P.sub.app A to B) [0741] The blood-brain barrier penetration potential classification: [0742] High when [0743] P.sub.app A to B3.010.sup.6 cm/s, and efflux <3.0 [0744] Moderate when [0745] P.sub.app A to B3.010.sup.6 cm/s, and 10>efflux3.0 [0746] Low when either [0747] P.sub.app A to B3.010.sup.6 cm/s, and efflux10, or when [0748] .Math. P.sub.app A to B<3.010.sup.6 cm/s.

Substrate

[0749] Test compound at 5 M in HBSSg with maximum DMSO concentration not greater than 1%.

Assay System

[0750] Confluent monolayers of MDR1-MDCK cells, 7 to 11 days old.

Assay Conditions

[0751] Receiver well with 1% BSA in modified Hanks buffer (HBSSg) [0752] Apical and basolateral side at pH 7.4 [0753] Dose two monolayers in each direction (N=2) [0754] Dose apical side for (A to B) assessment [0755] Dose basolateral side for (B to A) assessment [0756] Sample both apical and basolateral sides at 120 minutes [0757] Determine the concentrations of test compound using a generic LC-MS/MS method with a minimum 4 point calibration curve.

Assay QC

[0758] The quality of the cell monolayer batch is verified using control compounds before monolayers are released for use [0759] The quality of each monolayer used in the assay is verified by a TEER measurement and by calculating the P.sub.app for a control compound.

TABLE-US-00026 TABLE 19 MDCK MDCK MDCK permeability Microsome Microsome permeability permeability (MDRI-MDCK); stability stability (MDRI-MDCK); (MDR1-MDCK); Mean; P.sub.app (human); in (mouse); in Mean; P.sub.app Mean; P.sub.app Ratio Compound vitro T.sub.1/2 vitro T.sub.1/2 (A B) (B A) (B A/A B) number (min) (min) (10.sup.6 cm/s) (10.sup.6 cm/s) (efflux ratio) 108005 0.69 0.1 16.31 167.3 1.21 6.17 5.1 108954 8.59 9.84 6.28 0.6 1.98 21.22 10.7 114687 12.3 6.4 119048 1.4 0.5 1.65 70 42.3 125976 26.2 36 0.2 61.2 301 125978 0.6 0.6 10.8 81.2 7.49 126012 0.47 56.2 120 126014 0.17 32.1 187 126190 0.08 15.7 199 126366 0.43 60 138 126393 0.59 54.5 92.5 126395 6.48 57.6 8.9 126397 104.9 >145 126400 0.41 48.9 119 127430 >145 74.5 90285 9.978 7.685 1.6843 21.698 12.883 1.37 30.24 22.14 13.849 9.3765 0.6771 14.94 11.71 0.78 90709 36.014 8.364 16.725 18.114 1.083 7.5106 27.86 3.7095 90991 >145 61.984 0.3759 8.8128 23.447 0.7265 1.3224 1.8201 92737 2.27 1.79 24.75 13.8 14.41 6.52 0.45 93429 107828 6.49 5.55 7.24 1.3 1.08 23.96 22.1 107829 8.877 2.084 1.28 27.89 21.84 14.8 8.72 0.59 109152 0.97 14.8 14.76 1 1.79 35.64 19.9

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Equivalents and Scope

[0819] In the claims and throughout, articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0820] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0821] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art.

[0822] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.