ANTI-PARASITIC COMPOUNDS AND USES THEREOF

Abstract

The present disclosure provides compounds of Formula (I′), Formula (II), and Formula (III). The compounds described herein may useful in treating and/or preventing protozoan infections in a subject in need thereof, treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof, treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), and may be useful in treating and/or preventing infectious diseases in a subject in need thereof. Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including a compound described herein.

##STR00001##

Claims

1. A compound of Formula (I′): ##STR00331## or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; X1 is —CR.sup.4—, —O, or —S—; R.sup.A1 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R.sup.A).sub.2′-SR, —CN, —SCN, or —NO.sub.2; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3A is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is halogen, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ##STR00332## R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each instance of R.sup.A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I′-A), Formula (I′-B), or Formula (I′-C): ##STR00333## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.A1 is of the formula: —(CH.sub.2).sub.x1R.sup.1, wherein: x1 is 0, 1, 2, 3, 4, 5, or 6; and R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2.

4. (canceled)

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3A is hydrogen.

6. The compound of claim 1, wherein the compound is of Formula (′-A): ##STR00334## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; R.sup.2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

7. The compound of claim 1, wherein the compound is of Formula (′-B): ##STR00335## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; R.sup.2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ##STR00336## and each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

8. The compound of claim 1, wherein the compound is of Formula (I′-C): ##STR00337## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; R.sup.2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: ##STR00338## or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

11-13. (canceled)

14. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: ##STR00339## or a pharmaceutically acceptable salt thereof.

15. (canceled)

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R.sup.A is hydrogen.

17. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is —NH(CH.sub.2).sub.aR.sup.a, wherein: a is 1, 2, 3, 4, 5, or 6; R.sup.a is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a2, —N(R.sup.a1).sub.2, or —SR.sup.a2; each instance of R.sup.a1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.ai are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and R.sup.a2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group, or a sulfur protecting group.

18-19. (canceled)

20. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is of the formula: ##STR00340## wherein: b is 0, 1, 2, 3, 4, 5, or 6; c is 0, 1, 2, 3, 4, or 5; each instance of R.sup.a3 is independently substituted or unsubstituted alkyl, halogen, —OR.sup.a4, —N.sub.3, —N(R.sup.a4).sub.2, —SR.sup.a4, —CN, —SCN, —SO.sub.2R.sup.a4, —C(═O)R.sup.a4, —C(═O)OR.sup.a4, —C(═O)N(R.sup.a4).sub.2, or —NO.sub.2, or two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and each instance of R.sup.a4 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

21. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is of the formula: ##STR00341## wherein: b is 0, 1, 2, 3, 4, 5, or 6; T is —CH— or —N—, as valency permits; U is —CH— or —N—, as valency permits; V is —CH— or —N—, as valency permits; W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; X is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits; A is —N— or —C—, as valency permits; B is —N— or —C—, as valency permits; R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.Z is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

22-23. (canceled)

24. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is of the formula: ##STR00342## wherein: Y is —CR.sup.E—, —O— or —NR.sup.F—; R.sup.E is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.F is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

25. (canceled)

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is of the formula: ##STR00343## wherein: d is 0, 1, 2, 3, 4, or 5; each instance of R.sup.b1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b2, —N.sub.3, —N(R.sup.b3).sub.2, —SR.sup.b2, —CN, —SCN, —SO.sub.2R.sup.b2, —C(═O)R.sup.b2, —C(═O)OR.sup.b2, —C(═O)N(R.sup.b3).sub.2, or —N.sub.02; and R.sup.b2 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl; and each instance of R.sup.b3 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

27-29. (canceled)

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is of the formula: —(CH.sub.2).sub.eR.sup.B, wherein: e is 1, 2, 3, 4, 5, or 6; R.sup.B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b4, —N(R.sup.b5).sub.2, or —SR.sup.b4; R.sup.b4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group, or a sulfur protecting group; and each instance of R.sup.b5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.bs are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring.

31-34. (canceled)

35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is hydrogen or of the formula: ##STR00344## wherein: f is 1, 2, 3, 4, 5, or 6; R.sup.C is substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —N(R.sup.c2).sub.2, —NR.sup.c2C(═O)R.sup.c1, or —SR.sup.c1; R.sup.c1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; and each instance of R.sup.c2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

36-43. (canceled)

44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is of the formula: —C(═O)R.sup.D, C(═O)OR.sup.D, —C(═NR.sup.Y)R.sup.D, —C(═NR.sup.Y)OR.sup.D, —C(═S)R D, —C(═S)OR.sup.D, or —C(═O)N(R.sup.d1).sub.2, wherein: R.sup.Y is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.d1 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, a nitrogen protecting group, or two instances of R.sup.d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring; and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

45-51. (canceled)

52. A compound of Formula (II): ##STR00345## or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ##STR00346## R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

53. A compound of Formula (III): ##STR00347## or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.4 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ##STR00348## R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each instance of R.sup.A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

54. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

55. A method of treating and/or preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

56-66. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG. 1 shows exemplary results of compounds 21 and 37 in an initial in vivo efficacy assay for T. cruzi infection in a mouse model. The efficacy of compounds 21 (2015-FoleyC-021) and 37 (2015-FoleyC-037) in T. cruzi parasite reduction was measured as a luminescence reading, using an In Vivo Imaging System (IVIS) for T. cruzi parasites expressing luciferase after treatment with compounds 21 and 37 for four consecutive days, with 2 doses per day (bid) at 12 hours between the doses.

[0087] FIG. 2 shows exemplary results of compounds 50, 57, 58, and 89 in an initial in vivo efficacy assay in a mouse model. The efficacy of compounds 50, 57, 58, and 89 in T. cruzi parasite reduction was measured as a luminescence reading, using an In Vivo Imaging System (IVIS) for T. cruzi parasites expressing luciferase after treatment with compound 1 for four consecutive days, with 2 doses per day (bid) at 12 hours between the doses.

[0088] FIG. 3 shows exemplary results of Giemsa staining that reveals exemplary compounds (Tan003-M03, ent-Tan003-D20, Tan003-O08 (“008”) and Tan002-O12) inhibit parasite development before egress.

[0089] FIGS. 4A-4D show flow cytometry results showing exemplary compounds (Tan003-M03, ent-Tan003-D20, Tan003-O08, and Tan002-O12) block parasite stage progression prior to egress.

[0090] FIGS. 5A-5D show a rate of killing study showing that compounds Tan003-M03 and ent-Tan003-D20 are parasitocidal and prohibit progression beyond segmenter stages in asynchronous cultures when treated for at least 48 hours. FIG. 5A-5D show that this is not seen with treatment with compounds Tan003-O08 or Tan002-O12.

[0091] FIG. 6 shows exemplary results after treatment with compound Tan003-O08 for 72 hours, which significantly decreases viable parasites in asynchronous culture.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0092] The present disclosure provides, in one aspect, compounds of Formula (I′), Formula (I), Formula (II), Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The compounds may be useful in treating and/or preventing parasitic infections, particularly protozoan infections and also bacterial infections in a subject in need thereof, treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and treating plasmodial infections (e.g., malaria) in a subject in need thereof. The compounds may be useful in treating and/or preventing an infectious disease in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), and treating and/or preventing an infectious disease in a subject in need thereof, treating and/or preventing an parasitic disease in a subject in need thereof, treating and/or preventing a protozoan infection in need thereof, treating and/or preventing a trypanosomal infection in a subject in need thereof, treating a plasmodial infection (e.g., T. cruzi or Trypanosoma brucei infections) in a subject in need thereof, preventing a plasmodial infection (e.g., T. cruzi or Trypanosoma brucei infections) in a subject at risk of developing a plasmodial infection, treating a protozoan infection in a subject in need thereof, and preventing a protozoan infection in a subject at risk of developing a protozoan infection (e.g., trypanosomal infection from T. cruzi or Trypanosoma brucei, plasmodial infections). The compounds described herein may be anti-parasitic compounds, particularly anti-trypanosomal and/or anti-plasmodial compounds. The compounds may be useful as research tools (e.g., for studying trypanosomal infections (e.g., studying T. cruzi infections) and plasmodial infections in a subject, biological sample, tissue, or cell). Also provided are pharmaceutical compositions, kits, methods, and uses including a compound described herein.

[0093] Compounds

[0094] One aspect of the present disclosure provides the compounds described herein. The compounds may be useful in treating infectious disease, particularly in treating parasitic disease. The compounds may be useful in treating parasitic infections, particularly protozoan infections in a subject in need thereof, and also treating bacterial infections. The compounds may be useful in treating protozoan infections, particularly reating trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) infections) and/or plasmodial infections in a subject in need thereof, treating diseases in a subject in need thereof (e.g., Chagas diseaseand/or, malaria), treating infectious diseases in a subject in need thereof, particularly parasitic diseases, preventing protozoan infections in a subject at risk of developing a protozoan infection, preventing trypanosomal infections (e.g., T. cruzi or Trypanosoma brucei infections) in a subject at risk of developing a trypanosomal infection, preventing protozoan infections in a subject at risk of developing a protozoan infection (e.g., trypanosomal infections from T. cruzi or Trypanosoma brucei and/or plasmodial infections), preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, or sleeping sickness), preventing infectious diseases in a subject at risk of developing an infectious disease, particularly parasitic diseases, and/or as research tools (e.g., for studying trypanosomal infections (e.g., studying T. cruzi infections) and/or plasmodial infections in a subject, biological sample, tissue, or cell). The compounds described herein may be anti-trypanosomal and/or anti-plasmodial compounds. In certain embodiments, a compound described herein is a compound of Formula (I′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0095] Compounds of Formula (I′)

[0096] In certain embodiments, the compound of Formula (I′) is of the formula:

##STR00020##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0097] n is 1, 2, or 3;

[0098] X1 is —CR.sup.4—, —NR.sup.4—, —O—, or —S—;

[0099] R.sup.A1 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R.sup.A).sub.2′-SR, —CN, —SCN, or —NO.sub.2;

[0100] R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;

[0101] R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0102] R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0103] R.sup.3A is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0104] R.sup.4 is halogen, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,

##STR00021##

[0105] R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0106] each instance of R.sup.A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0107] In certain embodiments, the compound of Formula (I′) is of the formula:

##STR00022##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0108] n is 1, 2, or 3;

[0109] R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2;

[0110] R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;

[0111] R.sup.2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0112] R.sup.3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0113] R.sup.4 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,

##STR00023##

[0114] R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0115] each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0116] Formula (I′) includes substituent R.sup.A1. In certain embodiments, R.sup.A1 is hydrogen. In certain embodiments, R.sup.A1 is R.sup.A1 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.A1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.A1 is substituted or unsubstituted methyl. In certain embodiments, R.sup.A1 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.A1 is of the formula: —(CH.sub.2).sub.x1R.sup.1, wherein: xl is 0, 1, 2, 3, 4, 5, or 6; and R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2. In certain embodiments, x1 is 0. In certain embodiments, x1 is 1. In certain embodiments, x1 is 2. In certain embodiments, x1 is 3. In certain embodiments, x1 is 4. In certain embodiments, x1 is 5. In certain embodiments, x1 is 6. In certain embodiments, R.sup.A1 is of the formula: —(CH.sub.2)R.sup.1, and R.sup.1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2. In certain embodiments, R.sup.A1 is substituted or unsubstituted acyl. In certain embodiments, R.sup.A1 is of the formula: —C(═O)R.sup.1, In certain embodiments, R.sup.A1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.A1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.A1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.A1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.A1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.A1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.A1 is —OR, and R is substituted or unsubstituted C.sub.1-6 alkyl (e.g., -OMe or -OEt). In certain embodiments, R.sup.A1 is —N(R.sup.A).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.A is hydrogen. In certain embodiments, R.sup.1 is —NH.sub.2. In certain embodiments, R.sup.A1 is —SR, —CN, —SCN, or —NO.sub.2. In certain embodiments, R.sup.A1 is —SR. In certain embodiments, R.sup.A1 is —CN. In certain embodiments, R.sup.A1 is —SCN. In certain embodiments, R.sup.A1 is —NO.sub.2.

[0117] Formula (I′) and Formula (I) include substituent R.sup.1. In certain embodiments, R.sup.1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl. In certain embodiments, R.sup.1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is —OR, and R is substituted or unsubstituted C.sub.1-6 alkyl (e.g., -OMe or -OEt). In certain embodiments, R.sup.1 is of the formula: —NH(CH.sub.2).sub.aR.sup.a, wherein: a is 1, 2, 3, 4, 5, or 6; R.sup.a is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a2, —N(R.sup.a1).sub.2, or —SR.sup.a2; each instance of R.sup.a1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a nitrogen protecting group if attached to a nitrogen atom; and R.sup.a2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —N(R.sup.A).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.A is hydrogen. In certain embodiments, R.sup.1 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted alkyl (e.g., C.sub.1-6 substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A is a nitrogen protecting group if attached to a nitrogen atom. In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., morpholine or pyridine). In certain embodiments, R.sup.1 is

##STR00024##

In certain embodiments, R.sup.a is —CF.sub.3. In certain embodiments, R.sup.1 is

##STR00025##

In certain embodiments, R.sup.a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.1 is

##STR00026##

In certain embodiments, R.sup.a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is

##STR00027##

In certain embodiments, R.sup.a is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.a is substituted or unsubstituted benzyl. In certain embodiments, R.sup.a is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, R.sup.1 is

##STR00028##

In certain embodiments, R.sup.a is —OR.sup.a2 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.a is —N(R.sup.a1).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, R.sup.a is -NMe.sub.2. In certain embodiments, R.sup.1 is

##STR00029##

In certain embodiments, R.sup.a2 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, R.sup.a2 is a sulfur protecting group. In certain embodiments, R.sup.a is —SR.sup.a2 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)).

[0118] In certain embodiments, R.sup.1 is of the formula:

##STR00030##

wherein Y is —CR.sup.E, —O— or —NR.sup.F—; R.sup.E is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.F is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, Y is —CR.sup.E— (e.g., —CH— or -CMe-). In certain embodiments, Y is —O—. In certain embodiments, Y is —NR.sup.F— (e.g., —NH— or -NMe-). In certain embodiments, R.sup.E is hydrogen. In certain embodiments, R.sup.E is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.F is hydrogen. In certain embodiments, R.sup.F is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is:

##STR00031##

[0119] In certain embodiments, R.sup.1 is of the formula:

##STR00032##

wherein b is 0, 1, 2, 3, 4, 5, or 6; c is 0, 1, 2, 3, 4, or 5; R.sup.a3 is independently substituted or unsubstituted alkyl, halogen, —OR.sup.a4, —N3, —N(R.sup.a4).sub.2, —SR.sup.a4, —CN, —SCN, —SO.sub.2R.sup.a4, —C(═O)R.sup.a4, —C(═O)OR.sup.a4, —C(═O)N(R.sup.a4).sub.2, —NO.sub.2, or two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and R.sup.a4 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. In certain embodiments, b is 3. In certain embodiments, b is 4. In certain embodiments, b is 5. In certain embodiments, b is 6. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, c is 3. In certain embodiments, c is 4. In certain embodiments, c is 5. In certain embodiments, at least one instance of R.sup.a3 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.a3 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.a3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.a3 is —OR.sup.a4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, or -OBu). In certain embodiments, at least one instance of R.sup.a3 is —N.sub.3. In certain embodiments, at least one instance of R.sup.a3 is —N(R.sup.a4).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.a3 is —SR.sup.a4 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu). In certain embodiments, at least one instance of R.sup.a3 is —CN. In certain embodiments, at least one instance of R.sup.a3 is —SCN. In certain embodiments, at least one instance of R.sup.a3 is —SO.sub.2R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)OR.sup.a4 (e.g., —C(═O)OH, —C(═O)O (substituted or unsubstituted alkyl) (e.g., —C(═O)OMe). In certain embodiments, at least one instance of R.sup.a3 is —C(═O)N(R.sup.a4).sub.2. In certain embodiments, at least one instance of R.sup.a3 is —N.sub.02. In certain embodiments, two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl In certain embodiments, R.sup.1 is:

##STR00033##

In certain embodiments, R.sup.1 is:

##STR00034##

[0120] In certain embodiments, R.sup.1 is of the formula:

##STR00035##

wherein: b is 0, 1, 2, 3, 4, 5, or 6; T is —CH— or —N—, as valency permits; U is —CH— or —N—, as valency permits; V is —CH— or —N—, as valency permits; W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; X is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits; A is —N—, as valency permits; B is —N—, as valency permits; R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.Z is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, T is —CH— or —N—, as valency permits. In certain embodiments, T is —CH—. In certain embodiments, T is —N—. In certain embodiments, U is —CH— or —N—, as valency permits. In certain embodiments, U is —CH—. In certain embodiments, U is —N—. In certain embodiments, V is —CH— or —N—, as valency permits. In certain embodiments, V is —CH—. In certain embodiments, V is —N—. In certain embodiments, W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, W is —CH—. In certain embodiments, W is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, W is —O—. In certain embodiments, W is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, W is —S—. In certain embodiments, X is —CH—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, X is —CH—. In certain embodiments, X is —O—. In certain embodiments, X is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, X is —S—. In certain embodiments, Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits. In certain embodiments, Z is —CH—. In certain embodiments, Z is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, Z is —O—. In certain embodiments, Z is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, Z is —N—. In certain embodiments, Z is —S—. In certain embodiments, A is —N—, as valency permits. In certain embodiments, A is —N—. In certain embodiments, A is —C—. In certain embodiments, B is —N—, as valency permits. In certain embodiments, B is —N—. In certain embodiments, B is —C—. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Z is hydrogen. In certain embodiments, R.sup.Z is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is

##STR00036##

In certain embodiments, R.sup.1 is

##STR00037##

In certain embodiments, R.sup.1 is

##STR00038##

[0121] Formula (I′) and Formula (I) include substituent R.sup.2. In certain embodiments, R.sup.2 is substituted or unsubstituted alkyl (e.g., C.sub.1-6 alkyl). In certain embodiments, R.sup.2 is of the formula: —(CH.sub.2).sub.eR.sup.B, wherein: e is 1, 2, 3, 4, 5, or 6; R.sup.B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b4, —N(R.sup.b5).sub.2, or —SR.sup.b4; R.sup.b4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, or sulfur protecting group when attached to a sulfur atom; and each instance of R.sup.b5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or two instances of R.sup.b5 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 6. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is

##STR00039##

In certain embodiments, R.sup.B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is —OR.sup.b4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.B is —N(R.sup.bs).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or -NMe.sub.2). In certain embodiments, R.sup.B is -SRM (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)).

[0122] In certain embodiments, R.sup.2 is of the formula:

##STR00040##

wherein: each instance of R.sup.b5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or two instances of R.sup.b5 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, at least one instance of R.sup.b5 is hydrogen. In certain embodiments, at least one instance of R.sup.b5 is substituted or unsubstituted acyl. In certain embodiments, at least one instance of R.sup.b5 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.b5 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.b5 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, orp-toluenesulfonamide (Ts)). In certain embodiments, two instances of R.sup.b5 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl comprising zero, one, or two double bonds in the heterocyclic ring system, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of R.sup.b5 are taken together with the intervening atoms to form:

##STR00041##

In certain embodiments, R.sup.2 is

##STR00042##

[0123] In certain embodiments, R.sup.2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.2 is substituted benzyl. In certain embodiments, R.sup.2 is unsubstituted benzyl. In certain embodiments, R.sup.2 is substituted phenyl. In certain embodiments, R.sup.2 is unsubstituted phenyl. In certain embodiments, R.sup.2 is of the formula:

##STR00043##

wherein: d is 0, 1, 2, 3, 4, or 5; each instance of R.sup.b1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b2, —N.sub.3, —N(R.sup.b3).sub.2, —SR.sup.b2, —CN, —SCN, —SO.sub.2R.sup.b2, —C(═O)R.sup.b2, —C(═O)OR.sup.b2, —C(═O)N(R.sup.b3).sub.2, or —N.sub.02; and R.sup.b2 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl; and
each instance of R.sup.b3 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

[0124] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, R.sup.2 is

##STR00044##

In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, at least one instance of R.sup.b1 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.b1 is pyridinyl. In certain embodiments, at least one instance of R.sup.b1 is of the formula:

##STR00045##

In certain embodiments, at least one instance of R.sup.b1 is of the formula:

##STR00046##

In certain embodiments, at least one instance of R.sup.b1 is —OR.sup.b2 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.b1 is —N.sub.3. In certain embodiments, at least one instance of R.sup.b1 is —N(R.sup.b3).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, at least one instance of R.sup.b1 is —SR.sup.b2 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu)). In certain embodiments, at least one instance of R.sup.b1 is —CN. In certain embodiments, at least one instance of R.sup.b1 is —SCN. In certain embodiments, at least one instance of R.sup.b1 is —SO.sub.2R.sup.b2. In certain embodiments, at least one instance of R.sup.b1 is —C(═O)R.sup.b2, —C(═O)OR.sup.b2, or —C(═O)N(R.sup.b3).sub.2. In certain embodiments, at least one instance of R.sup.b is —N.sub.02. In certain embodiments, R.sup.2 is

##STR00047##

In certain embodiments, R.sup.2 is

##STR00048##

[0125] In certain embodiments, R.sup.2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl. In certain embodiments, R.sup.2 is substituted or unsubstituted pyridinyl.

[0126] Formula (I′) and Formula (I) also include substituent R.sup.3. In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.3 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is of the formula:

##STR00049##

wherein f is 1, 2, 3, 4, 5, or 6; R.sup.C is independently substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —N(R.sup.c2).sub.2, —NR.sup.c2C(═O)R.sup.c1, or —SR.sup.c1; R.sup.c1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group; and each instance of R.sup.c2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, R.sup.C is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.C is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.C is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.C is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.C is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is —OR.sup.c1 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., -OPh)). In certain embodiments, R.sup.c1 is an oxygen protecting group (e.g., t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM) or methylthiomethyl (MTM)). In certain embodiments, R.sup.C is —N(R.sup.c2).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, R.sup.c2 is an nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)) when attached to a nitrogen atom. In certain embodiments, when R.sup.C is —N(R.sup.c2).sub.2, one instance of R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl, and the other instance of R.sup.c2 is hydrogen. In certain embodiments, two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., piperidine or pyridine). In certain embodiments, R.sup.C is —NR.sup.c2C(═O)R.sup.c1 (e.g., —NHC(═O)(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)Ph, or —NHC(═O)(substituted phenyl)). In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)R.sup.c1, R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)R.sup.c1, R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.c2 is hydrogen. In certain embodiments, R.sup.C is —SR.sup.c1 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, R.sup.3 is:

##STR00050##

In certain embodiments, R.sup.3 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.3 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.3 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.3 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.3 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.3 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0127] Formula (I′) includes substituent R.sup.3A. In certain embodiments, R.sup.3A is hydrogen. In certain embodiments, R.sup.3A is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.3A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3A is of the formula:

##STR00051##

##STR00052##

In certain embodiments, R.sup.3A is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.3A is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.3A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.3A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.3A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.3A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0128] Formula (I′) includes substituent X1. In certain embodiments, X1 is —CR.sup.4—. In certain embodiments, X1 is —NR.sup.4—. In certain embodiments, X1 is —O—. In certain embodiments, X1 is —S—.

[0129] Formula (I′) and Formula (I) also include substituent R.sup.4. In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.4 is substituted or unsubstituted acyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)R.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)OR.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00053##

In certain embodiments, R.sup.4 is of the formula: —C(═NR.sup.Y)R.sup.D, wherein R.sup.Y is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or nitrogen protecting group; and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is —C(═NH)Me. In certain embodiments, R.sup.4 is of the formula: —C(═NR.sup.Y)OR.sup.D, wherein R.sup.Y is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or nitrogen protecting group; and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is —C(═NH)OMe. In certain embodiments, R.sup.4 is of the formula: —C(═O)N(R.sup.d1).sub.2, and each instance of R.sup.d1 is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00054##

In certain embodiments, R.sup.4 is of the formula: —C(═O)N(R.sup.d1).sub.2, and each instance of R.sup.d1 is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, nitrogen protecting group, or two instances of R.sup.d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, each instance of R.sup.d1 is independently a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, two instances of R.sup.d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.4 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.4 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.4 is

##STR00055##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4

##STR00056##

In certain embodiments, R.sup.4 is

##STR00057##

In certain embodiments, R.sup.4 is

##STR00058##

In certain embodiments, R.sup.4 is

##STR00059##

In certain embodiments, R.sup.4 is

##STR00060##

In certain embodiments, R.sup.4 is

##STR00061##

In certain embodiments, R.sup.4 is

##STR00062##

In certain embodiments, R.sup.4 is

##STR00063##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00064##

In certain embodiments, R.sup.4 is

##STR00065##

In certain embodiments, R.sup.4 is

##STR00066##

In certain embodiments, R.sup.4 is

##STR00067##

In certain embodiments, R.sup.4 is

##STR00068##

In certain embodiments, R.sup.4 is

##STR00069##

In certain embodiments, R.sup.4 is

##STR00070##

[0130] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0131] In certain embodiments, the compound of Formula (I′) is of the formula:

##STR00071##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein n, R.sup.1, R.sup.2, and R.sup.3 are as described herein.

[0132] In certain embodiments, the compound of Formula (I′) is of the formula:

##STR00072##

[0133] In certain embodiments, the compound of Formula (I′) is of the formula:

##STR00073##

[0134] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00074##

or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00075## ##STR00076## ##STR00077##

or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00078## ##STR00079##

or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00080## ##STR00081## ##STR00082## ##STR00083##

or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00084## ##STR00085## ##STR00086##

or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00087## ##STR00088##

or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00089## ##STR00090## ##STR00091##

or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the compound of Formula (I′) is of one of the following formulae:

##STR00092## ##STR00093## ##STR00094##

or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00095##

or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00096##

or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00097##

or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00098##

or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00099##

or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00100##

or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the compound of Formula (I) is of one of the following formulae:

##STR00101##

or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the compound of Formula (I′) or (I) is of the formula:

##STR00102## ##STR00103## ##STR00104## ##STR00105##

or a pharmaceutically acceptable salt thereof.

[0150] In certain embodiments, the compound of Formula (I′) or (I) is of the formula:

##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112##

or a pharmaceutically acceptable salt thereof.

[0151] Compounds of Formula (II)

[0152] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00113##

or a pharmaceutically acceptable salt thereof, wherein:

[0153] n is 1, 2, or 3;

[0154] R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2;

[0155] R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;

[0156] R.sup.2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0157] R.sup.3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0158] R.sup.4 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,

##STR00114##

[0159] R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0160] each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0161] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00115##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0162] n is 1, 2, or 3;

[0163] R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2;

[0164] R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;

[0165] R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0166] R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0167] R.sup.4 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,

##STR00116##

[0168] R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0169] each instance of R.sup.A is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0170] Formula (II) includes substituent R.sup.1. In certain embodiments, R.sup.1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl. In certain embodiments, R.sup.1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is —OR, and R is substituted or unsubstituted C.sub.1-6 alkyl (e.g., -OMe or -OEt). In certain embodiments, R.sup.1 is of the formula: —NH(CH.sub.2).sub.aR.sup.a, wherein: a is 1, 2, 3, 4, 5, or 6; R.sup.a is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a2, —N(R.sup.a1).sub.2, or —SR.sup.a2; each instance of R.sup.a1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a nitrogen protecting group if attached to a nitrogen atom; and R.sup.a2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —N(R.sup.A).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.A is hydrogen. In certain embodiments, R.sup.1 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted alkyl (e.g., C.sub.1-6 substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.A is a nitrogen protecting group if attached to a nitrogen atom. In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., morpholine or pyridine). In certain embodiments, R.sup.1 is

##STR00117##

In certain embodiments, R.sup.a is —CF.sub.3. In certain embodiments, R.sup.1 is

##STR00118##

##STR00119##

##STR00120##

##STR00121##

##STR00122##

[0171] In certain embodiments, R.sup.1 is of the formula:

##STR00123##

wherein Y is —CR.sup.E—, —O— or —NR.sup.F—; R.sup.E is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.F is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, Y is —CR.sup.E— (e.g., —CH— or -CMe-). In certain embodiments, Y is —O—. In certain embodiments, Y is —NR.sup.F— (e.g., —NH— or -NMe-). In certain embodiments, R.sup.E is hydrogen. In certain embodiments, R.sup.E is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.F is hydrogen. In certain embodiments, R.sup.F is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is:

##STR00124##

[0172] In certain embodiments, R.sup.1 is of the formula:

##STR00125##

wherein b is 0, 1, 2, 3, 4, 5, or 6; c is 0, 1, 2, 3, 4, or 5; R.sup.a3 is independently substituted or unsubstituted alkyl, halogen, —OR.sup.a4, —N.sub.3, —N(R.sup.a4).sub.2, —SR.sup.a4, —CN, —SCN, —SO.sub.2R.sup.a4, —C(═O)R.sup.a4, —C(═O)OR.sup.a4, —C(═O)N(R.sup.a4).sub.2, —NO.sub.2, or two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and R.sup.a4 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. In certain embodiments, b is 3. In certain embodiments, b is 4. In certain embodiments, b is 5. In certain embodiments, b is 6. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, c is 3. In certain embodiments, c is 4. In certain embodiments, c is 5. In certain embodiments, at least one instance of R.sup.a3 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.a3 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.a3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.a3 is —OR.sup.a4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, or -OBu). In certain embodiments, at least one instance of R.sup.a3 is —N.sub.3. In certain embodiments, at least one instance of R.sup.a3 is —N(R.sup.a4).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.a3 is —SR.sup.a4 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu). In certain embodiments, at least one instance of R.sup.a3 is —CN. In certain embodiments, at least one instance of R.sup.a3 is —SCN. In certain embodiments, at least one instance of R.sup.a3 is —SO.sub.2R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)OR.sup.a4 (e.g., —C(═O)OH, —C(═O)O (substituted or unsubstituted alkyl) (e.g., —C(═O)OMe). In certain embodiments, at least one instance of R.sup.a3 is —C(═O)N(R.sup.a4).sub.2. In certain embodiments, at least one instance of R.sup.a3 is —N.sub.02. In certain embodiments, two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.1 is:

##STR00126##

In certain embodiments, R.sup.1 is:

##STR00127##

[0173] In certain embodiments, R.sup.1 is of the formula:

##STR00128##

wherein: b is 0, 1, 2, 3, 4, 5, or 6; T is —CH— or —N—, as valency permits; U is —CH— or —N—, as valency permits; V is —CH— or —N—, as valency permits; W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; X is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits; A is —N—, as valency permits; B is —N—, as valency permits; R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.Z is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, T is —CH— or —N—, as valency permits. In certain embodiments, T is —CH—. In certain embodiments, T is —N—. In certain embodiments, U is —CH— or —N—, as valency permits. In certain embodiments, U is —CH—. In certain embodiments, U is —N—. In certain embodiments, V is —CH— or —N—, as valency permits. In certain embodiments, V is —CH—. In certain embodiments, V is —N—. In certain embodiments, W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, W is —CH—. In certain embodiments, W is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, W is —O—. In certain embodiments, W is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, W is —S—. In certain embodiments, X is —CH—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, X is —CH—. In certain embodiments, X is —O—. In certain embodiments, X is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, X is —S—. In certain embodiments, Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits. In certain embodiments, Z is —CH—. In certain embodiments, Z is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, Z is —O—. In certain embodiments, Z is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, Z is —N—. In certain embodiments, Z is —S—. In certain embodiments, A is —N—, as valency permits. In certain embodiments, A is —N—. In certain embodiments, B is —N—, as valency permits. In certain embodiments, B is —N—. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Z is hydrogen. In certain embodiments, R.sup.Z is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is

##STR00129##

In certain embodiments, R.sup.1 is

##STR00130##

[0174] Formula (II) includes substituent R.sup.2. In certain embodiments, R.sup.2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.2 is alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.2 is of the formula: —(CH.sub.2).sub.eR.sup.B, wherein: e is 1, 2, 3, 4, 5, or 6; R.sup.B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b4, —N(R.sup.bs).sub.2, or —SR.sup.b4; R.sup.b4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, or sulfur protecting group when attached to a sulfur atom; and each instance of R.sup.b5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or two instances of R.sup.b5 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 6. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is

##STR00131##

In certain embodiments, R.sup.B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is —OR.sup.b4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., -OPh)). In certain embodiments, R.sup.B is —N(R.sup.b5).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or -NMe.sub.2). In certain embodiments, R.sup.B is —SR.sup.b4 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)).

[0175] In certain embodiments, R.sup.2 is of the formula:

##STR00132##

##STR00133##

In certain embodiments, R.sup.2 is

##STR00134##

[0176] In certain embodiments, R.sup.2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.2 is substituted benzyl. In certain embodiments, R.sup.2 is unsubstituted benzyl. In certain embodiments, R.sup.2 is substituted phenyl. In certain embodiments, R.sup.2 is unsubstituted phenyl. In certain embodiments, R.sup.2 is of the formula:

##STR00135##

wherein: d is 0, 1, 2, 3, 4, or 5; each instance of R.sup.b1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b2, —N.sub.3, —N(R.sup.b3).sub.2, —SR.sup.b2, —CN, —SCN, —SO.sub.2R.sup.b2, —C(═O)R.sup.b2, —C(═O)OR.sup.b2, —C(═O)N(R.sup.b3).sub.2, or —NO.sub.2; and R.sup.b2 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl; and
each instance of R.sup.b3 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

[0177] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, R.sup.2 is

##STR00136##

##STR00137##

In certain embodiments, at least one instance of R.sup.b1 is of the formula:

##STR00138##

In certain embodiments, at least one instance of R.sup.b1 is —OR.sup.b2 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.b1 is —N.sub.3. In certain embodiments, at least one instance of R.sup.b1 is —N(R.sup.b3).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, at least one instance of R.sup.b1 is —SR.sup.b2 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu)). In certain embodiments, at least one instance of R.sup.b1 is —CN. In certain embodiments, at least one instance of R.sup.b1 is —SCN. In certain embodiments, at least one instance of R.sup.b is —SO.sub.2R.sup.b2. In certain embodiments, at least one instance of R.sup.b is —C(═O)R.sup.b2, —C(═O)OR.sup.b2, or —C(═O)N(R.sup.b3).sub.2. In certain embodiments, at least one instance of R.sup.b is —NO.sub.2. In certain embodiments, R.sup.2 is

##STR00139##

In certain embodiments, R.sup.2 is

##STR00140##

[0178] In certain embodiments, R.sup.2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl. In certain embodiments, R.sup.2 is substituted or unsubstituted pyridinyl.

[0179] Formula (II) also includes substituent R.sup.3. In certain embodiments, R.sup.3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is of the formula:

##STR00141##

wherein f is 1, 2, 3, 4, 5, or 6; R.sup.C is independently substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —N(R.sup.c2).sub.2, —NR.sup.c2C(═O)R.sup.c1, or —SR.sup.c1; R.sup.c1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group; and each instance of R.sup.c2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, R.sup.C is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.C is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.C is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.C is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.C is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is —OR.sup.c1 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., -OPh)). In certain embodiments, R.sup.c1 is an oxygen protecting group (e.g., t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM) or methylthiomethyl (MTM)). In certain embodiments, R.sup.C is —N(R.sup.c2).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, R.sup.c2 is an nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)) when attached to a nitrogen atom. In certain embodiments, when R.sup.C is —N(R.sup.c2).sub.2, one instance of R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl, and the other instance of R.sup.c2 is hydrogen. In certain embodiments, two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., piperidine or pyridine). In certain embodiments, R.sup.C is —NR.sup.c2C(═O)R.sup.c1 (e.g., —NHC(═O)(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)Ph, or —NHC(═O)(substituted phenyl)). In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)Rel, R.sup.c is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)R.sup.c, R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.c2 is hydrogen. In certain embodiments, R.sup.C is —SR.sup.c1 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, R.sup.3 is:

##STR00142##

[0180] Formula (II) also includes substituent R.sup.4. In certain embodiments, R.sup.4 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is substituted or unsubstituted acyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)R.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)OR.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00143##

##STR00144##

In certain embodiments, R.sup.4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.4 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.4 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.4 is

##STR00145##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00146##

In certain embodiments, R.sup.4 is

##STR00147##

In certain embodiments, R.sup.4 is

##STR00148##

In certain embodiments, R.sup.4 is

##STR00149##

In certain embodiments, R.sup.4 is

##STR00150##

In certain embodiments, R.sup.4 is

##STR00151##

In certain embodiments, R.sup.4 is

##STR00152##

In certain embodiments, R.sup.4 is

##STR00153##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00154##

In certain embodiments, R.sup.4 is

##STR00155##

In certain embodiments, R.sup.4 is

##STR00156##

In certain embodiments, R.sup.4 is

##STR00157##

In certain embodiments, R.sup.4 is

##STR00158##

In certain embodiments, R.sup.4 is

##STR00159##

In certain embodiments, R.sup.4 is

##STR00160##

[0181] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0182] Compounds of Formula (III)

[0183] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00161##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

[0184] n is 1, 2, or 3;

[0185] R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, or —N(R.sup.A).sub.2;

[0186] R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;

[0187] R.sup.2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0188] R.sup.3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0189] R.sup.4 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,

##STR00162##

[0190] R.sup.X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0191] each instance of R.sup.A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or optionally two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0192] Formula (III) includes substituent R.sup.1. In certain embodiments, R.sup.1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl. In certain embodiments, R.sup.1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is —OR, and R is substituted or unsubstituted C.sub.1-6 alkyl (e.g., -OMe or -OEt). In certain embodiments, R.sup.1 is of the formula: —NH(CH.sub.2).sub.aR.sup.a, wherein: a is 1, 2, 3, 4, 5, or 6; R.sup.a is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a2, —N(R.sup.a1).sub.2, or —SR.sup.a2; each instance of R.sup.a1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a nitrogen protecting group if attached to a nitrogen atom; and R.sup.a2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —N(R.sup.A).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.A is hydrogen. In certain embodiments, R.sup.1 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted alkyl (e.g., C.sub.1-6 substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.A is a nitrogen protecting group if attached to a nitrogen atom. In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two R.sup.A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., morpholine or pyridine). In certain embodiments, R.sup.1 is

##STR00163##

In certain embodiments, R.sup.a is —CF.sub.3. In certain embodiments, R.sup.1 is

##STR00164##

##STR00165##

##STR00166##

##STR00167##

##STR00168##

[0193] In certain embodiments, R.sup.1 is of the formula:

##STR00169##

##STR00170##

[0194] In certain embodiments, R.sup.1 is of the formula:

##STR00171##

wherein b is 0, 1, 2, 3, 4, 5, or 6; c is 0, 1, 2, 3, 4, or 5; R.sup.a3 is independently substituted or unsubstituted alkyl, halogen, —OR.sup.a4, —N.sub.3, —N(R.sup.a4).sub.2, —SR.sup.a4, —CN, —SCN, —SO.sub.2R.sup.a4, —C(═O)R.sup.a4, —C(═O)OR.sup.a4, —C(═O)N(R.sup.a4).sub.2, —NO.sub.2, or two instances of R.sup.a are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; and R.sup.a4 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. In certain embodiments, b is 3. In certain embodiments, b is 4. In certain embodiments, b is 5. In certain embodiments, b is 6. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, c is 3. In certain embodiments, c is 4. In certain embodiments, c is 5. In certain embodiments, at least one instance of R.sup.a3 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.a3 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.a3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.a3 is —OR.sup.a4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, or -OBu). In certain embodiments, at least one instance of R.sup.a3 is —N.sub.3. In certain embodiments, at least one instance of R.sup.a3 is —N(R.sup.a4).sub.2 (e.g., -NMe.sub.2). In certain embodiments, at least one instance of R.sup.a3 is —SR.sup.a4 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu). In certain embodiments, at least one instance of R.sup.a3 is —CN. In certain embodiments, at least one instance of R.sup.a3 is —SCN. In certain embodiments, at least one instance of R.sup.a3 is —SO.sub.2R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)R.sup.a4. In certain embodiments, at least one instance of R.sup.a3 is —C(═O)OR.sup.a4 (e.g., —C(═O)OH, —C(═O)O (substituted or unsubstituted alkyl) (e.g., —C(═O)OMe). In certain embodiments, at least one instance of R.sup.a3 is —C(═O)N(R.sup.a4).sub.2. In certain embodiments, at least one instance of R.sup.a3 is —N.sub.02. In certain embodiments, two instances of R.sup.a3 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.1 is:

##STR00172##

In certain embodiments, R.sup.1 is:

##STR00173##

[0195] In certain embodiments, R.sup.1 is of the formula:

##STR00174##

wherein: b is 0, 1, 2, 3, 4, 5, or 6; T is —CH— or —N—, as valency permits; U is —CH— or —N—, as valency permits; V is —CH— or —N—, as valency permits; W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; X is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits; Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits; A is —N—, as valency permits; B is —N—, as valency permits; R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.Z is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, T is —CH— or —N—, as valency permits. In certain embodiments, T is —CH—. In certain embodiments, T is —N—. In certain embodiments, U is —CH— or —N—, as valency permits. In certain embodiments, U is —CH—. In certain embodiments, U is —N—. In certain embodiments, V is —CH— or —N—, as valency permits. In certain embodiments, V is —CH—. In certain embodiments, V is —N—. In certain embodiments, W is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, W is —CH—. In certain embodiments, W is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, W is —O—. In certain embodiments, W is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, W is —S—. In certain embodiments, X is —CH—, —O—, —NR.sup.A—, or —S—, as valency permits. In certain embodiments, X is —CH—. In certain embodiments, X is —O—. In certain embodiments, X is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, X is —S—. In certain embodiments, Z is —CH—, —C(R.sup.Z).sub.2—, —O—, —NR.sup.A—, —N—, or —S—, as valency permits. In certain embodiments, Z is —CH—. In certain embodiments, Z is —C(R.sup.Z).sub.2— (e.g., —CH.sub.2—). In certain embodiments, Z is —O—. In certain embodiments, Z is —NR.sup.A— (e.g., —NH— or -NMe-). In certain embodiments, Z is —N—. In certain embodiments, Z is —S—. In certain embodiments, A is —N—, as valency permits. In certain embodiments, A is —N—. In certain embodiments, B is —N—, as valency permits. In certain embodiments, B is —N—. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Z is hydrogen. In certain embodiments, R.sup.Z is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is

##STR00175##

In certain embodiments, R.sup.1 is

##STR00176##

[0196] Formula (III) includes substituent R.sup.2. In certain embodiments, R.sup.2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.2 is alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.2 is of the formula: —(CH.sub.2).sub.eR.sup.B, wherein: e is 1, 2, 3, 4, 5, or 6; R.sup.B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b4, —N(R.sup.bs).sub.2, or —SR.sup.b4; R.sup.b4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, or sulfur protecting group when attached to a sulfur atom; and each instance of R.sup.b5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or two instances of R.sup.b5 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 6. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is

##STR00177##

In certain embodiments, R.sup.B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.B is —OR.sup.b4 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., -OPh)). In certain embodiments, R.sup.B is —N(R.sup.bs).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or -NMe.sub.2). In certain embodiments, R.sup.B is —SR.sup.b4 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)).

[0197] In certain embodiments, R.sup.2 is of the formula:

##STR00178##

##STR00179##

In certain embodiments, R.sup.2 is

##STR00180##

[0198] In certain embodiments, R.sup.2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.2 is substituted benzyl. In certain embodiments, R.sup.2 is unsubstituted benzyl. In certain embodiments, R.sup.2 is substituted phenyl. In certain embodiments, R.sup.2 is unsubstituted phenyl. In certain embodiments, R.sup.2 is of the formula:

##STR00181##

wherein: d is 0, 1, 2, 3, 4, or 5; each instance of R.sup.b1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.b2, —N.sub.3, —N(R.sup.b3).sub.2, —SR.sup.b2, —CN, —SCN, —SO.sub.2R.sup.b2, —C(═O)R.sup.b2, —C(═O)OR.sup.b2, —C(═O)N(R.sup.b3).sub.2, or —NO.sub.2; and R.sup.b2 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl; and each instance of R.sup.b3 is independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl.

[0199] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, R.sup.2 is

##STR00182##

In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, at least one instance of R.sup.b is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.b1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.b is pyridinyl. In certain embodiments, at least one instance of R.sup.b1 is of the formula:

##STR00183##

In certain embodiments, at least one instance of R.sup.b1 is of the formula:

##STR00184##

In certain embodiments, at least one instance of R.sup.b1 is —OR.sup.b2 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.b1 is —N.sub.3. In certain embodiments, at least one instance of R.sup.b1 is —N(R.sup.b3).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, at least one instance of R.sup.b1 is —SR.sup.b2 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, or -SBu)). In certain embodiments, at least one instance of R.sup.b1 is —CN. In certain embodiments, at least one instance of R.sup.b1 is —SCN. In certain embodiments, at least one instance of R.sup.b1 is —SO.sub.2R.sup.b2. In certain embodiments, at least one instance of R.sup.b1 is —C(═O)R.sup.b2, —C(═O)OR.sup.b2, or —C(═O)N(R.sup.b3).sub.2. In certain embodiments, at least one instance of R.sup.b1 is —NO.sub.2. In certain embodiments, R.sup.2 is

##STR00185##

In certain embodiments, R.sup.2 is

##STR00186##

[0200] In certain embodiments, R.sup.2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl. In certain embodiments, R.sup.2 is substituted or unsubstituted pyridinyl.

[0201] Formula (III) also includes substituent R.sup.3. In certain embodiments, R.sup.3 is hydrogen. halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.3 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is of the formula:

##STR00187##

wherein f is 1, 2, 3, 4, 5, or 6; R.sup.C is independently substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —N(R.sup.c2).sub.2, —NR.sup.c2C(═O)R.sup.c1, or —SR.sup.c1; R.sup.c1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group; and each instance of R.sup.c2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group, or two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, R.sup.C is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.C is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.C is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.C is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.C is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.C is —OR.sup.c1 (e.g., —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -OMe, —OCF.sub.3, -OEt, —OPr, -OBu, or -OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.c1 is an oxygen protecting group (e.g., t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM) or methylthiomethyl (MTM)). In certain embodiments, R.sup.C is —N(R.sup.c2).sub.2 (e.g., —NH.sub.2, —NH (substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NHMe), or —N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -NMe.sub.2)). In certain embodiments, R.sup.c2 is an nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)) when attached to a nitrogen atom. In certain embodiments, when R.sup.C is —N(R.sup.c2).sub.2, one instance of R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl, and the other instance of R.sup.c2 is hydrogen. In certain embodiments, two R.sup.c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl (e.g., piperidine or pyridine). In certain embodiments, R.sup.C is —NR.sup.c2C(═O)R.sup.c1 (e.g., —NHC(═O)(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)Ph, or —NHC(═O)(substituted phenyl)). In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)R.sup.c1, R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.c2 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, when R.sup.C is —N(R.sup.c2)C(═O)R.sup.c1, R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.2 is hydrogen. In certain embodiments, R.sup.C is —SR.sup.c1 (e.g., —SH, —S(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., -SMe, -SEt, —SPr, -SBu, or -SBn), or —S(substituted or unsubstituted phenyl) (e.g., -SPh)). In certain embodiments, R.sup.3 is:

##STR00188##

[0202] Formula (III) also includes substituent R.sup.4. In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.4 is substituted or unsubstituted acyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)R.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is of the formula: —C(═O)OR.sup.D, and R.sup.D is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00189##

##STR00190##

##STR00191##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00192##

In certain embodiments, R.sup.4 is

##STR00193##

In certain embodiments, R.sup.4 is

##STR00194##

In certain embodiments, R.sup.4 is

##STR00195##

In certain embodiments, R.sup.4 is

##STR00196##

In certain embodiments, R.sup.4 is

##STR00197##

In certain embodiments, R.sup.4 is

##STR00198##

In certain embodiments, R.sup.4 is

##STR00199##

In certain embodiments, R.sup.X is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is

##STR00200##

In certain embodiments, R.sup.4 is

##STR00201##

In certain embodiments, R.sup.4 is

##STR00202##

In certain embodiments, R.sup.4 is

##STR00203##

In certain embodiments, R.sup.4 is

##STR00204##

In certain embodiments, R.sup.4 is

##STR00205##

In certain embodiments, R.sup.4 is

##STR00206##

[0203] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0204] The compounds described herein may be useful in treating infectious disease, particularly parasitic diseases. The compounds described herein may be useful in treating parasitic infections. The compounds described herein may be anti-parasitic compounds, particularly anti-trypanosomal and/or anti-plasmodial compounds. The compounds described herein may be useful in treating protozoan infections. The compounds described herein may be useful in treating bacterial infections. The compounds described herein may be useful in treating trypanosomal infections (e.g. T. cruzi infections). The compounds described herein may be useful in treating plasmodial infections. The compounds described herein may be anti-trypanosomal compounds. The compounds described herein may be anti-plasmodial compounds. The compounds may be useful in treating protozoan infections in a subject in need thereof and/or preventing protozoan infections in a subject at risk of developing a protozoan infection, treating trypanosomal infections in a subject in need thereof and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) in a subject at risk of developing a trypanosomal infection, treating plasmodial infections in a subject in need thereof and/or preventing plasmodial infection in a subject at risk of developing a plasmodial infection, and treating parasitic disease in a subject in need thereof and/or preventing parasitic diseases in a subject at risk of developing a parasitic disease. The compounds may be useful in treating infectious disease in a subject in need thereof and/or preventing an infectious disease in a subject at risk of developing an infectious disease (e.g., Chagas disease, malaria, and/or sleeping sickness), and/or as research tools (e.g., for studying trypanosomal infections (e.g., studying T. cruzi infections) and/or plasmodial infections in a subject, biological sample, tissue, or cell).

[0205] Pharmaceutical Compositions, Kits, and Administration

[0206] The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient.

[0207] The pharmaceutical compositions described herein may be useful in treating infectious disease, particularly parasitic diseases. The pharmaceutical compositions described herein may be useful in treating parasitic infections. The pharmaceutical compositions described herein may be pharmaceutical compositions with anti-parasitic compounds, particularly pharmaceutical compositions with anti-trypanosomal and/or anti-plasmodial pharmaceutical compounds. The pharmaceutical compositions described herein may be useful in treating bacterial infections. The pharmaceutical compositions described herein may be useful in treating and/or preventing protozoan infections. The pharmaceutical compositions described herein may be useful in treating trypanosomal infections in a subject in need thereof and/or preventing trypanosomal infections (e.g. T. cruzi infections) in a subject at risk of developing a trypanosomal infection. The pharmaceutical compositions described herein may be useful in treating plasmodial infections in a subject in need thereof and/or preventing plasmodial infections in a subject at risk of developing a plasmodial infection. The compounds described herein may be anti-trypanosomal and/or anti-plasmodial compounds. The pharmaceutical compositions may be useful in treating protozoan infections in a subject in need thereof and/or preventing protozoan infections (e.g., trypanosomal infections from T. cruzi or Trypanosoma brucei and/or plasmodial infections) in a subject at risk of developing a protozoan infection, treating trypanosomal infections in a subject in need thereof and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) in a subject at risk of developing a trypanosomal infection, and/or plasmodial infections in a subject at risk of developing a plasmodial infection, treating infectious disease in a subject in need thereof and/or preventing an infectious disease in a subject at risk of developing an infectious disease (e.g., Chagas disease, sleeping sickness, and malaria), particularly treating parasitic diseases in a subject in need thereof, and as research tools (e.g., for studying trypanosomal infections (e.g., studying T. cruzi infections) and/or plasmodial infections in a subject, biological sample, tissue, or cell). The pharmaceutical compositions may be useful as pharmaceutical compositions with anti-trypanosomal and/or anti-plasmodial compounds.

[0208] In certain embodiments, the subject being treated with a compound of Formula (I′), Formula (I), Formula (II), or Formula (III) is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. 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 certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0209] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a therapeutically effective amount is effective for treating a disease. In certain embodiments, a therapeutically effective amount is effective for treating an infectious disease (e.g., Chagas diseaseand/or, sleeping sickness, malaria). In certain embodiments, a therapeutically effective amount is effective for treating an parasitic disease. In certain embodiments, a therapeutically effective amount is effective for treating an parasitic infection. In certain embodiments, a therapeutically effective amount is effective for treating a bacterial infection. In certain embodiments, a therapeutically effective amount is effective for treating a protozoan infection. In certain embodiments, a therapeutically effective amount is effective for treating a trypanosomal and/or plasmodial infection. In certain embodiments, a therapeutically effective amount is effective for treating a T. cruzi infection. In certain embodiments, a therapeutically effective amount is effective for treating a plasmodial infection. In certain embodiments, a prophylactically effective amount is effective for preventing a disease. In certain embodiments, a prophylactically effective amount is effective for preventing an infectious disease (e.g., Chagas disease and/or malaria). In certain embodiments, a prophylactically effective amount is effective for preventing a parasitic disease. In certain embodiments, a prophylactically effective amount is effective for preventing a parasitic infection. In certain embodiments, a prophylactically effective amount is effective for preventing a protozoan infection. In certain embodiments, a prophylactically effective amount is effective for preventing a trypanosomal and/or plasmodial infection. In certain embodiments, a prophylactically effective amount is effective for preventing a T. cruzi infection. In certain embodiments, a prophylactically effective amount is effective for preventing a plasmodial infection.

[0210] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0211] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0212] 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 composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0213] 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 composition.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0220] 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.

[0221] 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.

[0222] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0223] 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.

[0224] 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®.

[0225] 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.

[0226] 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.

[0227] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0232] 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.

[0233] 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.

[0234] 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 polethylene glycols and the like.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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 composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the 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).

[0241] 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.

[0242] 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.

[0243] 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.

[0244] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0245] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0246] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0247] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0248] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, 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 biological sample, tissue, or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, 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 biological sample, 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 biological sample, 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 biological sample, tissue, or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, 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.

[0249] In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, 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.

[0250] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0251] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating and/or preventing protozoan infections in a subject in need thereof, treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof, treating and/or preventing diseases (e.g., Chagas disease, malaria, and/or sleeping sickness), and treating and/or preventing infectious diseases in a subject, biological sample, tissue, or cell. The compounds or compositions can also be administered in combination with additional pharmaceutical agents that improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, tissue, or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. 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.

[0252] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be 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. Each additional pharmaceutical agent may be 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 administered separately in different doses. 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.

[0253] The additional pharmaceutical agents include, but are not limited to, anti-parasitic agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-parasitic agent. In certain embodiments, the additional pharmaceutical agent is an anti-trypsanosomal agent. In certain embodiments, the additional pharmaceutical agent is an anti-plasmodial agent. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., infectious disease, parasitic infection, protozoan infection, trypanosomal infection, plasmodial infection, Chagas disease, malaria, or sleeping sickness).

[0254] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0255] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. The kits described herein may be useful in treating protozoan infections in a subject in need thereof, treating trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) infections) and/or treating plasmodial infections in a subject in need thereof, treating diseases in a subject in need thereof (e.g., Chagas disease and/or malaria), treating infectious diseases in a subject in need thereof, preventing protozoan infections, preventing trypanosomal infections (e.g., T. cruzi or Trypanosoma brucei infections) and/or plasmodial infections in a subject at risk of developing a protozoan or plamsodial infection, preventing protozoan infections in a subject at risk of developing a protozoan infection (e.g., trypanosomal infections from T. cruzi or Trypanosoma brucei and/or plasmodial infections), preventing infectious diseases in a subject at risk of developing an infectious disease, and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness). The kits described herein may also be useful as research tools (e.g., for studying trypanosomal infections (e.g., studying T. cruzi and/or plasmodial infections) in a subject, biological sample, tissue, or cell).

[0256] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in 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 (e.g., Chagas disease and/or malaria) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing an infectious disease (e.g., Chagas disease and/or malaria) in a subject at risk of developing an infectious disease. In certain embodiments, the kits and instructions provide for modulating (e.g., inhibiting) the activity of T. cruzi and/or plasmodial activity in a subject, biological sample, tissue, or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0257] Methods of Treatment and Uses

[0258] The protozoan parasite T. cruzi is associated with a number of diseases (e.g., Chagas disease). The protozoan parasite plasmodium is associated with a number of diseases (e.g., malaria). The compounds described herein may be capable of treating and/or preventing protozoan infections in a subject in need thereof, treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof. The compounds described herein may be capable of treating and/or preventing bacterial infections in a subject in need thereof. The compounds described herein may be capable of treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness).

[0259] The present disclosure thus provides methods of treating and/or preventing protozoan infections in a subject in need thereof, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein. Another aspect of the present disclosure relates to treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein. Another aspect of the present disclosure relates to treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein. Another aspect of the present disclosure relates to treating and/or preventing infectious diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein.

[0260] The present disclosure provides methods of treating and/or preventing protozoan infections in a subject in need thereof, the methods comprising killing or inhibiting the growth of protozoan parasites. Another aspect of the present disclosure relates to treating and/or preventing trypanosomal and/or plasmodial infections in a subject in need thereof, the methods comprising killing or inhibiting the growth of protozoan parasites. Another aspect of the present disclosure relates to treating and/or preventing diseases in a subject in need thereof, the methods comprising killing or inhibiting the growth of protozoan parasites. Another aspect of the present disclosure relates to treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), the methods comprising killing or inhibiting the growth of protozoan parasites. The present disclosure provides methods of treating and/or preventing infectious diseases, the methods comprising killing or inhibiting the growth of protozoan parasites. In certain embodiments, the method comprises killing protozoan parasites. In certain embodiments, the method comprises inhibiting the growth of protozoan parasites. In certain embodiments, the IC.sub.50 is below 5.0 μM. In certain embodiments, the IC.sub.50 is below 1.0 μM. In certain embodiments, the IC.sub.50 is below 0.5 μM. In certain embodiments, the IC.sub.50 is below 0.1 μM. In certain embodiments, the IC.sub.50 is below 0.05 μM.

[0261] In certain embodiments, a disease being treated and/or prevented is an infectious disease. In certain embodiments, a disease being treated and/or prevented is an parasitic disease. In certain embodiments, a disease described herein is a protozoan infectious disease. In certain embodiments, the disease is a plasmodial infectious disease. In certain embodiments, the disease is a trypanosomal infectious disease. In certain embodiments, the disease is a Leishmania infectious disease. In certain embodiments, a disease is a Trypanosoma cruzi (T. cruzi) infection. In certain embodiments, the disease is Chagas disease. In certain embodiments, the disease is sleeping sickness. In certain embodiments, the disease is leishmaniasis. In certain embodiments, the disease is malaria.

[0262] In still another aspect, the present disclosure provides the pharmaceutical compositions described herein for use in a method described herein (e.g., a method of treating and/or preventing protozoan infections in a subject in need thereof, a method of treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi (T. cruzi) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof, a method of treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), and a method of treating and/or preventing infectious diseases in a subject in need thereof.

EXAMPLES

[0263] 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 their scope.

[0264] Preparation and Characterization of the Compounds Described Herein

[0265] Preparation of the Compounds

[0266] The compounds provided herein can be prepared from readily available starting materials using methods known in the art, such as the methods described in Mauger et al., Eur. Pat. Appl., 1746097, 24 Jan. 2007, and the methods described in Nitsche et al., Journal of Medicinal Chemistry, 56(21), 8389-8403; 2013, and Bauer et al., Organic Letters, 12(9), 2084-2087; 2010 and Moura-Letts et al., Proceedings of the National Academy of Science USA, 108(17), 6745-6750; 2011. Where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0267] Materials and Methods

[0268] Reagents were obtained from Aldrich Chemical (www.sigma-aldrich.com) or Acros Organics (www.fishersci.com) and used without further purification. Optima or HPLC grade solvents were obtained from Fisher Scientific (www.fishersci.com), degassed with Ar, and purified on a solvent drying system. Reactions were performed in flame-dried glassware under positive Ar pressure with magnetic stirring. TLC was performed on 0.25 mm E. Merck silica gel 60 F254 plates and visualized under UV light (254 nm) or by staining with potassium permanganate (KMnO4), cerium ammonium molybdenate (CAM), or iodine (I2). Silica flash chromatography was performed on E. Merck 230-400 mesh silica gel 60. Optical rotations were recorded on a JASCO model P-1020 digital polarimeter. IR spectra were recorded on a Bruker Optics Tensor 27 FTIR spectrometer with Pike technologies MIRacle ATR (attenuated total reflectance, ZnSe crystal) accessory and peaks reported in cm.sup.1. NMR spectra were recorded on a Bruker Avance III 500 instrument or Bruker Avance III 600 instrument at 24° C. in CDCl3 unless otherwise indicated. Spectra were processed using Bruker TopSpin or Mnova (www.mestrelab.com/software/mnova-nmr), and chemical shifts are expressed in ppm relative to TMS (1H, 0 ppm) or residual solvent signals: CDCl3 (.sup.13C, 77.0 ppm); coupling constants are expressed in Hz. Mass spectra were obtained at the MSKCC Analytical Core Facility on a Waters Acuity SQD LC-MS by electrospray (ESI) ionization or atmospheric pressure chemical ionization (AP-CI).

[0269] General Preparation of Exemplary Compounds

##STR00207## ##STR00208##

Synthesis of Anti Analogues

[0270] ##STR00209##

Synthesis of Deshydroxyethyl Analogues

[0271] ##STR00210## ##STR00211##

Synthesis of Syn Analogues

Example 1. Preparation of Compound 21

(R)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-propane-2-sulfinamide

[0272] ##STR00212##

[0273] In a 100 mL roundbottom flask, LiHMDS (1.0 M in THF, 3.0 mL, 3.0 mmol, 1.1 equiv) was dissolved in 22 mL anhyd hexanes and cooled to 0° C. 1-bromo-3-ethynylbenzene (415 μL, 3.3 mmol, 1.2 equiv) was added and the reaction removed from the cold bath and stirred for 15 min. The reaction was recooled to 0° C., and (R,E)-N-(3-((tert-butyldiphenylsilyl)oxy)propylidene)-2-methylpropane-2-sulfinamide (1.15 g, 2.77 mmol, 1.0 equiv) was transferred via cannula into the reaction in 5.5 mL anhyd hexanes. The reaction was allowed to warm to room temperature with stirring for 12 h. Equal volumes of saturated aqueous NH.sub.4Cl and Et.sub.2O (20 mL each) were added to the reaction mixture. The layers were separated and the aq layer extracted with Et.sub.2O (3×20 mL) then EtOAc (1×20 mL). The combined organic extracts were washed with brine (1×20 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. .sup.1H NMR analysis of the crude sample indicated the product was produced in >20:1 d.r. Purification by silica flash chromatography (2:1 hexanes/EtOAc) yielded the N-propargyl sulfinamide as a sticky brown foam (1.05 g, 63%). TLC: R.sub.f 0.47 (40% EtOAc/hexanes). [α].sub.D.sup.20: −10.4° (c 0.55, CHCl.sub.3). IR (ATR): 2958, 2931, 2858, 1590, 1556, 1473, 1428, 1111, 1073, 762, 703. .sup.1H-NMR (600 MHz,): δ 7.67 (ddd, J=8.1, 2.7, 1.4 Hz, 4H), 7.52 (t, J=1.7 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.39-7.33 (m, 4H), 7.32 (dt, J=7.7, 1.3 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 4.59 (q, J=6.9 Hz, 1H), 3.91 (ddd, J=10.5, 6.6, 5.1 Hz, 1H), 3.86 (ddd, J=10.5, 6.4, 5.1 Hz, 1H), 3.61 (d, J=7.4 Hz, 1H), 2.11-1.96 (m, 2H), 1.21 (s, 9H), 1.06 (s, 9H). .sup.13C-NMR (151 MHz,): δ 135.5, 134.4, 133.3, 133.3, 131.5, 130.4, 129.7, 129.6, 127.7, 127.7, 124.6, 122.0, 90.2, 83.6, 60.3, 56.3, 45.6, 39.5, 26.8, 22.5, 19.2. HRMS m/z calcd for C.sub.31H.sub.38NO.sub.2NaSiSBr ([M+Na].sup.+) 618.1474; found 618.1462.

(R)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide

[0274] ##STR00213##

[0275] In a 100 mL roundbottom flask, (R)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-propane-2-sulfinamide (5.18 g, 8.68 mmol, 1.0 equiv) was dissolved in 43 mL DMF and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 416 mg, 10.4 mmol, 1.2 equiv) was added, followed by propargyl bromide (80% in toluene, 1.4 mL, 13.0 mmol, 1.5 equiv) and the mixture was stirred at 0° C. for 40 min, then allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of 50 mL saturated aqueous NH.sub.4Cl, then diluted with 50 mL of Et.sub.2O. The organic layer was washed with water (3×50 mL), then the combined aqueous layers extracted with Et.sub.2O (2×50 mL). The combined organic extracts were washed with brine (1×50 mL), dried (MgSO.sub.4), filtered, and concentrated by rotary evaporation.

[0276] Purification by silica flash chromatography (10%.fwdarw.30% EtOAc/hexanes) yielded the diyne as a sticky brown foam (5.14 g, 93%). TLC: R.sub.f 0.60 (30% EtOAc/hexanes). [α].sub.D.sup.21: +22.8° (c 1.0, CHCl.sub.3). IR (ATR): 3306, 2959, 2932, 2858, 1590, 1557, 1473, 1428, 1362, 1111, 1083, 761, 704. .sup.1H-NMR (600 MHz): δ 7.70-7.63 (m, 4H), 7.51 (t, J=1.7 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.36 (m, 3H), 7.36-7.31 (m, 2H), 7.30 (dt, J=7.7, 1.3 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 4.76 (dd, J=9.1, 6.2 Hz, 1H), 4.18 (dd, J=19.1, 2.6 Hz, 1H), 3.91 (dt, J=10.2, 5.0 Hz, 1H), 3.84 (ddd, J=10.5, 8.5, 4.0 Hz, 1H), 3.50 (dd, J=19.1, 2.4 Hz, 1H), 2.27 (dddd, J=13.4, 8.5, 6.2, 4.8 Hz, 1H), 2.15 (t, J=2.5 Hz, 1H), 2.13-2.06 (m, 1H), 1.26 (s, 9H), 1.06 (s, 9H). .sup.13C-NMR (151 MHz): δ 135.6, 135.5, 134.5, 133.5, 133.4, 131.6, 130.4, 129.7, 129.7, 129.6, 127.7, 127.7, 124.4, 122.0, 88.1, 84.6, 81.8, 77.0, 71.4, 60.1, 58.6, 37.6, 26.8, 22.9, 19.2, 14.2. HRMS m/z calcd for C.sub.34H.sub.40NO.sub.2NaSiSBr ([M+Na].sup.+) 656.1630; found 656.1633.

Ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0277] ##STR00214##

[0278] In a 500 mL roundbottom flask, Rh(COD).sub.2BF.sub.4 (493 mg, 1.21 mmol, 15 mol %) and rac-BINAP (1.01 g, 1.62 mmol, 20 mol %) were dissolved in 260 mL of degassed 1,2-dichloroethane. Ethyl cyanoformate (4.0 mL, 40.5 mmol, 5.0 equiv) was added, followed by a solution of (R)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide (5.14 g, 8.10 mmol, 1.0 equiv) in 10 mL of 1,2-dichloroethane. The mixture was heated to 75° C. (oil bath, ext temp) for 4 h, then cooled to room temperature and concentrated by rotary evaporation. Purification by silica flash chromatography (25.fwdarw.45% EtOAc/hexanes) yielded the pyrrolopyridinecarboxylate as an orange foam (5.08 g, 85%). TLC: R.sub.f 0.14 (30% EtOAc/hexanes). [α].sub.D.sup.19: +30.7° (c 1.0, CHCl.sub.3). IR (ATR): 3071, 3050, 3050, 2932, 2858, 1742, 1717, 1576, 1227 1108, 1075, 741, 703. .sup.1H-NMR (600 MHz): δ 7.96 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.60 (dt, J=7.7, 1.2 Hz, 1H), 7.53 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.50-7.45 (m, 2H), 7.45-7.39 (m, 4H), 7.36-7.30 (m, 4H), 7.11 (t, J=7.8 Hz, 1H), 5.74 (dt, J=8.1, 2.6 Hz, 3H), 5.17 (d, J=15.9 Hz, 1H), 4.52 (dq, J=10.9, 7.1 Hz, 1H), 4.44 (dq, J=10.9, 7.1 Hz, 1H), 4.00 (ddd, J=15.8, 2.0, 1.0 Hz, 1H), 3.67 (ddd, J=10.4, 8.9, 4.9 Hz, 1H), 3.46 (ddd, J=10.4, 6.1, 4.2 Hz, 1H), 1.73 (dddd, J=14.6, 9.1, 6.2, 3.2 Hz, 1H), 1.53-1.47 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.22 (s, 9H), 0.98 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.9, 152.1, 151.5, 147.7, 140.5, 139.3, 135.5, 135.4, 133.4, 133.2, 132.1, 131.9, 130.2, 129.7, 129.7, 127.7, 127.6, 126.7, 123.2, 118.5, 68.5, 62.0, 59.3, 58.6, 45.7, 37.7, 26.8, 23.7, 19.1, 14.3. HRMS m/z calcd for C.sub.38H.sub.46N.sub.2O.sub.4SiSBr ([M+H].sup.+) 733.2131; found 733.2120.

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di-methylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0279] ##STR00215##

[0280] In a 100 mL roundbottom flask, Ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (556 mg, 0.758 mmol, 1.0 equiv), Na.sub.2PdCl.sub.4 (22 mg, 0.0758 mmol, 10 mol %), t-Bu.sub.3PHBF.sub.4 (33 mg, 0.114 mmol, 15 mol %), and CuI (29 mg, 0.152 mmol, 20 mol %) were dissolved in 4.7 mL of degassed 1,2-dimethoxyethane and 14.1 mL of degassed i-Pr.sub.2NH. N,N-dimethylprop-2-yn-1-amine (408 μL, 3.79 mmol, 5.0 equiv) was added, then the mixture heated to 75° C. (oil bath, ext temp) for 24 h. The reaction was cooled to room temperature and diluted with EtOAc, then filtered through Celite and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a dark orange foam (496 mg, 89%). TLC: R.sub.f 0.25 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +29.0° (c 1.0, CHCl.sub.3). IR (ATR): 3071, 3050, 2956, 2859, 2777, 1741, 1718, 1577, 1472, 1256, 1219, 1107, 1076, 742, 703. .sup.1H-NMR (600 MHz): δ 7.94 (s, 1H), 7.83 (s, 1H), 7.60 (dt, J=7.8, 1.4 Hz, 1H), 7.48 (ddd, J=8.0, 6.3, 1.4 Hz, 3H), 7.43-7.37 (m, 4H), 7.33 (td, J=7.2, 1.5 Hz, 4H), 7.23 (t, J=7.8 Hz, 1H), 5.73 (dt, J=7.8, 2.5 Hz, 1H), 5.16 (d, J=15.7 Hz, 1H), 4.51 (dq, J=10.9, 7.1 Hz, 1H), 4.44 (dq, J=10.9, 7.1 Hz, 1H), 3.98 (d, J=14.9 Hz, OH), 3.64 (ddd, J=10.3, 8.7, 5.1 Hz, 1H), 3.50 (s, 2H), 3.44 (ddd, J=10.5, 6.3, 4.4 Hz, 1H), 2.38 (s, 6H), 1.74 (dddd, J=14.6, 9.2, 6.3, 3.2 Hz, 1H), 1.52-1.45 (m, 1H), 1.43 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 0.97 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.0, 153.0, 151.2, 147.6, 139.2, 138.8, 135.5, 135.4, 133.3, 133.2, 132.3, 132.0, 129.7, 129.6, 128.7, 127.7, 127.6, 127.6, 124.0, 118.3, 85.3, 85.0, 68.6, 61.9, 59.4, 58.5, 48.6, 45.7, 44.3, 37.5, 26.8, 23.7, 19.0, 14.3. HRMS m/z calcd for C.sub.43H.sub.54N.sub.3O.sub.4SSi ([M+H].sup.+) 736.3604; found 736.3615.

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0281] ##STR00216##

[0282] To a 10 mL roundbottom flask containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (247 mg, 0.336 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH2Cl2/toluene, 3.36 mL, 0.671 mmol, 2.0 equiv). The mixture was stirred at room temperature for 17 h, then carefully quenched by dropwise addition of 0.5 mL MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×5 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes.fwdarw.100% EtOAc) yielded (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo¬[3,4 c]¬¬-pyridine-6-carboxamide as a light orange foam (203 mg, 72%). TLC: R.sub.f 0.50 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +22.1° (c 1.0, CHCl.sub.3). IR (ATR): 3388, 3052, 2978, 2945, 2912, 2873, 2779, 1670, 1574, 1526, 1490, 1445, 1253, 1040, 929, 737. .sup.1H-NMR (600 MHz): δ 8.33 (t, J=6.3 Hz, 1H), 8.10 (s, 1H), 7.73 (t, J=1.7 Hz, 1H), 7.59 (dt, J=7.8, 1.4 Hz, 1H), 7.53 (dt, J=7.7, 1.3 Hz, 1H), 7.47-7.40 (m, 1H), 6.86 (d, J=1.7 Hz, 1H), 6.82 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.93 (q, J=1.4 Hz, 2H), 5.66 (dt, J=5.9, 2.6 Hz, 1H), 5.20 (d, J=15.7 Hz, 1H), 4.64-4.49 (m, 2H), 4.14 (d, J=14.5 Hz, 1H), 3.54 (ddd, J=10.8, 7.7, 6.1 Hz, 1H), 3.41 (ddd, J=11.2, 6.7, 5.1 Hz, 1H), 2.38 (s, 6H), 1.78-1.67 (m, 1H), 1.63-1.59 (m, 2H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 151.8, 151.4, 149.4, 147.9, 146.9, 138.6, 137.4, 132.4, 132.1, 131.4, 128.8, 127.8, 123.9, 121.0, 115.8, 108.4, 108.3, 101.0, 85.8, 84.5, 68.6, 58.5, 58.4, 48.6, 46.0, 44.4, 43.2, 37.5, 23.8. HRMS m/z calcd for C.sub.33H.sub.39N.sub.4O.sub.5S ([M+H].sup.+) 603.2641; found 603.2643.

Preparation of Dimethylaluminum Piperonylamide Stock Solution

[0283] To a 10 mL roundbottom flask containing piperonylamine (125 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH2Cl2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at rt. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethyl-amino)prop-1-yn-1-yl)phenyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 21)

[0284] ##STR00217##

[0285] In a 10 mL roundbottom flask, (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo¬[3,4 c]¬¬-pyridine-6-carboxamide (190 mg, 0.226 mmol, 1.0 equiv) was dissolved in 2.3 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 339 μL, 0.339 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 3 mL EtOAc and 3 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (1×3 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation.

[0286] Purification by silica flash chromatography (10% MeOH/EtOAc) yielded pyrrolopyridinecarboxamide compound 21 as a light yellow foam (98 mg, 72%).

Preparation of Compound 79

[0287] Preparation of enantiomer 79 is analogous to the synthesis of compound 21.

Example 2. Preparation of Compound 37

(R)—N—((R)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0288] ##STR00218##

[0289] To a 10 mL roundbottom flask containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (247 mg, 0.336 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (R)-1-benzylpyrrolidin-3-amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 3.36 mL, 0.671 mmol, 2.0 equiv). The mixture was stirred at room temperature for 22 h, then carefully quenched by dropwise addition of 0.5 mL MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×5 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% CH.sub.2Cl.sub.2.fwdarw.10% MeOH/CH.sub.2Cl.sub.2) yielded (R)—N—((R)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a yellow foam (218 mg, 75%). TLC: R.sub.f 0.19 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +25.5° (c 1.0, CHCl.sub.3). IR (ATR): 3384, 3068, 2955, 2858, 2783, 1674, 1574, 1519, 1472, 1454, 1428, 1111, 1076, 755, 702. .sup.1H-NMR (600 MHz): δ 8.25 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.46 (d, J=6.8 Hz, 2H), 7.43-7.28 (m, 13H), 7.23 (t, J=7.2 Hz, 1H), 5.71 (d, J=6.8 Hz, 1H), 5.14 (d, J=15.8 Hz, 1H), 4.73-4.58 (m, 1H), 3.96 (d, J=15.4 Hz, 1H), 3.70 (d, J=12.9 Hz, 1H), 3.66-3.55 (m, 2H), 3.48 (s, 2H), 3.43 (dt, J=10.5, 5.5 Hz, 1H), 2.87 (td, J=8.7, 4.4 Hz, 1H), 2.75 (dd, J=9.6, 6.6 Hz, 1H), 2.67 (dd, J=9.7, 3.5 Hz, 1H), 2.44-2.39 (m, 1H), 2.38 (s, 6H), 2.36-2.31 (m, 1H), 1.82-1.67 (m, 2H), 1.54-1.42 (m, 1H), 1.21 (s, 9H), 0.95 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.2, 151.6, 151.3, 149.3, 138.9, 138.9, 138.3, 135.5, 135.4, 133.3, 133.2, 132.3, 131.5, 129.6, 129.6, 128.8, 128.7, 128.3, 127.8, 127.6, 127.6, 127.0, 124.0, 115.5, 85.7, 84.8, 68.4, 60.5, 60.0, 59.4, 58.5, 52.8, 48.6, 48.6, 45.9, 44.4, 37.7, 32.3, 26.8, 23.8, 19.0. HRMS m/z calcd for C.sub.52H.sub.64N.sub.5O.sub.3SSi ([M+H].sup.+) 866.4499; found 866.4496.

Preparation of dimethylaluminum (R)-1-benzylpyrrolidin-3-amide Stock Solution

[0290] To a 10 mL roundbottom flask containing (R)-1-benzylpyrrolidin-3-amine (173 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH2Cl2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at room temperature. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)—N—((R)-1-Benzylpyrrolidin-3-yl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 37)

[0291] ##STR00219##

[0292] In a 10 mL roundbottom flask, (R)—N—((R)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (205 mg, 0.237 mmol, 1.0 equiv) was dissolved in 2.4 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 355 μL, 0.355 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 3 mL EtOAc and 3 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (1×3 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation.

[0293] Purification by silica flash chromatography (10% MeOH/EtOAc) yielded pyrrolopyridinecarboxamide 37 as a light yellow foam (102 mg, 68%). TLC: R.sub.f 0.44 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +10.7° (c 1.0, CHCl.sub.3). IR (ATR): 3378, 2951, 2974, 2869, 2822, 2785, 1669, 1573, 1522, 1455, 1265, 1070, 751, 701. .sup.1H-NMR (600 MHz): δ 8.29 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.37-7.30 (m, 4H), 7.25-7.23 (m, 1H), 5.72-5.60 (m, 1H), 5.19 (d, J=15.7 Hz, 1H), 4.74-4.58 (m, 1H), 4.12 (d, J=15.6 Hz, 1H), 3.70 (d, J=12.9 Hz, 1H), 3.62 (d, J=12.9 Hz, 1H), 3.54 (dt, J=10.8, 6.9 Hz, 1H), 3.49 (s, 2H), 3.41 (dt, J=11.0, 5.2 Hz, 1H), 2.89 (td, J=8.7, 4.1 Hz, 1H), 2.74 (dd, J=9.7, 6.6 Hz, 1H), 2.70 (dd, J=9.8, 3.4 Hz, 1H), 2.44-2.40 (m, 1H), 2.39 (s, 6H), 2.38-2.31 (m, 1H), 1.81-1.68 (m, 2H), 1.64-1.56 (m, 1H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.2, 151.6, 151.3, 149.5, 138.7, 137.2, 132.5, 131.4, 128.8, 128.7, 128.3, 128.3, 128.0, 127.1, 123.9, 115.6, 85.6, 84.7, 68.6, 60.4, 59.9, 58.5, 58.4, 52.7, 48.6, 48.5, 46.0, 44.3, 37.6, 32.3, 23.8. HRMS m/z calcd for C.sub.36H.sub.46N.sub.5O.sub.3S ([M+H].sup.+) 628.3321; found 628.3331.

Preparation of Compound 88

[0294] Preparation of enantiomer 88 is analogous to the synthesis of compound 37.

Example 3. Preparation of Compound 89

(R)—N—((S)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0295] ##STR00220##

[0296] To a 10 mL roundbottom flask containing Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (333 mg, 0.452 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (S)-1-benzylpyrrolidin-3-amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 4.5 mL, 0.905 mmol, 2.0 equiv). The mixture was stirred at room temperature for 12 h, then carefully quenched by dropwise addition of 0.5 mL MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×5 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% CH.sub.2Cl.sub.2.fwdarw.10% MeOH/CH.sub.2Cl.sub.2) yielded (R)—N—((S)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky yellow foam (338 mg, 86%). TLC: R.sub.f 0.45 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +92.030 (c 1.0, CHCl.sub.3). IR (ATR): 3387, 2954, 2859, 2786, 1673, 1575, 1520, 1109, 1076, 758, 703. .sup.1H-NMR (600 MHz): δ 8.23 (d, J=8.2 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.9 Hz, 2H), 7.44-7.36 (m, 4H), 7.36-7.29 (m, 7H), 7.28-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.21 (t, J=7.2 Hz, 1H), 5.71 (d, J=6.9 Hz, 1H), 5.14 (d, J=15.8 Hz, 1H), 4.70-4.58 (m, 1H), 3.97 (d, J=15.0 Hz, 1H), 3.70-3.55 (m, 3H), 3.50 (s, 2H), 3.43 (dt, J=10.5, 5.8 Hz, 1H), 2.87 (td, J=8.5, 7.9, 4.2 Hz, 1H), 2.76 (dd, J=9.8, 6.8 Hz, 1H), 2.63 (dd, J=9.8, 3.7 Hz, 1H), 2.50-2.31 (m, 8H), 1.87-1.77 (m, 1H), 1.77-1.68 (m, 1H), 1.56-1.45 (m, 1H), 1.21 (s, 9H), 0.96 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.3, 151.6, 151.3, 149.2, 138.9, 138.7, 138.2, 135.4, 135.4, 133.3, 133.2, 132.2, 131.6, 129.6, 129.6, 128.8, 128.7, 128.2, 127.7, 127.6, 127.6, 127.0, 123.9, 115.4, 85.5, 84.9, 68.4, 60.2, 60.0, 59.3, 58.5, 52.7, 48.7, 48.6, 45.8, 44.3, 37.7, 32.5, 26.8, 23.8, 19.0. HRMS m/z calcd for C.sub.52H.sub.64N.sub.5O.sub.3SSi ([M+H].sup.+) 866.4499; found 866.4534.

Preparation of dimethylaluminum (S)-1-benzylpyrrolidin-3-amide Stock Solution

[0297] To a 10 mL roundbottom flask containing (S)-1-benzylpyrrolidin-3-amine (173 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH2Cl2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at rt. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)—N—((S)-1-benzylpyrrolidin-3-yl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 89)

[0298] ##STR00221##

[0299] In a 10 mL roundbottom flask, (R)—N—((S)-1-Benzylpyrrolidin-3-yl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (312 mg, 0.360 mmol, 1.0 equiv) was dissolved in 2.3 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 540 μL, 0.540 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 5 h. The reaction mixture was diluted with 3 mL EtOAc and 3 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (1×3 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/EtOAc) yielded compound 89 as a light yellow foam (150 mg, 66%). TLC: R.sub.f 0.19 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +77.9° (c 1.0, CHCl.sub.3). IR (ATR): 3376, 3063, 2950, 2869, 2789, 1667, 1574, 1523, 1454, 1361, 1068, 757. .sup.1H-NMR (600 MHz): δ 8.24 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.33-7.29 (m, 2H), 7.25-7.18 (m, 2H), 5.69-5.63 (m, 1H), 5.18 (d, J=15.7 Hz, 1H), 4.68-4.57 (m, 2H), 4.12 (d, J=15.6 Hz, 1H), 3.68-3.58 (m, 2H), 3.54 (dt, J=10.8, 6.9 Hz, 1H), 3.49 (s, 2H), 3.41 (dt, J=11.2, 5.9 Hz, 1H), 2.91-2.84 (m, 1H), 2.74 (dd, J=9.6, 6.9 Hz, 1H), 2.64 (dd, J=10.8, 2.7 Hz, 1H), 2.47-2.33 (m, 8H), 1.85-1.76 (m, 1H), 1.77-1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.3, 151.6, 151.2, 149.4, 138.7, 138.3, 137.2, 132.4, 131.4, 128.8, 128.8, 128.3, 128.0, 127.1, 123.8, 115.5, 85.2, 84.9, 68.6, 60.1, 59.9, 58.5, 58.4, 52.7, 48.6, 48.3, 46.0, 44.0, 37.6, 32.4, 23.8. HRMS m/z calcd for C.sub.36H.sub.46N.sub.5O.sub.3S ([M+H].sup.+) 628.3321; found 628.3323.

Example 4. Preparation of Compound 51

Ethyl (R)-4-(3-bromophenyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (Compound 51)

[0300] ##STR00222##

[0301] In a small vial, ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (19 mg, 0.0255 mmol, 1.0 equiv) was dissolved in 0.25 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 33 μL, 0.331 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 15 min, then allowed to warm to room temperature. After 3 h, the reaction mixture was diluted with 1 mL EtOAc and 1 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (3% MeOH/EtOAc) yielded compound 51 as a light yellow foam (9 mg, 72%). TLC: R.sub.f 0.47 (10% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (600 MHz): δ 7.99 (s, 1H), 7.91 (t, J=1.8 Hz, 1H), 7.67 (ddd, J=7.7, 1.7, 1.0 Hz, 1H), 7.58 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 5.67 (ddd, J=6.8, 3.4, 2.0 Hz, 1H), 5.21 (dd, J=15.6, 1.0 Hz, 1H), 4.51 (dq, J=10.8, 7.1 Hz, 1H), 4.45 (dq, J=10.9, 7.1 Hz, 1H), 4.13 (ddd, J=15.7, 2.2, 1.0 Hz, 1H), 3.57 (ddt, J=11.3, 7.9, 5.8 Hz, 1H), 3.52-3.41 (m, 1H), 1.79-1.68 (m, 1H), 1.68-1.58 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.31 (s, 9H), 1.07 (t, J=5.4 Hz, 1H). .sup.13C-NMR (151 MHz): δ 164.9, 152.2, 151.4, 147.9, 140.4, 138.2, 132.3, 131.6, 130.2, 127.0, 123.1, 118.5, 68.7, 62.1, 58.5, 58.5, 45.8, 37.5, 23.8, 14.3. LRMS (ESI+) m/z calcd for C.sub.22H.sub.27BrN.sub.2O.sub.4S ([M+H].sup.+) 495.09; found 494.9.

Example 5. Preparation of Compound 90

Ethyl (R)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (Compound 90)

[0302] ##STR00223##

[0303] In a small vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (22 mg, 0.0299 mmol, 1.0 equiv) was dissolved in 0.30 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 45 μL, 0.448 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (5% MeOH/EtOAc) yielded pyrrolopyridinecarboxylate 90 as a light yellow foam (13 mg, 65%). TLC: R.sub.f 0.32 (10% MeOH/CH.sub.2Cl.sub.2). .sup.1H-NMR (600 MHz): δ 7.98 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.67 (dt, J=7.8, 1.5 Hz, 1H), 7.51 (dt, J=7.7, 1.4 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 5.67 (ddd, J=6.0, 3.3, 2.0 Hz, 1H), 5.20 (d, J=16.4 Hz, 1H), 4.51 (dq, J=10.9, 7.1 Hz, 1H), 4.44 (dq, J=10.8, 7.1 Hz, 1H), 4.13 (ddd, J=15.6, 2.1, 1.0 Hz, 1H), 3.53 (ddd, J=10.8, 7.7, 6.1 Hz, 1H), 3.49 (s, 2H), 3.42 (ddd, J=10.8, 6.7, 5.1 Hz, 1H), 2.38 (s, 6H), 1.76-1.69 (m, 1H), 1.64-1.56 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.0, 153.0, 151.2, 147.9, 138.6, 138.1, 132.4, 131.7, 128.7, 128.1, 123.9, 118.3, 85.3, 84.9, 68.8, 62.0, 58.5, 58.4, 48.5, 45.8, 44.2, 37.5, 23.7, 14.3. HRMS m/z calcd for C.sub.27H.sub.36N.sub.3O.sub.4S ([M+H].sup.+) 498.2427; found 498.2446.

Preparation of Compound 91

[0304] Preparation of enantiomer 91 is analogous to the synthesis of compound 90.

Example 6. Preparation of Compound 77

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenyl-silyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0305] ##STR00224##

[0306] To a vial containing ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (22 mg, 0.0301 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide.sup.3 (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.30 mL, 0.0602 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-bromophenyl)-3-(2-((tert-butyldi¬phenyl-silyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky orange foam (18 mg, 72%). TLC: R.sub.f 0.26 (50% EtOAc/hexanes). [α].sub.D.sup.20: +61.2° (c 1.0, CHCl.sub.3). IR (ATR): 3392, 2956, 2932, 2859, 1674, 1574, 1525, 1490, 1444, 1253, 1189, 1108, 1074, 1043, 933, 760, 704. .sup.1H-NMR (600 MHz): δ 8.29 (t, J=6.3 Hz, 1H), 8.08 (s, 1H), 7.79 (t, J=1.8 Hz, 1H), 7.58-7.52 (m, 2H), 7.48-7.44 (m, 2H), 7.44-7.36 (m, 4H), 7.36-7.29 (m, 4H), 7.12 (t, J=7.9 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 6.83 (dd, J=8.0, 1.7 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 5.93 (s, 1H), 5.71 (dt, J=7.8, 2.6 Hz, 1H), 5.16 (d, J=15.8 Hz, 1H), 4.65-4.52 (m, 2H), 4.00 (ddd, J=15.8, 2.0, 1.0 Hz, 1H), 3.66 (ddd, J=10.4, 8.6, 4.9 Hz, 1H), 3.45 (ddd, J=10.5, 6.0, 4.5 Hz, 1H), 1.79-1.66 (m, 1H), 1.54-1.44 (m, 1H), 1.22 (s, 9H), 0.96 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.7, 152.0, 150.5, 149.2, 147.9, 146.9, 140.5, 138.6, 135.5, 135.4, 133.4, 133.2, 132.2, 132.1, 131.6, 130.3, 129.7, 129.7, 127.7, 127.6, 126.6, 123.0, 121.0, 115.9, 108.4, 108.3, 101.0, 68.4, 59.3, 58.6, 45.9, 43.2, 37.8, 26.8, 23.8, 19.1. HRMS m/z calcd for C.sub.44H.sub.49BrN.sub.3O.sub.5SSi ([M+H].sup.+) 838.2346; found 838.2344.

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-bromophenyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 77)

[0307] ##STR00225##

[0308] In a small vial, (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-bromophenyl)-3-(2-((tert-butyldi¬phenyl-silyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (18 mg, 0.0215 mmol, 1.0 equiv) was dissolved in 0.21 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 28 μL, 0.279 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 5 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (75% EtOAc/hexanes) yielded pyrrolopyridinecarboxamide 77 as a light yellow foam (7 mg, 58%). TLC: R.sub.f 0.56 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +37.8° (c 0.74, CHCl.sub.3). IR (ATR): 3391, 2957, 2924, 1666, 1572, 1527, 1491, 1444, 1252, 1041, 932, 758. .sup.1H-NMR (600 MHz): δ 8.30 (t, J=6.3 Hz, 1H), 8.11 (s, 1H), 7.82 (t, J=1.9 Hz, 1H), 7.63-7.54 (m, 2H), 7.36 (t, J=7.8 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.82 (dd, J=7.9, 1.6 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 5.99-5.91 (m, 2H), 5.65 (dt, J=5.9, 2.6 Hz, 1H), 5.20 (d, J=15.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.66-3.53 (m, 1H), 3.51-3.36 (m, 1H), 1.72 (dddd, J=14.5, 7.9, 6.6, 3.3 Hz, 1H), 1.63-1.58 (m, 2H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.7, 152.0, 150.6, 149.4, 147.9, 146.9, 140.3, 137.6, 132.3, 132.1, 131.4, 130.3, 126.8, 123.0, 121.0, 116.0, 108.4, 108.3, 101.0, 68.6, 58.5, 58.5, 46.0, 43.3, 37.6, 23.8. HRMS m/z calcd for C.sub.28H.sub.31BrN.sub.3O.sub.5S ([M+H].sup.+) 600.1168; found 600.1152.

Preparation of Compound 78

[0309] Preparation of enantiomer 78 is analogous to the synthesis of compound 77.

Example 7. Preparation of Compound 86(R)—N—((R)-1-Benzylpyrrolidin-3-yl)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0310] ##STR00226##

[0311] To a 10 mL roundbottom flask containing ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (24 mg, 0.0330 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (R)-1-benzylpyrrolidin-3-amide.sup.4 (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.33 mL, 0.0660 mmol, 2.0 equiv). The mixture was stirred at room temperature for 20 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (1×5 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded (R)—N—((R)-1-Benzylpyrrolidin-3-yl)-4-(3-bromophenyl)-3-(2-((tert-butyl¬diphenyl-silyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky orange foam (25 mg, 89%). TLC: R.sub.f 0.68 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +40.4° (c 1.0, CHCl.sub.3). IR (ATR): 3388, 3069, 2956, 2859, 2797, 1672, 1573, 1520, 1474, 1428, 1217, 1108, 1074, 942, 757, 702. .sup.1H-NMR (600 MHz): δ 8.24 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.65-7.56 (m, 2H), 7.48-7.44 (m, 2H), 7.44-7.41 (m, 2H), 7.41-7.37 (m, 2H), 7.37-7.28 (m, 8H), 7.25-7.20 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 5.72 (ddd, J=8.0, 3.2, 1.8 Hz, 1H), 5.15 (d, J=16.3 Hz, 1H), 4.74-4.59 (m, 1H), 3.97 (d, J=15.7 Hz, OH), 3.70 (d, J=12.9 Hz, 1H), 3.66 (ddd, J=10.1, 8.5, 4.8 Hz, 1H), 3.62 (d, J=12.9 Hz, 1H), 3.45 (ddd, J=10.4, 6.0, 4.4 Hz, 1H), 2.90 (td, J=8.3, 7.5, 3.5 Hz, 1H), 2.73 (dd, J=9.8, 6.3 Hz, 1H), 2.70 (dd, J=9.8, 3.6 Hz, 1H), 2.51-2.27 (m, 2H), 1.83-1.66 (m, 2H), 1.57-1.43 (m, 1H), 1.21 (s, 9H), 0.97 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.1, 151.9, 150.4, 149.3, 140.6, 138.8, 138.4, 135.5, 135.4, 133.4, 133.1, 132.1, 131.6, 130.3, 129.7, 129.7, 128.7, 128.3, 127.6, 127.6, 127.0, 126.7, 123.0, 115.7, 68.4, 60.5, 60.0, 59.3, 58.5, 52.7, 48.6, 45.8, 37.8, 32.3, 26.8, 23.8, 19.1. HRMS m/z calcd for C.sub.47H.sub.56BrN.sub.4O.sub.3SSi ([M+H].sup.+) 863.3026; found 863.3022.

(R)—N—((R)-1-Benzylpyrrolidin-3-yl)-4-(3-bromophenyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 86)

[0312] ##STR00227##

[0313] In a small vial, (R)—N—((R)-1-Benzylpyrrolidin-3-yl)-4-(3-bromophenyl)-3-(2-((tert-butyl¬diphenyl-silyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (25 mg, 0.0293 mmol, 1.0 equiv) was dissolved in 0.29 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 44 μL, 0.439 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (3% MeOH/EtOAc) yielded pyrrolopyridinecarboxylamide 86 as a light yellow foam (14 mg, 76%). TLC: R.sub.f 0.50 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +19.6° (c 1.0, CHCl.sub.3). IR (ATR): 3381, 2956, 2802, 1667, 1573, 1524, 1453, 1238, 1070, 923, 758, 670. .sup.1H-NMR (600 MHz): δ 8.27 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.88 (t, J=1.8 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.37-7.29 (m, 4H), 7.26-7.24 (m, 1H), 5.71-5.61 (m, 1H), 5.18 (d, J=15.8 Hz, 1H), 4.74-4.50 (m, 1H), 4.12 (d, J=14.6 Hz, 1H), 3.71 (d, J=12.8 Hz, 1H), 3.63 (d, J=12.9 Hz, 1H), 3.56 (ddd, J=10.7, 7.8, 6.0 Hz, 1H), 3.43 (ddd, J=11.1, 6.6, 5.0 Hz, 1H), 2.91 (td, J=8.5, 7.9, 3.5 Hz, 1H), 2.76-2.65 (m, 2H), 2.45-2.26 (m, 2H), 1.84-1.66 (m, 2H), 1.66-1.54 (m, 1H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.0, 151.9, 150.4, 149.5, 140.4, 138.6, 137.4, 132.3, 131.4, 130.3, 128.8, 128.3, 127.1, 126.9, 123.0, 115.8, 68.6, 60.4, 59.9, 58.4, 58.4, 52.7, 48.6, 45.9, 37.6, 32.3, 23.8. HRMS m/z calcd for C.sub.31H.sub.38BrN.sub.4O.sub.3S ([M+H].sup.+) 625.1848; found 625.1872.

Preparation of Compound 87

[0314] Preparation of enantiomer 87 is analogous to the synthesis of compound 86.

Synthesis of Anti Analogues

Example 8. Preparation of Compound 85

1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-ol

[0315] ##STR00228##

[0316] In a 25 mL roundbottom flask, 1-bromo-3-ethynylbenzene (243 μL, 1.94 mmol, 1.1 equiv) was dissolved in 10 mL THF and cooled to −78° C. A solution of LiHMDS (1 M in THF, 1.9 mL, 1.85 mmol, 1.05 equiv) was added dropwise, then the mixture allow to warm to room temperature and stir for 15 min. The reaction was cooled again to −78° C. and a solution of 3-((tert-butyldiphenylsilyl)oxy)propanal (552 mg, 1.77 mmol, 1.0 equiv) in 1.8 mL THF was added by cannula. The reaction was allowed to warm to room temperature and was stirred for 12 hr. 10 mL saturated aqueous NH.sub.4Cl was added to quench the reaction, followed by 10 mL Et.sub.2O, then the aq layer was extracted with Et.sub.2O (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried (MgSO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10-20% EtOAc/hexanes) yielded the propargyl alcohol as a clear yellow oil (802 mg, 92%). TLC: R.sub.f 0.49 (20% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.76-7.64 (m, 4H), 7.56 (t, J=1.8 Hz, 1H), 7.48-7.32 (m, 8H), 7.18 (t, J=7.9 Hz, 1H), 4.92 (td, J=6.4, 4.3 Hz, 1H), 4.12 (ddd, J=10.5, 8.2, 3.7 Hz, 1H), 3.89 (ddd, J=10.3, 5.9, 4.2 Hz, 1H), 3.49 (d, J=6.4 Hz, 1H), 2.20-2.07 (m, 1H), 2.03-1.96 (m, 1H), 1.06 (s, 9H). .sup.13C-NMR (151 MHz): δ 135.5, 134.5, 132.7, 131.5, 130.3, 129.9, 129.7, 127.8, 124.7, 122.0, 91.0, 83.5, 62.2, 61.9, 38.5, 26.8, 19.0.

1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-one

[0317] ##STR00229##

[0318] In a 25 mL roundbottom flask, the propargyl alcohol (802 mg, 1.63 mmol, 1.0 equiv) was dissolved in 10.8 mL CH.sub.2Cl.sub.2 and cooled to 0° C. Dess-Martin periodinane (758 mg, 1.79 mmol, 1.1 equiv) was added and the mixture was stirred at 0° C. for 15 min, then allowed to warm to room temperature. After 5 h, 8 mL sat aq NaHCO.sub.3 was added to quench the reaction and the layers separated. The aq layer was extracted with CH.sub.2Cl.sub.2 (2×8 mL), then the combined organic extracts were washed with brine (1×8 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% EtOAc/hexanes) yielded the alkynone as a light yellow oil (763 mg, 95%). TLC: R.sub.f 0.47 (10% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.69-7.64 (m, 5H), 7.59 (ddd, J=8.1, 2.0, 1.1 Hz, 1H), 7.46-7.40 (m, 3H), 7.38-7.34 (m, 4H), 7.28-7.24 (m, 1H), 4.08 (t, J=6.1 Hz, 2H), 2.88 (t, J=6.1 Hz, 2H), 1.03 (s, 9H). .sup.13C-NMR (151 MHz): δ 186.0, 135.6, 135.5, 133.8, 133.2, 131.5, 130.0, 129.7, 127.7, 122.3, 121.9, 88.7, 88.3, 59.4, 48.3, 26.7, 19.2.

(S)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-propane-2-sulfinamide

[0319] ##STR00230##

[0320] In a 15 mL roundbottom flask, the alkynone (328 mg, 0.667 mmol, 1.0 equiv)] and (S)-2-methylpropane-2-sulfinamide (89 mg, 0.734 mmol, 1.1 equiv) were dissolved in 2.7 mL THF and Ti(OEt).sub.4 (technical grade, ca. 20% Ti, 699 μL, 3.34 mmol, 5.0 equiv) was added at room temperature. The reaction was heated to 60° C. until full consumption of the alkynone (24 h), then cooled to −48° C. and solid NaBH.sub.4 (101 mg, 2.67 mmol, 4.0 equiv) was added in one portion. The reaction was stirred at −48° C. for 1 h, then allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by the slow addition of 1.5 mL MeOH, then the mixture was poured into vigorously stirring brine (5 mL) and diluted with 10 mL EtOAc. The layers were separated and the aq layer extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (25-45% EtOAc/hexanes) yielded the N-propargyl sulfinamide as a light yellow oil (263 mg, 66%). TLC: R.sub.f 0.46 (33% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.68 (ddd, J=7.9, 3.4, 1.4 Hz, 4H), 7.51 (t, J=1.8 Hz, 1H), 7.47-7.32 (m, 8H), 7.29 (dt, J=7.7, 1.3 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 4.66 (dt, J=7.3, 6.0 Hz, 1H), 3.90 (tdd, J=10.6, 9.2, 4.9 Hz, 2H), 3.73 (d, J=5.8 Hz, 1H), 2.25-2.11 (m, 1H), 2.05 (dddd, J=13.4, 7.3, 5.8, 4.4 Hz, 1H), 1.22 (s, 9H), 1.07 (s, 9H). .sup.13C-NMR (151 MHz): δ 135.6, 135.5, 134.4, 133.2, 133.2, 131.5, 130.3, 129.7, 129.7, 129.7, 127.8, 127.7, 124.7, 122.0, 89.7, 83.6, 60.9, 56.0, 46.6, 39.5, 26.9, 22.5, 19.2.

(S)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide

[0321] ##STR00231##

[0322] In a 10 mL roundbottom flask, (S)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-propane-2-sulfinamide (252 mg, 0.422 mmol, 1.0 equiv) was dissolved in 2.1 mL DMF and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 20 mg, 0.507 mmol, 1.2 equiv) was added, followed by propargyl bromide (80% in toluene, 68 μL, 0.633 mmol, 1.5 equiv) and the mixture was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for 1.5 h. The reaction was quenched by the addition of 5 mL sat aq NH.sub.4Cl, then diluted with 5 mL of Et.sub.2O. The organic layer was washed with water (3×5 mL), then the combined aq layers extracted with Et.sub.2O (2×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (MgSO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10%.fwdarw.30% EtOAc/hexanes) yielded (S)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide as a sticky orange foam (175 mg, 65%). TLC: R.sub.f 0.68 (40% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.73-7.67 (m, 4H), 7.53 (t, J=1.8 Hz, 1H), 7.46-7.31 (m, 8H), 7.15 (t, J=7.9 Hz, 1H), 4.73 (dd, J=10.4, 4.9 Hz, 1H), 4.15 (dd, J=18.4, 2.6 Hz, 1H), 3.93-3.75 (m, 2H), 3.57 (d, J=18.3 Hz, 1H), 2.23 (t, J=2.5 Hz, 1H), 2.17-2.07 (m, 1H), 2.07-1.97 (m, 1H), 1.25 (s, 9H), 1.07 (s, 9H). .sup.13C-NMR (151 MHz): δ 135.6, 135.6, 134.5, 133.4, 133.3, 131.4, 130.5, 129.7, 129.7, 129.6, 127.7, 127.7, 124.6, 121.9, 88.5, 84.1, 80.3, 72.3, 60.2, 58.2, 38.4, 26.8, 23.2, 19.2; 2 C not observed.

Ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0323] ##STR00232##

[0324] In a vial, Rh(COD).sub.2BF.sub.4 (13 mg, 0.0328 mmol, 15 mol %) and rac-BINAP (27 mg, 0.0438 mmol, 20 mol %) were dissolved in 6.3 mL of degassed 1,2-dichloroethane. Ethyl cyanoformate (108 μL, 1.09 mmol, 5.0 equiv) was added, followed by a solution of (S)—N—((R)-1-(3-Bromophenyl)-5-((tert-butyldiphenylsilyl)oxy)pent-1-yn-3-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide (139 mg, 0.219 mmol, 1.0 equiv) in 1 mL of 1,2-dichloroethane. The vial was sealed with a Teflon-faced screw cap and the mixture was heated to 75° C. (oil bath, ext temp) for 4 h, then cooled to room temperature and concentrated by rotary evaporation. Purification by silica flash chromatography (20.fwdarw.40% EtOAc/hexanes) yielded ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as an orange foam (143 mg, 89%). TLC: R.sub.f 0.31 (33% EtOAc/hexanes). [α].sub.D.sup.19: +41.7° (c 1.0, CHCl.sub.3). IR (ATR): 3072, 3055, 2960, 2859, 1741, 1718, 1573, 1473, 1446, 1428, 1390, 1367, 1332, 1266, 1227, 1106, 1089, 906, 759, 741. .sup.1H-NMR (600 MHz): δ 7.94 (s, 1H), 7.91 (t, J=1.9 Hz, 1H), 7.67 (dt, J=7.7, 1.3 Hz, 1H), 7.51 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.44-7.36 (m, 6H), 7.35-7.29 (m, 4H), 7.22 (t, J=7.8 Hz, 1H), 5.67 (t, J=5.6 Hz, 1H), 4.68-4.57 (m, 2H), 4.54 (dq, J=10.9, 7.1 Hz, 1H), 4.44 (dq, J=10.8, 7.1 Hz, 1H), 3.47 (dt, J=10.6, 6.5 Hz, 1H), 3.36 (dt, J=10.6, 6.4 Hz, 1H), 1.82-1.66 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.23 (s, 9H), 0.89 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.0, 152.1, 151.0, 147.5, 141.5, 140.7, 135.4, 135.3, 133.2, 133.2, 132.1, 131.9, 130.3, 129.6, 129.6, 127.6, 126.9, 123.1, 118.1, 62.0, 60.1, 58.0, 57.8, 56.8, 36.5, 26.7, 22.9, 19.0, 14.4.

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(di-methylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0325] ##STR00233##

[0326] In a vial, ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butyl-sulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (51 mg, 0.0695 mmol, 1.0 equiv), Na.sub.2PdCl.sub.4 (2 mg, 0.00695 mmol, 10 mol %), t-Bu.sub.3PHBF.sub.4 (3 mg, 0.0104 mmol, 15 mol %), and CuI (3 mg, 0.0139 mmol, 20 mol %) were dissolved in 0.4 mL of degassed 1,2-dimethoxyethane and 1.3 mL of degassed i-Pr.sub.2NH. N,N-dimethylprop-2-yn-1-amine (37 μL, 0.347 mmol, 5.0 equiv) was added, then the vial was sealed with a Teflon-faced screw cap and the mixture heated to 75° C. (oil bath, ext temp) for 24 h. The reaction was cooled to room temperature and diluted with EtOAc, then filtered through Celite and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a dark orange oil (48 mg, 94%). TLC: R.sub.f 0.41 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.21: +85.7° (c 1.0, CHCl.sub.3). .sup.1H-NMR (500 MHz): δ 7.92 (s, 1H), 7.85 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.43-7.35 (m, 6H), 7.34-7.28 (m, 5H), 5.69 (t, J=5.3 Hz, 1H), 4.69-4.58 (m, 2H), 4.57-4.49 (m, 1H), 4.49-4.40 (m, 1H), 3.51 (s, 2H), 3.48-3.42 (m, 1H), 3.41-3.28 (m, 1H), 2.38 (s, 6H), 1.83-1.74 (m, 1H), 1.74-1.65 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.23 (s, 9H), 0.88 (s, 9H). .sup.13C-NMR (126 MHz): δ 165.1, 153.0, 150.7, 147.5, 141.2, 138.9, 135.4, 135.3, 133.3, 132.2, 132.0, 129.6, 128.7, 128.0, 127.6, 124.0, 117.8, 85.1, 77.2, 61.9, 60.1, 58.0, 57.5, 57.0, 48.6, 44.2, 36.4, 26.7, 22.9, 18.9, 14.3. HRMS m/z calcd for C.sub.43H.sub.54N.sub.3O.sub.4SSi ([M+H].sup.+) 736.3604; found 736.3604.

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0327] ##STR00234##

[0328] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(di¬methyl-amino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (20 mg, 0.0227 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide.sup.3 (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.28 mL, 0.0554 mmol, 2.0 equiv). The mixture was stirred at room temperature for 12 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL sat aq NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky yellow foam (14 mg, 62%). TLC: R.sub.f 0.25 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +93.3° (c 1.0, CHCl.sub.3). IR (ATR): 3391, 3070, 2933, 2859, 2777, 1672, 1573, 1523, 1489, 1444, 1361, 1328, 1251, 1090, 1041, 931, 756, 703. .sup.1H-NMR (600 MHz): δ 8.36 (t, J=6.3 Hz, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.42-7.33 (m, 6H), 7.33-7.27 (m, 5H), 6.87 (d, J=1.6 Hz, 1H), 6.83 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.93 (s, 2H), 5.67 (t, J=5.4 Hz, 1H), 4.69-4.53 (m, 4H), 3.50 (s, 2H), 3.45 (dt, J=10.7, 6.6 Hz, 1H), 3.34 (dt, J=10.7, 6.5 Hz, 1H), 2.38 (s, 6H), 1.83-1.65 (m, 3H), 1.22 (s, 9H), 0.87 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 151.4, 151.3, 149.0, 147.9, 146.9, 140.8, 138.9, 135.4, 135.3, 133.3, 133.2, 132.3, 132.2, 131.7, 129.6, 129.5, 128.8, 127.9, 127.6, 127.6, 123.9, 121.0, 115.3, 108.4, 108.2, 101.0, 85.5, 84.9, 60.1, 58.0, 56.6, 53.4, 48.6, 44.3, 43.2, 36.6, 26.7, 22.8, 18.9. HRMS m/z calcd for C.sub.49H.sub.57N.sub.4O.sub.5SSi ([M+H].sup.+) 841.3819; found 841.3840.

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(dimethyl-amino)prop-1-yn-1-yl)phenyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 85)

[0329] ##STR00235##

[0330] In a small vial, (R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((S)-tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (14 mg, 0.0171 mmol, 1.0 equiv) was dissolved in 0.17 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 22 μL, 0.223 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/EtOAc) yielded the pyrrolopyridinecarboxamide 85 as a light yellow foam (8 mg, 82%). TLC: R.sub.f 0.47 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +133.5° (c 0.85, CHCl.sub.3). IR (ATR): 3387, 2948, 2781, 1668, 1573, 1526, 1490, 1445, 1362, 1330, 1252, 1041, 929, 759. .sup.1H-NMR (600 MHz): δ 8.35 (t, J=6.2 Hz, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 6.85 (d, J=1.4 Hz, 1H), 6.82 (dd, J=8.0, 1.4 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.93 (q, J=1.5 Hz, 2H), 5.67 (t, J=4.4 Hz, 1H), 4.83 (d, J=15.7 Hz, 1H), 4.66-4.53 (m, 3H), 3.49 (s, 2H), 3.38-3.17 (m, 2H), 2.38 (s, 6H), 2.05-1.93 (m, 1H), 1.70 (dq, J=15.1, 5.6 Hz, 1H), 1.32 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 151.6, 151.1, 149.3, 147.9, 146.9, 138.8, 138.7, 132.4, 132.1, 131.5, 128.9, 127.8, 124.0, 121.0, 115.6, 108.4, 108.3, 101.0, 85.6, 84.7, 59.9, 58.5, 58.2, 54.8, 48.5, 44.2, 43.2, 35.7, 23.3. HRMS m/z calcd for C.sub.33H.sub.39N.sub.4O.sub.5S ([M+H].sup.+) 603.2641; found 603.2628.

Preparation of Compound 84

[0331] Preparation of enantiomer 84 is analogous to the synthesis of compound 85.

Synthesis of Deshydroxyethyl Compounds

Example 9. Preparation of Compound 49

3-(3-Bromophenyl)propiolaldehyde

[0332] ##STR00236##

[0333] In a 250 mL roundbottom flask, 3-(3-bromophenyl)prop-2-yn-1-ol (1.54 g, 7.30 mmol, 1.0 equiv) was dissolved in 73 mL CH.sub.2Cl.sub.2. Dess-Martin periodinane (3.40 g, 8.03 mmol, 1.1 equiv) was added at room temperature and the mixture was stirred at 1 h. 50 mL sat aq NaHCO.sub.3 was added to quench the reaction and the layers separated. The aq layer was extracted with CH.sub.2Cl.sub.2 (2×50 mL), then the combined organic extracts were washed with brine (1×8 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (30% EtOAc/hexanes) yielded the propargyl aldehyde as a white solid (1.41 g, 93%). TLC: R.sub.f 0.79 (33% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 9.42 (s, 1H), 7.74 (t, J=1.7 Hz, 1H), 7.62 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 7.53 (dt, J=7.7, 1.2 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H). .sup.13C-NMR (151 MHz): δ 176.4, 135.6, 134.3, 131.7, 130.1, 122.4, 121.3, 92.6, 88.7.

[0334] 3-(3-bromophenyl)prop-2-yn-1-ol was prepared according to literature procedure: Nanayakkara, P.; Alper, H. Adv. Synth. Catal. 2006, 348, 545-550.

(R)—N-(3-(3-Bromophenyl)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide

[0335] ##STR00237##

[0336] In a 50 mL roundbottom flask, 3-(3-Bromophenyl)propiolaldehyde (688 mg, 3.29 mmol, 1.0 equiv)] and (R)-2-methylpropane-2-sulfinamide (439 mg, 3.62 mmol, 1.1 equiv) were dissolved in 13.2 mL THF and Ti(OEt).sub.4 (technical grade, ca. 20% Ti, 1.7 mL, 8.23 mmol, 2.5 equiv) was added at room temperature. After full consumption of the 3-(3-Bromophenyl)propiolaldehyde (2 h), the reaction was cooled to −48° C. and solid NaBH.sub.4 (498 mg, 13.2 mmol, 4.0 equiv) was added in one portion. The reaction was stirred at −48° C. for 30 min, then allowed to warm to room temperature and stirred for 2.5 h. The reaction was quenched by the slow addition of 7 mL MeOH, then the mixture was poured into vigorously stirring brine (7 mL) and diluted with 15 mL EtOAc. The layers were separated and the aq layer extracted with EtOAc (3×15 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded the N-propargyl sulfinamide as a light yellow oil (836 mg, 81%). TLC: R.sub.f 0.10 (33% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.58 (t, J=1.8 Hz, 1H), 7.45 (ddd, J=8.1, 2.0, 1.1 Hz, 1H), 7.36 (dt, J=7.8, 1.3 Hz, 1H), 7.17 (t, J=7.9 Hz, 1H), 4.17 (dd, J=17.0, 5.3 Hz, 1H), 4.09 (dd, J=17.0, 6.5 Hz, 1H), 3.47 (t, J=6.0 Hz, 1H), 1.26 (s, 9H). .sup.13C-NMR (151 MHz): δ 134.4, 131.6, 130.3, 129.7, 124.5, 122.1, 86.8, 83.0, 56.2, 35.4, 22.5.

(R)—N-(3-(3-bromophenyl)prop-2-yn-1-yl)-2-methyl-N-(prop-2-yn-1-yl)propane-2-sulfinamide

[0337] ##STR00238##

[0338] In a 50 mL roundbottom flask, (R)—N-(3-(3-Bromophenyl)prop-2-yn-1-yl)-2-methylpropane-2-sulfinamide (815 mg, 2.59 mmol, 1.0 equiv) was dissolved in 13 mL DMF and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 114 mg, 2.85 mmol, 1.1 equiv) was added, followed by propargyl bromide (80% in toluene, 419 μL, 3.89 mmol, 1.5 equiv) and the mixture was stirred at 0° C. for 2 h. The reaction was quenched by the addition of 15 mL sat aq NH.sub.4Cl, then diluted with 15 mL of Et.sub.2O. The organic layer was washed with water (3×15 mL), then the combined aq layers extracted with Et.sub.2O (2×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried (MgSO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10%.fwdarw.30% EtOAc/hexanes) yielded the diyne as a viscous yellow oil (831 mg, 91%). TLC: R.sub.f 0.53 (40% EtOAc/hexanes). .sup.1H-NMR (600 MHz): δ 7.58 (t, J=1.8 Hz, 1H), 7.45 (ddd, J=8.1, 2.1, 1.1 Hz, 1H), 7.36 (dt, J=7.7, 1.3 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 4.20 (d, J=18.7 Hz, 1H), 4.10-3.96 (m, 2H), 3.81 (dd, J=18.0, 1.9 Hz, 1H), 2.32 (t, J=2.4 Hz, 1H), 1.24 (s, 9H). .sup.13C-NMR (151 MHz): δ 134.4, 131.6, 130.3, 129.7, 124.5, 122.0, 85.5, 83.4, 78.8, 73.1, 58.8, 25.4, 22.6.

Ethyl (R)-4-(3-bromophenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0339] ##STR00239##

[0340] In a 200 mL roundbottom flask, Rh(COD).sub.2BF.sub.4 (121 mg, 0.298 mmol, 15 mol %) and rac-BINAP (248 mg, 0.398 mmol, 20 mol %) were dissolved in 60 mL of degassed 1,2-dichloroethane. The mixture was cooled to 0° C., then ethyl cyanoformate (982 μL, 9.95 mmol, 5.0 equiv) was added, followed by a solution of the diyne (701 mg, 1.99 mmol, 1.0 equiv) in 6.3 mL of 1,2-dichloroethane. The mixture was stirred at 0° C. for 14 h, then cooled to room temperature and concentrated by rotary evaporation. Purification by silica flash chromatography (25.fwdarw.45% EtOAc/hexanes) yielded ethyl (R)-4-(3-bromophenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as an orange foam (478 mg, 53%). TLC: R.sub.f 0.43 (50% EtOAc/hexanes). [α].sub.D.sup.19: −39.7° (c 1.0, CHCl.sub.3). IR (ATR): 3060, 2981, 2865, 1740, 1717, 1575, 1563, 1457, 1390, 1368, 1331, 1305, 1225, 1071, 1021, 747. .sup.1H-NMR (600 MHz): δ 7.99 (s, 1H), 7.95 (t, J=1.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 5.06 (d, J=15.3 Hz, 1H), 4.99 (d, J=15.5 Hz, 1H), 4.68 (d, J=15.0 Hz, 1H), 4.54-4.44 (m, 3H), 1.46 (t, J=7.1 Hz, 3H), 1.27 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.0, 151.7, 150.7, 147.8, 140.3, 135.6, 132.3, 131.4, 130.2, 126.6, 123.0, 118.2, 62.1, 58.2, 23.2, 14.3; 2C not observed.

Ethyl (R)-2-(tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (Compound 49)

[0341] ##STR00240##

[0342] In a vial, pyrrolopyridinecarboxylate (203 mg, 0.450 mmol, 1.0 equiv), Na.sub.2PdCl.sub.4 (13 mg, 0.0450 mmol, 10 mol %), t-Bu.sub.3PHBF.sub.4 (20 mg, 0.0675 mmol, 15 mol %), and CuI (17 mg, 0.0899 mmol, 20 mol %) were dissolved in 2.8 mL of degassed 1,2-dimethoxyethane and 8.4 mL of degassed i-Pr.sub.2NH. N,N-dimethylprop-2-yn-1-amine (242 μL, 2.25 mmol, 5.0 equiv) was added, then the vial was sealed with a Teflon-faced screw cap and the mixture heated to 75° C. (oil bath, ext temp) for 12 h. The reaction was cooled to room temperature and diluted with EtOAc, then filtered through Celite and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded pyrrolopyridinecarboxylate 49 as a dark orange oil (194 mg, 95%). TLC: R.sub.f 0.17 (70% EtOAc/hexanes). [α].sub.D.sup.19: −39.9° (c 1.0, CHCl.sub.3). IR (ATR): 2978, 2943, 2908, 2864, 2823, 2777, 1740, 1717, 1575, 1457, 1425, 1392, 1368, 1333, 1301, 1255, 1087, 1069, 1022, 948, 749. .sup.1H-NMR (600 MHz): δ 7.98 (s, 1H), 7.83 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 5.06 (d, J=15.2 Hz, 1H), 4.99 (d, J=15.3 Hz, 1H), 4.69 (d, J=15.1 Hz, 1H), 4.55-4.44 (m, 3H), 3.50 (s, 2H), 2.39 (s, 6H), 1.45 (t, J=7.2 Hz, 3H), 1.27 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 152.5, 150.5, 147.7, 138.5, 135.5, 132.5, 131.4, 128.7, 127.9, 124.0, 118.0, 85.2, 84.9, 62.0, 58.2, 48.6, 44.3, 23.2, 14.3; 2C not observed. LRMS (ESI+) m/z calcd for C.sub.25H.sub.31N.sub.3O.sub.3S ([M+H].sup.+) 454.21; found 454.0.

Preparation of Compound 50

[0343] Preparation of enantiomer 50 is analogous to the synthesis of compound 49.

Example 10. Preparation of Compound 57

(R)—N-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(tert-butylsulfinyl)-4-(3-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 57)

[0344] ##STR00241##

[0345] To a vial containing pyrrolopyridinecarboxylate 49 (127 mg, 0.280 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide.sup.3 (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 2.8 mL, 0.560 mmol, 2.0 equiv). The mixture was stirred at room temperature for 12 h, then carefully quenched by addition dropwise addition of 0.5 mL of MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL sat aq NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×5 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/CH.sub.2Cl.sub.2) yielded pyrrolopyridinecarboxamide 57 as a light yellow foam (128 mg, 82%). TLC: R.sub.f 0.33 (10% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: −33.6° (c 1.0, CHCl.sub.3). IR (ATR): 3392, 2976, 2846, 2866, 2823, 2778, 1672, 1574, 1524, 1504, 1490, 1445, 1253, 1066, 1039, 931, 744. .sup.1H-NMR (600 MHz): δ 8.37 (t, J=6.3 Hz, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.84 (dd, J=7.9, 1.3 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 5.94 (s, 2H), 5.05 (d, J=14.5 Hz, 1H), 4.98 (d, J=15.3 Hz, 1H), 4.65 (d, J=14.8 Hz, 1H), 4.61 (d, J=6.2 Hz, 2H), 4.53 (d, J=15.3 Hz, 1H), 3.48 (s, 2H), 2.38 (s, 6H), 1.26 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 151.1, 150.9, 149.2, 147.9, 146.9, 138.4, 134.9, 132.5, 132.1, 131.2, 128.7, 127.6, 123.8, 121.0, 115.5, 108.4, 108.3, 101.0, 85.7, 84.6, 58.2, 48.6, 44.4, 43.3, 23.3. LRMS (ESI+) m/z calcd for C.sub.31H.sub.34N.sub.4O.sub.4S ([M+H].sup.+) 559.23; found 559.2.

Preparation of Compound 58

[0346] Preparation of enantiomer 58 is analogous to the synthesis of compound 57.

Synthesis of Tan003-M03

[0347] ##STR00242## ##STR00243##

Ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0348] ##STR00244##

[0349] To a 40 mL vial was added ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (517 mg, 0.705 mmol, 1.0 equiv), 2-(benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (344 mg, 1.41 mmol, 2.0 equiv), and Na.sub.2CO.sub.3 (224 mg, 2.11 mmol, 3.0 equiv). Degassed 1,2-dimethoxyethane (7.0 mL) and degassed deionized water (0.7 mL) were added, and the whole solution purged with argon for ˜10 minutes.

[0350] Bis(triphenylphosphine)palladium dichloride (25 mg, 0.0352 mmol, 0.05 equiv) was quickly added to the reaction, then it was capped with a teflon-lined cap and stirred at 60° C. After 12 hours, the reaction was cooled to room temperature, then diluted with EtOAc and deionized water. The aqueous layer was extracted with EtOAc (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hex, then 20% EtOAc/CH.sub.2Cl.sub.2) yielded ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a white foam (527 mg, 97%).

[0351] TLC: R.sub.f 0.28 (40% EtOAc/hexanes). [α].sub.D.sup.20: +92.2° (c 1.0, CHCl.sub.3). IR (ATR): 3409, 3070, 2958, 2930, 2858, 1740, 1718, 1574, 1473, 1451, 1428, 1258, 1227, 1108, 1077, 940, 752, 703. .sup.1H-NMR (600 MHz): δ 8.22 (t, J=1.8 Hz, 1H), 7.98 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.46-7.42 (m, 2H), 7.42-7.37 (m, 3H), 7.37-7.32 (m, 2H), 7.32-7.28 (m, 1H), 7.27 (d, J=6.3 Hz, 3H), 7.25-7.22 (m, 2H), 7.08 (s, 1H), 5.77 (d, J=7.0 Hz, 1H), 5.19 (d, J=15.7 Hz, 1H), 4.53 (dq, J=10.8, 7.1 Hz, 1H), 4.46 (dq, J=10.9, 7.1 Hz, 1H), 4.01 (d, J=14.8 Hz, 1H), 3.69-3.55 (m, 1H), 3.54-3.34 (m, 1H), 1.84-1.72 (m, 1H), 1.58-1.49 (m, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 0.91 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 155.3, 154.9, 153.4, 151.2, 147.7, 139.3, 139.2, 135.4, 135.3, 133.3, 133.2, 131.1, 129.6, 129.6, 129.3, 129.1, 128.3, 127.6, 127.5, 125.4, 125.2, 124.4, 122.9, 121.0, 118.3, 111.3, 102.0, 68.7, 61.9, 59.4, 58.5, 45.8, 37.6, 26.7, 23.7, 19.0, 14.3. HRMS m/z calcd for C.sub.46H.sub.50N.sub.2O.sub.5SSi ([M+Na].sup.+) 793.3107; found 793.3077.

Ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0352] ##STR00245##

[0353] To a 20 mL vial was added ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (527 mg, 0.683 mmol, 1.0 equiv). Methanol (6.8 mL) was added and the reaction cooled to 0° C., then HCl (4.0 M in dioxane, 188 μL, 0.752 mmol, 1.1 equiv) was added. After 2 hours, the reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/hexanes) yielded ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (451 mg, 99%).

[0354] TLC: R.sub.f 0.48 (70% EtOAc/hexanes). [α].sub.D.sup.20: +188.8° (c 1.0, CHCl.sub.3). IR (ATR): 3365, 3070, 2931, 2857, 1736, 1718, 1568, 1451, 1428, 1390, 1258, 1108, 798, 702. .sup.1H-NMR (600 MHz): δ 8.21 (s, 1H), 8.02 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.55-7.49 (m, 5H), 7.44 (t, J=7.7 Hz, 1H), 7.40-7.34 (m, 2H), 7.33-7.27 (m, 5H), 7.23 (t, J=7.4 Hz, 1H), 7.06 (s, 1H), 5.22 (d, J=9.2 Hz, 1H), 4.55 (dq, J=10.9, 7.1 Hz, 1H), 4.47 (dq, J=10.9, 7.1 Hz, 1H), 4.32 (s, 2H), 3.68 (ddd, J=10.5, 8.9, 3.6 Hz, 1H), 3.60 (dt, J=10.1, 4.8 Hz, 1H), 1.81-1.64 (m, 1H), 1.47 (t, J=7.1 Hz, 3H), 1.42-1.29 (m, 1H), 0.97 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.5, 155.4, 154.9, 153.9, 153.7, 147.2, 142.2, 139.6, 135.4, 135.4, 133.3, 133.2, 130.9, 129.7, 129.6, 129.1, 129.1, 128.4, 127.6, 127.6, 125.2, 125.2, 124.4, 122.9, 121.0, 118.5, 111.2, 101.8, 61.9, 61.5, 61.1, 51.1, 35.5, 26.8, 19.0, 14.4. HRMS m/z calcd for C.sub.42H.sub.43N.sub.2O.sub.4Si ([M+H].sup.+) 667.2992; found 667.2969.

Ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0355] ##STR00246##

[0356] In a 20 mL vial, ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (451 mg, 0.676 mmol, 1.0 equiv) was dissolved in 6.8 mL of CH.sub.2Cl.sub.2 and cooled to 0° C. NEt.sub.3 (141 L, 1.41 mmol, 1.5 equiv) was added, followed by 2-isocyanatopropane (80 μL, 0.812 mmol, 1.2 equiv), and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched by addition of 5 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography yielded ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a colorless film (465 mg, 91%).

[0357] TLC: R.sub.f 0.37 (50% EtOAc/hexanes). [α].sub.D.sup.20: +144.0° (c 1.0, CHCl.sub.3). IR (ATR): 3378, 3070, 2965, 2932, 2858, 1722, 1641, 1527, 1453, 1371, 1234, 1107, 739, 703. .sup.1H-NMR (600 MHz): δ 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.42-7.26 (m, 9H), 7.25-7.22 (m, 2H), 7.20 (t, J=7.5 Hz, 2H), 7.09 (s, 1H), 5.84 (s, 1H), 5.17 (d, J=15.7 Hz, 1H), 4.94 (s, 1H), 4.54 (dq, J=10.9, 7.1 Hz, 1H), 4.50-4.40 (m, 2H), 4.15-4.04 (m, 1H), 3.71-3.57 (m, 1H), 3.55-3.44 (m, 1H), 1.94-1.78 (m, 1H), 1.46 (t, J=7.1 Hz, 3H), 1.41-1.28 (m, 1H), 1.17 (dd, J=9.5, 6.6 Hz, 6H), 0.87 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 156.5, 155.2, 154.9, 153.6, 149.2, 147.6, 139.3, 139.1, 135.3, 135.3, 133.0, 133.0, 131.3, 129.7, 129.7, 129.3, 129.1, 128.1, 127.6, 127.6, 125.5, 125.2, 124.5, 123.0, 121.0, 118.3, 111.2, 102.1, 62.0, 60.2, 59.4, 53.4, 50.9, 42.7, 27.0, 23.4, 23.4, 19.0, 14.3. HRMS m/z calcd for C.sub.46H.sub.49N.sub.3O.sub.5SiNa ([M+Na].sup.+) 774.3339; found 774.3307.

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-N.SUP.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0358] ##STR00247##

[0359] In a 20 mL vial, ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (465 mg, 0.618 mmol, 1.0 equiv, azeotroped 3× with toluene) was dissolved in 6.2 mL CH.sub.2Cl.sub.2 at room temperature. A pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 6.2 mL, 1.24 mmol, 2.0 equiv) was slowly added and the mixture was stirred at room temperature for 17 h, then carefully quenched by dropwise addition of 2 mL MeOH followed by dilution with 10 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (20% EtOAc/CH.sub.2Cl.sub.2) yielded (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a colorless film (454 mg, 91%).

[0360] TLC: R.sub.f 0.23 (20% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +144.3° (c 1.0, CHCl.sub.3). IR (ATR): 3380, 3071, 2962, 2932, 2859, 1685, 1641, 1522, 1383, 1274, 1162, 1056, 751, 702. .sup.1H-NMR (600 MHz): δ 8.42 (t, J=6.8 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.41-7.36 (m, 2H), 7.35-7.31 (m, 4H), 7.31-7.27 (m, 2H), 7.25-7.22 (m, 2H), 7.22-7.17 (m, 2H), 7.09 (s, 1H), 5.87 (s, 1H), 5.09 (d, J=15.5 Hz, 1H), 4.77 (s, 1H), 4.47 (dd, J=15.5, 1.7 Hz, 2H), 4.34-4.16 (m, 1H), 4.11-3.98 (m, 2H), 3.66-3.55 (m, 1H), 3.54-3.44 (m, 1H), 1.94 (s, 1H), 1.40 (s, 1H), 1.18 (t, J=6.8 Hz, 6H), 0.85 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.3, 156.3, 156.3, 155.0, 154.9, 152.3, 149.9, 147.9, 139.2, 139.0, 135.3, 135.3, 133.0, 133.0, 131.3, 129.7, 129.7, 129.4, 129.0, 127.8, 127.6, 127.6, 125.6, 124.9, 124.7, 124.1 (q, J=277.6 Hz), 123.1, 121.1, 116.0, 111.3, 102.3, 60.1, 59.6, 51.0, 42.7, 40.8 (q, J=34.7 Hz), 26.9, 23.4, 23.4, 19.0. HRMS m/z calcd for C.sub.46H.sub.47N.sub.4O.sub.4SiF.sub.3Na ([M+Na].sup.+) 827.3216; found 827.3246.

Preparation of dimethylaluminum 2,2,2-trifluoroethylamide Stock Solution

[0361] To a 10 mL roundbottom flask containing 2,2,2-trifluoroethylamine (78 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH2Cl2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at rt. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-N.SUP.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (Tan003-M03)

[0362] ##STR00248##

[0363] In a 20 mL vial, (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (454 mg, 0.564 mmol, 1.0 equiv) was dissolved in 5.6 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 846 μL, 0.846 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 10 mL EtOAc and 5 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography yielded Tan003-M03 as a colorless film (313 mg, 98%). TLC: R.sub.f 0.31 (80% EtOAc/hexanes). [α].sub.D.sup.19: +180.4° (c 1.0, CHCl.sub.3). IR (ATR): 3317, 3068, 2971, 1683, 1630, 1525, 1420, 1274, 1162, 802, 751. .sup.1H-NMR (600 MHz): δ 8.44 (t, J=6.8 Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.67-7.60 (m, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.31 (t, J=7.1 Hz, 1H), 7.26-7.24 (m, 1H), 7.15 (s, 1H), 6.06 (d, J=10.1 Hz, 1H), 4.93 (d, J=14.7 Hz, 1H), 4.81-4.48 (m, 2H), 4.35-4.16 (m, 1H), 4.16-3.99 (m, 2H), 3.58-3.49 (m, 1H), 3.49-3.38 (m, 1H), 1.91-1.73 (m, 1H), 1.32-1.17 (m, 7H). .sup.13C-NMR (151 MHz): δ 164.3, 157.3, 155.0, 152.2, 148.9, 148.1, 148.1, 139.4, 138.4, 131.3, 129.5, 129.0, 128.0, 126.0, 124.7, 124.7, 124.1 (q, J=279.1 Hz), 121.1, 115.9, 111.2, 102.3, 59.2, 58.5, 50.9, 43.0, 40.8 (q, J=34.9 Hz), 37.8, 23.4, 23.4. HRMS m/z calcd for C.sub.30H.sub.29N.sub.4O.sub.4F.sub.3Na ([M+Na].sup.+) 589.2039; found 589.2026.

Preparation of ent-Tan003-M03

[0364] The synthesis of enantiomer ent-Tan003-M03 is analogous to the synthesis of Tan003-M03.

Synthesis of Tan003-O08: [Synthesis of Ent-Tan003-O08 is Analogous]

[0365] ##STR00249## ##STR00250##

[0366] To a 40 mL vial was added ethyl (R)-4-(3-bromophenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (876 mg, 1.19 mmol, 1.0 equiv), pyridin-3-ylboronic acid (293 mg, 2.39 mmol, 2.0 equiv), and Na.sub.2CO.sub.3 (122 mg, 1.15 mmol, 3.0 equiv). Degassed ethanol (11.9 mL) was added, and the whole solution purged with argon for ˜10 minutes. Bis(triphenylphosphine)palladium dichloride (42 mg, 0.0597 mmol, 0.05 equiv) was quickly added to the reaction, then it was capped with a teflon-lined cap and stirred at 60° C. After 12 hours, the reaction was cooled to room temperature, then diluted with EtOAc, filtered through Celite, and concentrated by rotary evaporation. Purification by silica flash chromatography (50.fwdarw.80% EtOAc/hexanes) yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a white foam (819 mg, 94%).

[0367] TLC: R.sub.f 0.13 (60% EtOAc/hexanes). [α].sub.D.sup.20: +61.8° (c 1.0, CHCl.sub.3). IR (ATR): 3398, 3070, 2958, 2931, 2858, 1741, 1718, 1578, 1472, 1428, 1225, 1108, 1076, 758, 705. .sup.1H-NMR (600 MHz): δ 8.89 (s, 1H), 8.61 (d, J=4.0 Hz, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.89 (dt, J=7.9, 1.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.47-7.34 (m, 8H), 7.30-7.28 (m, 2H), 7.28-7.26 (m, 2H), 5.79 (d, J=7.0 Hz, 1H), 5.20 (d, J=15.8 Hz, 1H), 4.52 (dq, J=10.9, 7.1 Hz, 1H), 4.44 (dq, J=10.9, 7.1 Hz, 1H), 4.02 (d, J=15.0 Hz, 1H), 3.66 (ddd, J=10.4, 8.5, 5.0 Hz, 1H), 3.48 (ddd, J=10.5, 6.1, 4.5 Hz, 1H), 1.85-1.73 (m, 1H), 1.61-1.52 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.22 (s, 9H), 0.93 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.9, 153.2, 151.2, 148.6, 148.3, 147.6, 139.5, 139.1, 138.4, 136.0, 135.3, 135.2, 134.4, 133.2, 133.1, 129.6, 129.6, 129.4, 127.8, 127.6, 127.5, 127.5, 127.5, 123.5, 118.2, 68.6, 61.8, 59.3, 58.4, 45.7, 37.5, 26.6, 23.6, 18.9, 14.3. HRMS m/z calcd for C.sub.43H.sub.50N.sub.3O.sub.4SSi ([M+H].sup.+) 732.3291; found 732.3293.

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0368] ##STR00251##

[0369] In a 20 mL vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (410 mg, 0.560 mmol, 1.0 equiv, azeotroped 3× with toluene) was dissolved in 2.8 mL CH.sub.2Cl.sub.2 at room temperature. A pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 2.8 mL, 1.12 mmol, 2.0 equiv) was slowly added and the mixture was stirred at room temperature for 17 h, then carefully quenched by dropwise addition of 2 mL MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (80% EtOAc/hexanes.fwdarw.100% EtOAc) yielded (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a light yellow foam (440 mg, 94%). TLC: R.sub.f 0.50 (100% EtOAc). [α].sub.D.sup.19: +62.5° (c 1.0, CHCl.sub.3). IR (ATR): 3396, 3069, 3047, 2957, 2930, 2896, 2858, 1673, 1575, 1523, 1504, 1490, 1445, 1428, 1253, 1111, 1075, 1041, 930, 740, 705. .sup.1H-NMR (600 MHz): δ 8.86 (s, 1H), 8.63 (d, J=3.9 Hz, 1H), 8.33 (t, J=6.1 Hz, 1H), 8.10 (s, 1H), 7.86-7.80 (m, 2H), 7.66 (d, J=7.8 Hz, 2H), 7.49-7.33 (m, 8H), 7.30-7.23 (m, 5H), 6.85 (s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.92 (s, 2H), 5.75 (d, J=6.4 Hz, 1H), 5.19 (d, J=15.8 Hz, 1H), 4.60 (dd, J=14.8, 6.2 Hz, 1H), 4.55 (dd, J=14.8, 6.1 Hz, 1H), 4.02 (d, J=15.6 Hz, 1H), 3.64 (ddd, J=10.3, 8.2, 5.0 Hz, 1H), 3.47 (dt, J=10.7, 5.4 Hz, 1H), 1.83-1.61 (m, 1H), 1.62-1.49 (m, 1H), 1.21 (s, 9H), 0.91 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 151.8, 151.6, 149.2, 148.8, 148.3, 147.9, 146.9, 139.5, 138.5, 138.4, 135.9, 135.4, 135.3, 134.5, 133.3, 133.2, 132.1, 129.6, 129.6, 129.6, 127.8, 127.7, 127.6, 127.1, 123.6, 121.0, 115.7, 108.4, 108.2, 101.0, 68.6, 59.4, 58.5, 45.9, 43.2, 37.7, 26.7, 23.7, 19.0; 1 C not observed. HRMS m/z calcd for C.sub.49H.sub.53N.sub.4O.sub.5SSi ([M+H].sup.+) 837.3506; found 837.3474.

Preparation of Dimethylaluminum Piperonylamide Stock Solution

[0370] To a 10 mL roundbottom flask containing piperonylamine (125 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH2Cl2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at rt. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Tan003-O08)

[0371] ##STR00252##

[0372] In a 20 mL vial, (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (440 mg, 0.526 mmol, 1.0 equiv) was dissolved in 5.3 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 788 μL, 0.788 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 10 mL EtOAc and 5 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (5% MeOH/EtOAc) yielded Tan003-O08 as a light yellow film 259 mg, 82%).

[0373] TLC: R.sub.f 0.25 (5% MeOH/EtOAc). [α].sub.D.sup.19: +46.1° (c 1.0, CHCl.sub.3). IR (ATR): 3385, 2951, 2928, 1668, 1575, 1526, 1490, 1445, 1253, 1041, 931, 757. .sup.1H-NMR (600 MHz): δ 8.95-8.83 (m, 1H), 8.62 (d, J=3.7 Hz, 1H), 8.33 (t, J=6.2 Hz, 1H), 8.12 (s, 1H), 7.92 (dt, J=7.9, 1.8 Hz, 1H), 7.87 (t, J=1.7 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.40 (dd, J=7.7, 4.8 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.81 (dd, J=8.0, 1.7 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.93 (ABq, J.sub.AB=1.5 Hz, 2H), 5.73 (dt, J=5.3, 2.6 Hz, 1H), 5.22 (d, J=15.8 Hz, 1H), 4.65-4.49 (m, 2H), 4.19-4.13 (m, 2H), 3.59 (ddd, J=10.6, 8.0, 5.8 Hz, 1H), 3.45 (ddd, J=11.0, 6.5, 4.9 Hz, 1H), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 151.9, 151.7, 149.4, 148.8, 148.3, 147.9, 146.9, 139.3, 138.5, 137.6, 136.0, 134.6, 132.1, 129.6, 128.0, 128.0, 127.0, 123.7, 121.0, 115.8, 108.4, 108.3, 101.0, 68.6, 58.5, 58.4, 46.0, 43.3, 37.5, 23.8. HRMS m/z calcd for C.sub.33H.sub.35N.sub.4O.sub.5S ([M+H].sup.+) 599.2328; found 599.2316.

Preparation of ent-Tan003-O08

[0374] The synthesis of enantiomer ent-Tan003-O08 is analogous to the synthesis of Tan003-O08.

Synthesis of ent-Tan003-D20

[0375] ##STR00253## ##STR00254##

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0376] In a 20 mL vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (410 mg, 0.560 mmol, 1.0 equiv, azeotroped 3× with toluene) was dissolved in 2.8 mL CH.sub.2Cl.sub.2 at room temperature. A pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 2.8 mL, 1.12 mmol, 2.0 equiv) was slowly added and the mixture was stirred at room temperature for 17 h, then carefully quenched by dropwise addition of 2 mL MeOH followed by dilution with 5 mL of CH.sub.2Cl.sub.2 and careful addition of 5 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (80% EtOAc/hexanes.fwdarw.100% EtOAc) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a light yellow foam (386 mg, 85%).

[0377] TLC: R.sub.f 0.53 (100% EtOAc). [α].sub.D.sup.20: +58.7° (c 1.0, CHCl.sub.3). IR (ATR): 3392, 3049, 2958, 2930, 2858, 1674, 1576, 1523, 1427, 1266, 1229, 1107, 1073, 940, 736, 701. .sup.1H-NMR (600 MHz): δ 8.88 (s, 1H), 8.64 (s, 1H), 8.46 (t, J=6.3 Hz, 1H), 8.08 (s, 1H), 7.91-7.83 (m, 2H), 7.68 (dd, J=11.5, 7.9 Hz, 2H), 7.47-7.32 (m, 9H), 7.28-7.27 (m, 1H), 7.26-7.23 (m, 3H), 7.10 (t, J=7.5 Hz, 1H), 7.06 (t, J=9.4, 9.0 Hz, 1H), 5.77 (d, J=6.5 Hz, 1H), 5.18 (d, J=15.8 Hz, 1H), 4.76 (dd, J=15.2, 6.4 Hz, 1H), 4.71 (dd, J=15.2, 6.2 Hz, 1H), 4.01 (d, J=15.5 Hz, 1H), 3.64 (ddd, J=10.2, 8.5, 5.1 Hz, 2H), 3.47 (dt, J=10.5, 5.4 Hz, 1H), 1.81-1.74 (m, 1H), 1.61-1.50 (m, 1H), 1.21 (s, 9H), 0.91 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.1 Hz), 160.9, 151.9, 151.6, 149.1, 148.8, 148.3, 139.5, 138.5, 138.4, 136.0, 135.4, 135.3, 134.4, 133.3, 133.2, 130.0 (d, J=4.3 Hz), 129.6, 129.6, 129.6, 129.2 (d, J=8.1 Hz), 127.7, 127.6, 127.2, 125.2 (d, J=14.8 Hz), 124.3 (d, J=3.6 Hz), 123.6, 115.7, 115.4 (d, J=21.2 Hz), 68.6, 59.4, 58.5, 45.9, 37.7, 37.4 (d, J=4.0 Hz), 26.7, 23.7, 19.0; 1 C not observed. HRMS m/z calcd for C.sub.48H.sub.52FN.sub.4O.sub.3SSi ([M+H].sup.+) 811.3513; found 811.3505.

Preparation of dimethylaluminum (2-fluorobenzyl)amide Stock Solution

[0378] To a 10 mL roundbottom flask containing 2-fluorobenzyl)amine (114 μL, 1.0 mmol, 1.0 equiv) in 9.5 mL of CH.sub.2Cl.sub.2 was slowly added trimethylaluminum solution (2 M in toluene, 0.5 mL, 1.0 mmol, 1.0 equiv) at rt. The mixture was stirred for >2 h before use. Solution can be stored at −20° C. for at least 1 month.

(R)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (ent-Tan003-D20)

[0379] ##STR00255##

[0380] In a 20 mL vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (386 mg, 0.476 mmol, 1.0 equiv) was dissolved in 4.6 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 714 μL, 0.714 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 10 mL EtOAc and 5 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% EtOAc.fwdarw.10% MeOH/EtOAc) yielded ent-Tan003-D20 as a light yellow foam (189 mg, 69%).

[0381] TLC: R.sub.f 0.28 (5% MeOH/EtOAc). [α].sub.D.sup.19: +49.10 (c 1.0, CHCl.sub.3). IR (ATR): 3388, 2958, 1670, 1575, 1526, 1475, 1230, 1063, 756. .sup.1H-NMR (600 MHz): δ 8.91 (s, 1H), 8.64 (d, J=4.1 Hz, 1H), 8.45 (t, J=6.3 Hz, 1H), 8.11 (s, 1H), 7.94 (dt, J=7.9, 1.9 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.45-7.37 (m, 2H), 7.26-7.23 (m, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.06 (t, J=9.7, 8.8 Hz, 1H), 5.74 (dt, J=6.1, 2.8 Hz, 2H), 5.22 (d, J=15.8 Hz, 1H), 4.84-4.64 (m, 2H), 4.15 (d, J=16.7 Hz, 1H), 3.59 (ddd, J=10.6, 8.0, 5.8 Hz, 1H), 3.45 (dt, J=11.0, 5.7 Hz, 1H), 1.85-1.70 (m, 1H), 1.68-1.60 (m, 2H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.2 Hz), 151.9, 151.6, 149.4, 148.9, 148.4, 139.3, 138.5, 137.6, 136.0, 134.5, 130.0 (d, J=4.3 Hz), 129.6, 129.2 (d, J=8.2 Hz), 128.0, 127.9, 127.1, 125.2 (d, J=14.8 Hz), 124.3 (d, J=3.5 Hz), 123.7, 115.7, 115.4 (d, J=21.3 Hz), 68.7, 58.5, 58.4, 46.0, 37.5, 37.5 (d, J=4.0 Hz), 23.8. HRMS m/z calcd for C.sub.32H.sub.34FN.sub.4O.sub.3S ([M+H].sup.+) 573.2336; found 573.2330.

Preparation of Tan003-D20

[0382] The synthesis of enantiomer Tan003-D20 is analogous to the synthesis of ent-Tan003-D20.

Synthesis of Tan002-O12

Ethyl (R)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (Tan002-O12)

[0383] ##STR00256##

[0384] In a 20 mL vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (387 mg, 0.591 mmol, 1.0 equiv) was dissolved in 5.9 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 886 μL, 0.886 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 4.5 h. The reaction mixture was diluted with 10 mL EtOAc and 5 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (1×5 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes) yielded Tan002-O12 as a white foam (191 mg, 77%).

[0385] TLC: R.sub.f 0.22 (70% EtOAc/hexanes). [α].sub.D.sup.20: +30.5° (c 1.0, CHCl.sub.3). IR (ATR): 3410, 2982, 1737, 1577, 1456, 1429, 1394, 1370, 1229, 1051, 756. .sup.1H-NMR (600 MHz): δ 7.97 (s, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.48 (t, J=7.3 Hz, 2H), 7.46-7.42 (m, 1H), 5.74-5.62 (m, 1H), 5.20 (d, J=15.7 Hz, 1H), 4.51 (dq, J=10.8, 7.1 Hz, 1H), 4.44 (dq, J=10.8, 7.1 Hz, 1H), 4.13 (d, J=15.5 Hz, 1H), 3.58-3.46 (m, 1H), 3.45-3.31 (m, 1H), 1.75-1.67 (m, 1H), 1.65-1.55 (m, 1H), 1.43 (t, J=7.1 Hz, 3H), 1.30 (s, 9H), 1.08 (s, 1H). .sup.13C-NMR (151 MHz): δ 165.1, 153.9, 151.0, 147.8, 138.5, 138.0, 129.3, 128.8, 128.5, 118.1, 68.9, 62.0, 58.6, 58.3, 45.8, 37.3, 23.7, 14.3. HRMS m/z calcd for C.sub.22H.sub.28N.sub.2O.sub.4SNa ([M+Na].sup.+) 439.1667; found 439.1660.

[0386] Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate was prepared according to literature procedure: Bauer, R. A.; DiBlasi, C. M.; Tan, D. S. Org. Lett. 2010, 12, 2084-2087.

Preparation of Compound 247

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0387] ##STR00257##

[0388] In a 4 m vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (38 mg, 0.0519 mmol, 1.0 equiv) was dissolved in 0.13 mL THF and 0.13 mL MeOH at room temperature. Aq. NH.sub.3 (˜30% solution, 0.26 mL, 5.19 mmol, 100 equiv) was added and the mixture was stirred at room temperature for 18 h, then diluted with 1 mL EtOAc and 1 mL sat. aq. NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (1% NEt.sub.3/EtOAc) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a light yellow foam (31 mg, 84%). TLC: R.sub.f 0.32 (5% MeOH/EtOAc). [α].sub.D.sup.21: +73.9° (c 1.0, CHCl.sub.3). IR (ATR): 3400, 3224, 3070, 2958, 2958, 2931, 2858, 1690, 1646, 1574, 1471, 1382, 1111, 1087, 943, 756, 703. .sup.1H-NMR (600 MHz): δ 8.89 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.87 (dq, J=3.9, 2.0 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47-7.35 (m, 8H), 7.30-7.28 (m, 1H), 7.27-7.24 (m, 2H), 5.85 (d, J=4.6 Hz, 1H), 5.82-5.75 (m, 1H), 5.19 (d, J=15.8 Hz, 1H), 4.02 (d, J=15.5 Hz, 1H), 3.66 (ddd, J=10.4, 8.3, 5.0 Hz, 1H), 3.49 (dt, J=10.5, 5.1 Hz, 1H), 1.83-1.70 (m, 1H), 1.67-1.52 (m, 1H), 1.22 (s, 9H), 0.92 (s, 9H). .sup.13C-NMR (151 MHz): δ 166.3, 151.9, 151.7, 148.8, 148.8, 148.3, 139.5, 138.8, 138.4, 136.0, 135.4, 135.3, 134.5, 133.3, 133.2, 129.7, 129.6, 129.5, 127.7, 127.6, 127.6, 127.2, 123.6, 115.8, 68.6, 59.4, 58.5, 45.8, 37.7, 26.7, 23.7, 19.0; 1 C not observed. HRMS m/z calcd for C.sub.41H.sub.47N.sub.4O.sub.3SSi ([M+H].sup.+) 703.3138; found 703.3160.

(R)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 247)

[0389] ##STR00258##

[0390] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (30 mg, 0.0427 mmol, 1.0 equiv) was dissolved in 0.43 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 64 μL, 0.064 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (4% MeOH/EtOAc) yielded the compound 247 as a light yellow solid (16 mg, 79%). TLC: R.sub.f 0.08 (5% MeOH/EtOAc). [α].sub.D.sup.20: −18.1° (c 0.48, CHCl.sub.3). IR (ATR): 3443, 3297, 3053, 2958, 1682, 1574, 1455, 1390, 1266, 1048, 945, 753, 703. .sup.1H-NMR (600 MHz): δ 8.88 (s, 1H), 8.59 (d, J=4.1 Hz, 1H), 8.07 (s, 1H), 7.95 (dt, J=8.0, 1.9 Hz, 1H), 7.91 (s, 1H), 7.88 (d, J=4.4 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.39 (dd, J=7.9, 4.8 Hz, 1H), 5.90 (d, J=4.1 Hz, 1H), 5.83-5.70 (m, 1H), 5.21 (d, J=15.7 Hz, 1H), 4.15 (d, J=14.9 Hz, 1H), 3.60 (ddd, J=10.7, 8.0, 5.8 Hz, 1H), 3.45 (ddd, J=11.0, 6.5, 4.9 Hz, 1H), 1.85-1.72 (m, 1H), 1.72-1.59 (m, 1H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 166.2, 151.9, 151.7, 149.0, 148.7, 148.2, 139.2, 138.4, 137.9, 136.0, 134.6, 129.5, 128.0, 127.9, 127.0, 123.7, 115.8, 68.7, 58.5, 58.2, 45.9, 37.6, 23.8. HRMS m/z calcd for C.sub.25H.sub.29N.sub.4O.sub.3S ([M+H].sup.+) 465.1960; found 465.1959.

Preparation of Compound 237

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0391] ##STR00259##

[0392] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (34 mg, 0.0464 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.46 mL, 0.0929 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/hexanes) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky yellow foam (30 mg, 82%). TLC: R.sub.f 0.44 (50% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +56.8° (c 1.0, CHC.sub.3). IR (ATR): 3331, 3071, 2956, 2931, 2859, 1687, 1523, 1273, 1162, 1076, 740, 705. .sup.1H-NMR (600 MHz): δ 8.89 (s, 1H), 8.65 (s, 1H), 8.36 (t, J=6.8 Hz, 1H), 8.08 (s, 1H), 7.91-7.82 (m, 2H), 7.75-7.64 (m, 2H), 7.48 (t, J=7.7 Hz, 1H), 7.44-7.33 (m, 7H), 7.29-7.27 (m, 3H), 7.26-7.24 (m, 1H), 5.76 (ddd, J=7.7, 3.4, 1.8 Hz, 1H), 5.19 (d, J=15.9 Hz, 1H), 4.37-4.15 (m, 1H), 4.06-3.90 (m, 2H), 3.64 (ddd, J=10.4, 8.2, 5.0 Hz, 1H), 3.49 (dt, J=10.6, 5.4 Hz, 1H), 1.84-1.72 (m, 1H), 1.62-1.48 (m, 1H), 1.22 (s, 9H), 0.91 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.2, 152.1, 151.9, 148.9, 148.3, 148.0, 139.3, 138.5, 135.9, 135.4, 135.3, 134.4, 133.3, 133.1, 129.7, 129.7, 129.7, 127.9, 127.8, 127.6, 127.1, 124.1 (q, J=278.7 Hz), 123.7, 116.0, 68.6, 59.4, 58.5, 45.9, 40.8 (q, J=34.9 Hz), 37.6, 26.7, 23.7, 19.0; 2 C not observed. HRMS m/z calcd for C.sub.43H.sub.48F.sub.3N.sub.4O.sub.3SSi ([M+H].sup.+) 785.3169; found 785.3158.

(R)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 237)

[0393] ##STR00260##

[0394] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (29 mg, 0.0369 mmol, 1.0 equiv) was dissolved in 0.37 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 55 μL, 0.0554 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (1% MeOH/EtOAc) yielded compound 237 as a light yellow solid (10 mg, 50%). TLC: R.sub.f 0.06 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +59.0° (c 1.0, CHCl.sub.3). IR (ATR): 3389, 2957, 2926, 2872, 1682, 1576, 1524, 1475, 1422, 1392, 1272, 1159, 1056, 755, 712. .sup.1H-NMR (600 MHz): δ 8.91 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.38 (t, J=6.8 Hz, 1H), 8.10 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 5.75 (d, J=7.0 Hz, 1H), 5.23 (d, J=15.8 Hz, 1H), 4.23 (dq, J=15.8, 8.3, 7.7 Hz, 1H), 4.16 (d, J=15.6 Hz, 1H), 4.02 (ddd, J=15.1, 8.9, 6.3 Hz, 1H), 3.61 (ddd, J=10.6, 8.1, 5.6 Hz, 1H), 3.47 (ddd, J=10.9, 6.3, 4.9 Hz, 1H), 1.86-1.67 (m, 1H), 1.70-1.59 (m, 1H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.2, 152.1, 151.9, 148.8, 148.3, 148.3, 139.1, 138.5, 138.5, 135.9, 134.6, 129.7, 128.1, 128.0, 127.0, 124.1 (q, J=278.6 Hz), 123.7, 116.0, 68.7, 58.5, 58.3, 45.9, 40.8 (q, J=34.9 Hz), 37.6, 23.8. HRMS m/z calcd for C.sub.27H.sub.30F.sub.3N.sub.4O.sub.3S ([M+H].sup.+) 547.1991; found 547.1979.

Preparation of Compound 264

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 264)

[0395] ##STR00261##

[0396] In a small vial, (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (26 mg, 0.0311 mmol, 1.0 equiv) was dissolved in 0.31 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 31 μL, 0.124 mmol, 4 equiv) was added dropwise and the mixture was stirred at 0° C. for 5 min, then allowed to warm to room temperature and stirred for 10 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/CH.sub.2Cl.sub.2) yielded compound 264 as a light yellow film (7 mg, 46%). TLC: R.sub.f 0.08 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: −88.9° (c 0.22, CHCl.sub.3). IR (ATR): 3378, 3053, 2893, 1664, 1524, 1490, 1444, 1253, 1039, 928, 802, 736, 712. .sup.1H-NMR (600 MHz): δ 8.88 (d, J=2.4 Hz, 1H), 8.63 (dd, J=4.9, 1.6 Hz, 1H), 8.37 (t, J=6.2 Hz, 1H), 8.18 (s, 1H), 7.90 (dt, J=8.0, 2.0 Hz, 1H), 7.84 (s, 1H), 7.74-7.63 (m, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.40 (dd, J=7.9, 4.8 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.82 (dd, J=7.9, 1.7 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.93 (s, 2H), 5.19 (dd, J=9.6, 3.5 Hz, 1H), 4.67-4.53 (m, 2H), 4.40 (d, J=16.2 Hz, 1H), 4.31 (d, J=16.2 Hz, 1H), 3.72 (ddd, J=11.3, 8.8, 2.7 Hz, 1H), 3.61 (ddd, J=10.9, 5.4, 3.2 Hz, 1H), 1.58-1.40 (m, 2H). .sup.13C-NMR (151 MHz): δ 164.0, 154.3, 151.9, 149.1, 148.9, 148.3, 147.9, 146.9, 141.0, 139.7, 138.5, 136.0, 134.5, 132.1, 129.5, 127.8, 127.7, 126.9, 123.7, 121.0, 115.9, 108.4, 108.3, 101.0, 63.7, 62.0, 50.8, 43.2, 33.7. HRMS m/z calcd for C.sub.29H.sub.27N.sub.4O.sub.4 ([M+H].sup.+) 495.2032; found 495.2035.

Preparation of Compound 265

(R)—N-(2-fluorobenzyl)-3-(2-hydroxyethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 265)

[0397] ##STR00262##

[0398] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (18 mg, 0.0222 mmol, 1.0 equiv) was dissolved in 0.22 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 22 μL, 0.0888 mmol, 4 equiv) was added dropwise and the mixture was stirred at 0° C. for 5 min, then allowed to warm to room temperature and stirred for 10 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/CH.sub.2Cl.sub.2) yielded compound 265 as a light yellow film (5.5 mg, 53%). TLC: R.sub.f 0.08 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +17.5° (c 0.53, CHCl.sub.3). IR (ATR): 3377, 3319, 3050, 2918, 2850, 2363, 1668, 1571, 1524, 1491, 1472, 1422, 1266, 1229, 1062, 758, 737, 712. .sup.1H-NMR (600 MHz): δ 8.90 (d, J=2.2 Hz, 1H), 8.64 (dd, J=4.8, 1.3 Hz, 1H), 8.49 (t, J=6.2 Hz, 1H), 8.17 (s, 1H), 7.92 (dt, J=7.9, 1.9 Hz, 1H), 7.89 (s, 1H), 7.75-7.66 (m, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.47-7.37 (m, 2H), 7.26-7.23 (m, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.08-7.03 (m, 1H), 5.21 (dd, J=9.7, 3.4 Hz, 1H), 4.82-4.69 (m, 2H), 4.39 (d, J=16.2 Hz, 1H), 4.30 (d, J=16.2 Hz, 1H), 3.73 (ddd, J=11.3, 8.9, 2.5 Hz, 1H), 3.62 (ddd, J=10.9, 5.5, 3.2 Hz, 1H), 1.60-1.42 (m, 2H). .sup.13C-NMR (151 MHz): δ 164.1, 161.0 (d, J=246.2 Hz), 154.4, 151.8, 149.0, 148.9, 148.3, 141.0, 139.6, 138.5, 136.0, 134.5, 130.0 (d, J=4.2 Hz), 129.6, 129.2 (d, J=8.1 Hz), 127.8, 127.6, 127.0, 125.2 (d, J=14.7 Hz), 124.3 (d, J=3.6 Hz), 123.7, 115.8, 115.4 (d, J=21.2 Hz), 63.8, 62.0, 50.7, 37.5 (d, J=4.0 Hz), 33.7. HRMS m/z calcd for C.sub.28H.sub.26FN.sub.4O.sub.4 ([M+H].sup.+) 469.2040; found 469.2053.

Preparation of Compound 253

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0399] ##STR00263##

[0400] In a vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (303 mg, 0.414 mmol, 1.0 equiv) was dissolved in 4.1 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 124 μL, 0.497 mmol, 1.2 equiv) was added dropwise and the mixture was stirred at 0° C. for 2 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×10 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% EtOAc.fwdarw.1% MeOH/EtOAc) yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (225 mg, 86%). TLC: R.sub.f 0.53 (5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.21: +138.3° (c 1.0, CHCl.sub.3). IR (ATR): 3049, 2957, 2932, 2857, 1737, 1716, 1572, 1472, 1268, 1224, 1109, 739, 704. .sup.1H-NMR (600 MHz): δ 8.87 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.56-7.49 (m, 4H), 7.47 (t, J=7.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.37-7.29 (m, 5H), 5.21 (d, J=9.3 Hz, 1H), 4.53 (dq, J=10.8, 7.1 Hz, 1H), 4.45 (dq, J=10.8, 7.1 Hz, 1H), 4.34-4.26 (m, 2H), 3.74-3.64 (m, 1H), 3.64-3.54 (m, 1H), 1.80-1.65 (m, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.41-1.31 (m, 1H), 0.99 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.4, 154.0, 153.7, 148.6, 148.3, 147.3, 142.1, 139.9, 138.3, 136.2, 135.4, 135.4, 134.5, 133.2, 133.2, 129.7, 129.7, 129.3, 127.9, 127.7, 127.6, 127.6, 127.5, 123.5, 118.4, 61.9, 61.4, 60.9, 51.1, 35.4, 26.9, 26.8, 19.1, 14.34. HRMS m/z calcd for C.sub.39H.sub.42N.sub.3O.sub.3Si ([M+H].sup.+) 628.2995; found 628.2974.

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0401] ##STR00264##

[0402] In a vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (218 mg, 0.347 mmol, 1.0 equiv) was dissolved in 3.7 mL of CH.sub.2Cl.sub.2 and cooled to 0° C. NEt.sub.3 (73 μL, 0.521 mmol, 1.5 equiv) was added, followed by 2-isocyanatopropane (38 μL, 0.382 mmol, 1.2 equiv), and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched by addition of 2 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×3 mL). The combined organic extracts were washed with brine (1×3 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as an white solid film (214 mg, 86%). TLC: R.sub.f 0.21 (80% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.21: +100.8° (c 1.0, CHCl.sub.3). IR (ATR): 3369, 3071, 2967, 2932, 2858, 1724, 1638, 1579, 1530, 1371, 1233, 1108, 756, 704. .sup.1H-NMR (600 MHz): δ 8.89 (d, J=2.3 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.90 (dt, J=7.9, 1.8 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.43-7.31 (m, 9H), 7.29-7.27 (m, 1H), 7.22 (t, J=7.6 Hz, 2H), 5.85 (s, 1H), 5.10 (d, J=14.8 Hz, 1H), 4.53 (dq, J=10.8, 7.1 Hz, 1H), 4.50-4.40 (m, 2H), 4.17-3.95 (m, 1H), 3.66-3.58 (m, 1H), 3.53 (dt, J=10.8, 4.9 Hz, 1H), 2.04-1.88 (m, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.42-1.34 (m, 1H), 1.16 (d, J=6.6 Hz, 6H), 0.89 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 156.4, 153.6, 149.2, 148.7, 148.3, 147.7, 139.6, 139.0, 138.6, 136.1, 135.3, 135.3, 134.6, 133.1, 133.0, 129.8, 129.7, 129.6, 127.8, 127.7, 127.6, 127.6, 127.6, 123.6, 118.2, 62.0, 60.2, 59.6, 50.9, 42.7, 27.0, 23.4, 23.3, 19.1, 14.3. HRMS m/z calcd for C.sub.43H.sub.49N.sub.4O.sub.4Si ([M+H].sup.+) 713.3523; found 713.3540.

(R)—N.SUP.6.-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0403] ##STR00265##

[0404] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (82 mg, 0.115 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 1.15 mL, 0.230 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/CH.sub.2Cl.sub.2.fwdarw.100% EtOAc) yielded (R)—N.sup.6-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a sticky yellow foam (49 mg, 52%). TLC: R.sub.f 0.24 (80% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +94.1° (c 1.0, CHCl.sub.3). IR (ATR): 3367, 3050, 2963, 2931, 2858, 1642, 1521, 1445, 1378, 1252, 1110, 1040, 938, 735, 702. .sup.1H-NMR (600 MHz): δ 8.86 (s, 1H), 8.64 (d, J=4.2 Hz, 1H), 8.35 (t, J=6.1 Hz, 1H), 8.13 (s, 1H), 7.89-7.77 (m, 2H), 7.71-7.61 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.43-7.29 (m, 7H), 7.26-7.23 (m, 2H), 7.21 (t, J=7.5 Hz, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.82 (dd, J=7.9, 1.6 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.88-5.82 (m, 1H), 5.01 (d, J=15.3 Hz, 1H), 4.72-4.53 (m, 3H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.04 (dq, J=13.5, 6.7 Hz, 1H), 3.60-3.45 (m, 2H), 2.08-1.95 (m, 1H), 1.52-1.40 (m, 1H), 1.16 (d, J=6.6 Hz, 8H), 0.86 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 156.1, 152.1, 149.5, 149.1, 148.9, 148.3, 147.9, 146.9, 139.6, 138.5, 138.3, 135.9, 135.3, 135.2, 134.5, 133.1, 133.1, 132.1, 129.7, 129.7, 129.6, 127.8, 127.6, 127.6, 127.6, 127.1, 123.7, 121.0, 115.7, 108.4, 108.3, 101.0, 60.2, 59.7, 51.1, 43.2, 42.6, 26.9, 23.5, 23.4, 19.0. HRMS m/z calcd for C.sub.49H.sub.52N.sub.5O.sub.5Si ([M+H].sup.+) 818.3738; found 818.3715.

(R)—N.SUP.6.-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (Compound 253)

[0405] ##STR00266##

[0406] In a small vial, (R)—N.sup.6-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (39 mg, 0.0477 mmol, 1.0 equiv) was dissolved in 0.48 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 72 μL, 0.0715 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (3% MeOH/EtOAc) yielded compound 253 as a light yellow solid (18 mg, 66%). TLC: R.sub.f 0.21 (3% MeOH/EtOAc). [α].sub.D.sup.20: +116.9° (c 1.0, CHCl.sub.3). IR (ATR): 3308, 3052, 2970, 2930, 2877, 1663, 1629, 1524, 1444, 1380, 1252, 1238, 1186, 1038, 735, 712. .sup.1H-NMR (600 MHz): δ 8.88 (s, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.39 (t, J=6.1 Hz, 1H), 8.15 (s, 1H), 7.99 (dt, J=7.9, 1.7 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.85 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 6.06 (d, J=10.1 Hz, 1H), 5.93 (d, J=1.4 Hz, 2H), 4.89 (d, J=14.6 Hz, 1H), 4.78-4.51 (m, 4H), 4.06 (h, J=6.7 Hz, 1H), 3.65-3.48 (m, 1H), 3.44 (d, J=11.9 Hz, 1H), 1.92-1.75 (m, 1H), 1.27-1.10 (m, 7H). .sup.13C-NMR (151 MHz): δ 163.8, 157.4, 152.0, 149.3, 148.8, 148.6, 148.3, 147.9, 146.9, 138.9, 138.7, 138.6, 136.1, 134.8, 132.0, 129.7, 128.2, 127.9, 127.0, 123.7, 121.0, 115.6, 108.3, 108.3, 101.0, 59.1, 58.4, 51.0, 43.3, 43.0, 37.8, 23.4, 23.3. HRMS m/z calcd for C.sub.33H.sub.34N.sub.5O.sub.5 ([M+H].sup.+) 580.2560; found 580.2545.

Preparation of Compound 254

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.6.-(2-fluorobenzyl)-N.SUP.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0407] ##STR00267##

[0408] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (82 mg, 0.115 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 1.15 mL, 0.230 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/CH.sub.2Cl.sub.2.fwdarw.100% EtOAc) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.6-(2-fluorobenzyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a sticky yellow foam (47 mg, 52%). TLC: R.sub.f 0.26 (80% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +83.2° (c 1.0, CHCl.sub.3). IR (ATR): 3381, 3071, 3050, 2965, 2930, 2854, 1669, 1638, 1577, 1521, 1457, 1427, 1380, 1265, 1178, 1109, 1058, 894, 735, 702. .sup.1H-NMR (600 MHz): δ 8.89 (s, 1H), 8.65 (s, 1H), 8.48 (t, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.90-7.83 (m, 2H), 7.68 (d, J=7.8 Hz, 2H), 7.51-7.37 (m, 5H), 7.36-7.27 (m, 4H), 7.26-7.23 (m, 3H), 7.19 (t, J=7.5 Hz, 2H), 7.12-7.03 (m, 2H), 5.88 (s, 1H), 5.00 (d, J=15.4 Hz, 1H), 4.77 (dd, J=15.1, 6.4 Hz, 1H), 4.71 (dd, J=15.1, 6.2 Hz, 1H), 4.64 (bs, 1H), 4.47 (d, J=15.1 Hz, 1H), 4.09-4.00 (m, 1H), 3.60-3.44 (m, 2H), 2.06-1.94 (m, 1H), 1.52-1.38 (m, 1H), 1.17 (d, J=6.5 Hz, 6H), 0.85 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.2 Hz), 156.1, 152.0, 149.6, 149.0, 148.8, 148.2, 139.5, 138.6, 138.3, 135.9, 135.3, 135.2, 134.5, 133.1, 133.0, 130.1 (d, J=4.3 Hz), 129.7, 129.6, 129.6, 129.3 (d, J=8.1 Hz), 127.8, 127.6, 127.5, 127.2, 125.2 (d, J=14.8 Hz), 124.3 (d, J=3.6 Hz), 123.7, 115.6, 115.4 (d, J=21.2 Hz), 60.1, 59.8, 51.1, 42.6, 37.5 (d, J=4.1 Hz), 29.4, 26.9, 23.5, 23.4, 19.0. HRMS m/z calcd for C.sub.48H.sub.51FN.sub.5O.sub.3Si ([M+H].sup.+) 792.3745; found 792.3755.

(R)—N.SUP.6.-(2-fluorobenzyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (compound 254)

[0409] ##STR00268##

[0410] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-NV-(2-fluorobenzyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (42 mg, 0.0530 mmol, 1.0 equiv) was dissolved in 0.53 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 80 μL, 0.0795 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (3% MeOH/EtOAc) yielded compound 254 as a light yellow solid (21 mg, 70%). TLC: R.sub.f 0.21 (3% MeOH/EtOAc). [α].sub.D.sup.20: +119.80 (c 1.0, CHCl.sub.3). IR (ATR): 3319, 3066, 2969, 2874, 1668, 1630, 1525, 1457, 1382, 1292, 1230, 1178, 1058, 758, 713. .sup.1H-NMR (600 MHz): δ 8.90 (s, 1H), 8.62 (d, J=4.3 Hz, 1H), 8.51 (t, J=6.3 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.71-7.66 (m, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.43-7.37 (m, 2H), 7.26-7.23 (m, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.08-7.04 (m, 1H), 6.08 (d, J=10.2 Hz, 1H), 4.89 (d, J=14.6 Hz, 1H), 4.80-4.56 (m, 4H), 4.35 (bs, 1H), 4.05 (dq, J=13.3, 6.6 Hz, 1H), 3.55 (t, J=10.4 Hz, 1H), 3.51-3.38 (m, 1H), 1.91-1.72 (m, 1H), 1.27-1.15 (m, 7H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.2 Hz), 157.4, 151.9, 149.2, 148.7, 148.7, 148.3, 138.9, 138.7, 138.6, 136.1, 134.8, 130.0 (d, J=4.3 Hz), 129.7, 129.3 (d, J=8.2 Hz), 128.2, 127.8, 127.0, 125.0 (d, J=14.7 Hz), 124.3 (d, J=3.6 Hz), 123.7, 115.5, 115.4 (d, J=20.5 Hz), 59.1, 58.3, 51.0, 43.0, 37.8, 37.5 (d, J=4.0 Hz), 23.4, 23.3. HRMS m/z calcd for C.sub.32H.sub.33FN.sub.5O.sub.3([M+H].sup.+) 554.2567; found 554.2559.

Preparation of Compound 255

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-N.SUP.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0411] ##STR00269##

[0412] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (41 mg, 0.0575 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.58 mL, 0.115 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/CH.sub.2Cl.sub.2.fwdarw.100% EtOAc) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a sticky yellow foam (28 mg, 64%). TLC: R.sub.f 0.29 (80% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +89.0° (c 1.0, CHCl.sub.3). IR (ATR): 3367, 3075, 3050, 2963, 2933, 2859, 1684, 1639, 1520, 1382, 1268, 1158, 1110, 736, 702. .sup.1H-NMR (600 MHz): δ 8.89 (s, 1H), 8.66 (s, 1H), 8.38 (t, J=6.7 Hz, 1H), 8.10 (s, 1H), 7.91-7.83 (m, 2H), 7.69 (dd, J=13.6, 7.8 Hz, 2H), 7.49 (t, J=7.7 Hz, 1H), 7.42-7.29 (m, 7H), 7.28-7.27 (m, 1H), 7.26-7.24 (m, 1H), 7.21 (t, J=7.6 Hz, 2H), 5.88 (s, 1H), 5.02 (d, J=14.7 Hz, 1H), 4.65 (bs, 1H), 4.48 (dd, J=15.3, 2.0 Hz, 1H), 4.31-4.17 (m, 1H), 4.07-3.98 (m, 2H), 3.64-3.43 (m, 2H), 2.03-1.95 (m, 1H), 1.56-1.37 (m, 1H), 1.17 (d, J=6.6 Hz, 6H), 0.86 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.2, 156.1, 152.3, 149.8, 148.9, 148.3, 147.9, 139.3, 139.1, 138.6, 135.8, 135.3, 135.2, 135.1, 134.4, 133.1, 133.0, 129.8, 129.7, 128.0, 127.6, 127.6, 127.1, 124.1 (q, J=278.7 Hz), 123.7, 116.0, 60.1, 59.8, 51.1, 42.7, 40.8 (q, J=34.9 Hz), 35.2, 26.9, 23.5, 23.4, 19.0; 1 C not observed. HRMS m/z calcd for C.sub.43H.sub.47F.sub.3N.sub.5O.sub.3Si ([M+H].sup.+) 766.3400; found 766.3396.

(R)-3-(2-hydroxyethyl)-N.SUB.2.-isopropyl-4-(3-(pyridin-3-yl)phenyl)-N.SUB.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (compound 255)

[0413] ##STR00270##

[0414] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-(3-(pyridin-3-yl)phenyl)-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (28 mg, 0.0366 mmol, 1.0 equiv) was dissolved in 0.36 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 55 μL, 0.0548 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (3% MeOH/EtOAc) yielded compound 255 as a light yellow solid (10 mg, 54%).

[0415] TLC: R.sub.f 0.21 (3% MeOH/EtOAc). [α].sub.D.sup.20: +139.9° (c 1.0, CHCl.sub.3). IR (ATR): 3319, 1681, 1631, 1523, 1383, 1273, 1158, 1057, 736. .sup.1H-NMR (600 MHz): δ 8.90 (d, J=1.9 Hz, 1H), 8.62 (d, J=3.8 Hz, 1H), 8.42 (t, J=6.7 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.93 (s, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.72-7.60 (m, 2H), 7.41 (dd, J=7.8, 4.8 Hz, 1H), 6.08 (d, J=10.2 Hz, 1H), 4.92 (d, J=14.6 Hz, 1H), 4.84-4.60 (m, 2H), 4.26-4.14 (m, 2H), 4.14-3.96 (m, 2H), 3.56 (td, J=11.4, 2.6 Hz, 1H), 3.50-3.43 (m, 1H), 1.86-1.76 (m, 1H), 1.26-1.17 (m, 7H). .sup.13C-NMR (151 MHz): δ 164.2, 157.4, 152.2, 148.9, 148.8, 148.3, 148.1, 139.3, 138.7, 138.7, 136.0, 134.8, 129.8, 128.3, 127.9, 126.9, 124.0 (q, J=278.7, 278.1 Hz), 123.8, 115.9, 59.1, 58.3, 50.9, 43.0, 40.8 (q, J=35.0 Hz), 37.7, 23.4, 23.3. HRMS m/z calcd for C.sub.27H.sub.29F.sub.3N.sub.5O.sub.3([M+H].sup.+) 528.2222; found 528.2227.

Preparation of Compound 248

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0416] ##STR00271##

[0417] In a 4 mL vial, ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (23 mg, 0.0310 mmol, 1.0 equiv) was dissolved in 0.15 mL 1:1 THF/MeOH at room temperature. Aq. NH.sub.3 (˜30% solution, 0.15 mL, 8.01 mmol, 250 equiv) was added and the mixture was stirred at room temperature for 12 h, then diluted with 1 mL EtOAc and 1 mL sat. aq. NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes) yielded (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a light yellow solid film (19 mg, 83%). TLC: R.sub.f 0.29 (70% EtOAc/hexanes). [α].sub.D.sup.19: +135.5° (c 1.0, CHCl.sub.3). IR (ATR): 3449, 3360, 3070, 2963, 2930, 2857, 1688, 1638, 1573, 1528, 1452, 1378, 1260, 1109, 798, 739, 702. .sup.1H-NMR (600 MHz): δ 8.17 (s, 1H), 8.11 (s, 1H), 8.00-7.81 (m, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.46-7.37 (m, 3H), 7.36-7.30 (m, 4H), 7.30-7.27 (m, 2H), 7.25-7.23 (m, 2H), 7.20 (t, J=7.4 Hz, 2H), 7.10 (s, 1H), 5.87 (s, 1H), 5.69 (d, J=4.5 Hz, 1H), 5.09 (d, J=15.5 Hz, 1H), 4.80 (bs, 1H), 4.47 (dd, J=15.5, 2.3 Hz, 1H), 4.17-3.98 (m, J=6.5 Hz, 1H), 3.68-3.55 (m, 1H), 3.55-3.45 (m, 1H), 2.05-1.84 (m, 1H), 1.47-1.32 (m, 1H), 1.18 (t, J=6.4 Hz, 6H), 0.86 (s, 9H). .sup.13C-NMR (151 MHz): δ 166.3, 156.3, 155.0, 155.0, 152.2, 149.7, 148.7, 139.3, 138.7, 135.3, 135.3, 133.1, 133.0, 131.3, 129.7, 129.7, 129.3, 129.0, 127.9, 127.6, 27.6, 125.5, 124.9, 124.6, 123.1, 121.1, 115.7, 111.3, 102.2, 60.2, 59.6, 51.0, 42.7, 35.6, 26.9, 23.4, 23.4, 19.0. HRMS m/z calcd for C.sub.44H.sub.46N.sub.4O.sub.4SiNa ([M+Na].sup.+) 745.3186; found 745.3162.

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (compound 248)

[0418] ##STR00272##

[0419] In a small vial, (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (18 mg, 0.0249 mmol, 1.0 equiv) was dissolved in 0.25 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 37 μL, 0.0373 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% EtOAc) yielded the compound 248 as a light yellow solid film (6 mg, 53%). TLC: R.sub.f 0.17 (100% EtOAc). [α].sub.D.sup.19: +177.0° (c 0.64, CHCl.sub.3). IR (ATR): 3445, 3305, 2968, 2931, 2873, 1685, 1629, 1573, 1541, 1452, 1381, 1299, 1258, 1173, 1058, 800, 750. .sup.1H-NMR (600 MHz): δ 8.23 (s, 1H), 8.13 (s, 1H), 8.04-7.91 (m, 2H), 7.74 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.31 (ddd, J=8.2, 7.2, 1.3 Hz, 1H), 7.25-7.23 (m, 1H), 7.15 (s, 1H), 6.06 (d, J=10.1 Hz, 1H), 5.73 (d, J=4.4 Hz, 1H), 4.91 (d, J=14.6 Hz, 1H), 4.77-4.60 (m, 2H), 4.07 (h, J=6.7 Hz, 1H), 3.61-3.48 (m, 1H), 3.49-3.36 (m, 1H), 1.89-1.76 (m, 1H), 1.65 (s, 1H), 1.32-1.17 (m, 7H). .sup.13C-NMR (151 MHz): δ 166.2, 157.4, 155.1, 154.9, 152.1, 148.9, 148.6, 138.9, 138.7, 131.3, 129.4, 129.0, 128.0, 125.9, 124.7, 124.6, 123.1, 121.1, 115.6, 111.2, 102.3, 59.2, 58.5, 50.9, 43.0, 37.9, 23.4, 23.3. HRMS m/z calcd for C.sub.28H.sub.28N.sub.4O.sub.4Na ([M+Na].sup.+) 507.2008; found 507.2021.

Preparation of Compound 241

(R)—N.SUP.6.-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0420] ##STR00273##

[0421] To a vial containing ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (16 mg, 0.0209 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.21 mL, 0.0417 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)—N.sup.6-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a white foam (15 mg, 83%). TLC: R.sub.f 0.19 (25% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +139.0° (c 1.0, CHCl.sub.3). IR (ATR): 3376, 3069, 2930, 1667, 1521, 1490, 1446, 1379, 1256, 1110, 1042, 929, 738, 703. .sup.1H-NMR (600 MHz): δ 8.39 (t, J=6.2 Hz, 1H), 8.13 (d, J=5.7 Hz, 2H), 7.93 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.43-7.37 (m, 3H), 7.34-7.26 (m, 6H), 7.24 (t, J=7.6 Hz, 2H), 7.19 (t, J=7.5 Hz, 2H), 7.05 (s, 1H), 6.88 (d, J=1.7 Hz, 1H), 6.83 (dd, J=8.0, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.91 (s, 2H), 5.88-5.81 (m, 1H), 5.08 (d, J=15.4 Hz, 1H), 4.77 (bs, 1H), 4.63 (dd, J=14.9, 6.3 Hz, 1H), 4.56 (dd, J=14.9, 6.1 Hz, 1H), 4.47 (dd, J=15.7, 2.3 Hz, 1H), 4.07 (dq, J=13.5, 6.7 Hz, 1H), 3.64-3.51 (m, 1H), 3.52-3.43 (m, 1H), 2.00-1.86 (m, 1H), 1.44-1.32 (m, 1H), 1.17 (dd, J=6.6, 5.2 Hz, 6H), 0.85 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 156.3, 155.0, 154.9, 152.0, 149.6, 149.1, 147.9, 146.9, 139.3, 138.4, 135.3, 135.3, 133.1, 133.0, 132.2, 131.2, 129.7, 129.6, 129.3, 129.0, 127.9, 127.6, 127.6, 125.4, 124.9, 124.6, 123.1, 121.1, 121.0, 115.7, 111.3, 108.4, 108.3, 102.2, 101.0, 60.2, 59.6, 53.4, 51.1, 43.2, 42.6, 26.9, 23.4, 23.4, 19.0. HRMS m/z calcd for C.sub.52H.sub.52N.sub.4O.sub.6SiNa ([M+Na].sup.+) 879.3554; found 879.3517.

(R)—N.SUP.6.-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (compound 241)

[0422] ##STR00274##

[0423] In a small vial, (R)—N.sup.6-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (15 mg, 0.0173 mmol, 1.0 equiv) was dissolved in 0.17 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 26 μL, 0.0259 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes) yielded the compound 241 as a light yellow solid film (7 mg, 70%). TLC: R.sub.f 0.41 (2% MeOH/EtOAc). [α].sub.D.sup.19: +150.10 (c 1.0, CHCl.sub.3). IR (ATR): 3313, 3062, 2969, 2929, 2778, 1733, 1666, 1627, 1524, 1445, 1380, 1255, 1039, 928, 800, 750, 699. .sup.1H-NMR (600 MHz): δ 8.42 (t, J=6.2 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.63-7.57 (m, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.26-7.22 (m, 1H), 7.12 (s, 1H), 6.88 (d, J=1.7 Hz, 1H), 6.84 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.04 (d, J=10.2 Hz, 1H), 5.91 (s, 2H), 4.90 (d, J=14.7 Hz, 1H), 4.78-4.50 (m, 4H), 4.07 (dq, J=13.3, 6.7 Hz, 1H), 3.60-3.48 (m, 1H), 3.48-3.39 (m, 1H), 1.89-1.74 (m, 1H), 1.25 (t, J=6.4 Hz, 6H), 1.23-1.17 (m, 1H). .sup.13C-NMR (151 MHz): δ 163.8, 157.4, 155.0, 154.9, 152.0, 149.2, 148.6, 147.9, 146.9, 138.7, 138.7, 132.0, 131.2, 129.4, 129.0, 128.0, 125.8, 124.7, 124.6, 123.1, 121.1, 121.0, 115.6, 111.2, 108.4, 108.3, 102.2, 101.0. HRMS m/z calcd for C.sub.36H.sub.34N.sub.4O.sub.6Na ([M+Na].sup.+) 641.2376; found 641.2397.

Preparation of Compound 268

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.6.-(2-fluorobenzyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0424] ##STR00275##

[0425] To a vial containing ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (19 mg, 0.0247 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.25 mL, 0.0495 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.6-(2-fluorobenzyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a light yellow foam (11 mg, 53%). TLC: R.sub.f 0.22 (25% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: +149.4° (c 1.0, CHCl.sub.3). IR (ATR): 3386, 3071, 2963, 2932, 2858, 1673, 1524, 1456, 1456, 1383, 1258, 1177, 1110, 1059, 798, 751, 740, 703. .sup.1H-NMR (600 MHz): δ 8.50 (t, J=6.3 Hz, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.65-7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.46-7.37 (m, 4H), 7.35-7.30 (m, 4H), 7.30-7.27 (m, 2H), 7.25-7.21 (m, 3H), 7.18 (t, J=7.4 Hz, 2H), 7.11 (td, J=7.5, 1.2 Hz, 1H), 7.08-7.03 (m, 2H), 5.93-5.78 (m, 1H), 5.07 (d, J=15.2 Hz, 1H), 4.85-4.63 (m, 3H), 4.46 (dd, J=15.5, 1.7 Hz, 2H), 4.16-3.98 (m, 1H), 3.63-3.54 (m, 1H), 3.54-3.41 (m, 1H), 2.01-1.83 (m, 1H), 1.48-1.34 (m, 1H), 1.18 (t, J=6.2 Hz, 6H), 0.84 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.99, 161.0 (d, J=246.3 Hz), 156.3, 155.1, 155.0, 152.0, 149.6, 149.0, 139.2, 138.4, 135.3, 135.3, 133.1, 133.0, 131.2, 130.1 (d, J=4.2 Hz), 129.7, 129.6, 129.3, 129.2 (d, J=8.2 Hz), 129.1, 127.9, 127.6, 127.5, 125.5, 125.2 (d, J=14.7 Hz), 124.9, 124.6, 124.3 (d, J=3.6 Hz), 123.1, 121.1, 115.6, 115.4 (d, J=21.2 Hz), 111.3, 102.2, 60.2, 59.6, 51.0, 42.6, 37.4 (d, J=4.1 Hz), 35.6, 26.9, 23.5, 23.4, 19.0. HRMS m/z calcd for C.sub.51H.sub.51FN.sub.4O.sub.4SiNa ([M+Na].sup.+) 853.3561; found 853.3563.

(R)-4-(3-(benzofuran-2-yl)phenyl)-N.SUP.6.-(2-fluorobenzyl)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (compound 268)

[0426] ##STR00276##

[0427] In a small vial, (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.6-(2-fluorobenzyl)-N.sup.2-isopropyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (11 mg, 0.0129 mmol, 1.0 equiv) was dissolved in 0.13 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 19 μL, 0.0193 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes) yielded the compound 268 as a light yellow solid film (4 mg, 57%). TLC: R.sub.f 0.46 (2% MeOH/EtOAc). IR (ATR): 3319, 3067, 2964, 2874, 1669, 1629, 1524, 1455, 1382, 1261, 1175, 1097, 1034, 800, 751, 700. .sup.1H-NMR (600 MHz): δ 8.53 (t, J=6.3 Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.61 (t, J=7.4 Hz, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.29-7.27 (m, 1H), 7.25-7.23 (m, 1H), 7.14 (s, 1H), 7.12 (t, J=7.2 Hz, 1H), 7.07 (t, J=9.7, 8.7 Hz, 2H), 6.06 (d, J=10.0 Hz, 1H), 4.90 (d, J=14.6 Hz, 1H), 4.82-4.72 (m, 2H), 4.69-4.50 (m, 2H), 4.12-4.01 (m, 1H), 3.58-3.49 (m, 1H), 3.49-3.40 (m, 1H), 1.88-1.78 (m, 1H), 1.25 (t, J=6.7 Hz, 6H), 1.19-1.13 (m, 1H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.3 Hz), 157.3, 155.1, 155.0, 151.9, 149.2, 148.6, 138.7, 138.6, 135.3, 135.2, 131.3, 130.0 (d, J=4.2 Hz), 129.5, 129.3 (d, J=8.1 Hz), 129.1, 128.0, 127.6, 125.9, 125.1 (d, J=14.7 Hz), 124.8, 124.6, 124.3 (d, J=3.6 Hz), 123.1, 121.1, 115.5 (d, J=4.0 Hz), 115.4, 111.2, 102.2, 59.2, 58.6, 50.9, 43.0, 37.9, 37.5 (d, J=4.0 Hz), 23.4, 23.4. HRMS m/z calcd for C.sub.35H.sub.34FN.sub.4O.sub.4([M+H].sup.+) 593.2564; found 593.2571.

Preparation of Compound 219 (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0428] ##STR00277##

[0429] To a vial containing ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (25 mg, 0.0324 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.32 mL, 0.0648 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/hexanes) yielded (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a white foam (25 mg, 90%). TLC: R.sub.f 0.22 (50% EtOAc/hexanes). [α].sub.D.sup.19: +100.3° (c 1.0, CHCl.sub.3). IR (ATR): 3386, 3070, 2959, 2930, 2850, 1673, 1574, 1524, 1490, 1445, 1256, 1110, 1074, 1043, 929, 799, 754, 703. .sup.1H-NMR (600 MHz): δ 8.39 (t, J=6.2 Hz, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.46-7.36 (m, 5H), 7.36-7.28 (m, 3H), 7.28-7.26 (m, 2H), 7.26-7.23 (m, 3H), 7.05 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.91 (s, 2H), 5.76 (d, J=6.3 Hz, 1H), 5.19 (d, J=15.8 Hz, 1H), 4.64 (dd, J=14.9, 6.4 Hz, 1H), 4.54 (dd, J=14.9, 6.0 Hz, 1H), 4.01 (d, J=15.5 Hz, 1H), 3.63 (ddd, J=10.4, 8.3, 5.1 Hz, 1H), 3.45 (dt, J=10.6, 5.4 Hz, 1H), 1.84-1.69 (m, 1H), 1.60-1.48 (m, 1H), 1.21 (s, 9H), 0.89 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 155.1, 154.9, 151.7, 151.7, 149.2, 147.9, 146.9, 139.3, 138.5, 135.4, 135.4, 133.3, 133.2, 132.2, 131.1, 129.6, 129.6, 129.3, 129.0, 128.1, 127.5, 127.5, 125.4, 124.9, 124.5, 123.0, 121.0, 121.0, 115.7, 111.3, 108.4, 108.3, 102.1, 101.0, 68.5, 59.4, 58.5, 45.9, 43.2, 37.7, 26.7, 23.8, 18.9. HRMS m/z calcd for C.sub.52H.sub.53N.sub.3O.sub.6SSiNa ([M+Na].sup.+) 898.3322; found 898.3364.

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 219)

[0430] ##STR00278##

[0431] In a small vial, (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (25 mg, 0.0285 mmol, 1.0 equiv) was dissolved in 0.29 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 43 μL, 0.0428 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (80% EtOAc/hexanes) yielded compound 219 as a light yellow foam (15 mg, 84%). TLC: R.sub.f 0.08 (60% EtOAc/hexanes). [α].sub.D.sup.20: +77.4° (c 1.0, CHCl.sub.3). IR (ATR): 3385, 2926, 1668, 1574, 1526, 1490, 1256, 1041, 928, 800, 753. .sup.1H-NMR (600 MHz): δ 8.38 (t, J=6.1 Hz, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.31 (t, J=8.3 Hz, 1H), 7.26-7.23 (m, 1H), 7.10 (s, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.83 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.91 (s, 2H), 5.73 (ddd, J=5.9, 3.2, 1.8 Hz, 1H), 5.23 (d, J=15.7 Hz, 1H), 4.62 (dd, J=14.8, 6.3 Hz, 1H), 4.55 (dd, J=14.9, 6.1 Hz, 1H), 4.16 (d, J=16.8 Hz, 1H), 3.61-3.50 (m, 1H), 3.47-3.35 (m, 1H), 1.83-1.69 (m, 1H), 1.68-1.59 (m, 1H), 1.31 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.8, 155.0, 154.9, 151.8, 151.8, 149.4, 147.9, 146.9, 139.1, 137.5, 132.1, 131.1, 129.3, 129.0, 128.2, 125.6, 124.7, 124.6, 123.1, 121.1, 121.0, 115.7, 111.3, 108.4, 108.3, 102.2, 101.0, 68.6, 58.5, 58.4, 46.0, 43.3, 37.5, 23.8. HRMS m/z calcd for C.sub.36H.sub.35N.sub.3O.sub.6SNa ([M+Na].sup.+) 660.2144; found 660.2147.

Preparation of Compound 220

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0432] ##STR00279##

[0433] To a vial containing ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (24 mg, 0.0311 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.31 mL, 0.0623 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a light yellow foam (23 mg, 88%). TLC: R.sub.f 0.32 (50% EtOAc/hexanes). [α].sub.D.sup.20: +94.8° (c 1.0, CHCl.sub.3). IR (ATR): 3395, 3070, 2958, 2858, 1676, 1574, 1524, 1490, 1455, 1428, 1310, 1176, 1109, 1075, 942, 757, 703. .sup.1H-NMR (600 MHz): 8.49 (t, J=6.3 Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.64-7.57 (m, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.46-7.36 (m, 6H), 7.35-7.29 (m, 3H), 7.29-7.26 (m, 2H), 7.26-7.23 (m, 4H), 7.11 (t, J=7.5 Hz, 1H), 7.08-7.03 (m, 2H), 5.83-5.73 (m, 15H), 5.19 (d, J=15.8 Hz, 1H), 4.78 (dd, J=15.2, 6.4 Hz, 1H), 4.72 (dd, J=15.2, 6.2 Hz, 1H), 4.00 (d, J=15.0 Hz, 1H), 3.63 (ddd, J=10.4, 8.3, 5.1 Hz, 1H), 3.45 (ddd, J=10.6, 6.0, 4.7 Hz, 1H), 1.85-1.72 (m, 1H), 1.60-1.49 (m, 1H), 1.21 (s, 9H), 0.89 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.0, 161.0 (d, J=246.3 Hz), 155.1, 154.9, 151.8, 151.7, 149.1, 139.2, 138.5, 135.4, 135.4, 133.3, 133.2, 131.1, 130.0 (d, J=4.2 Hz), 129.6, 129.6, 129.3, 129.2 (d, J=8.1 Hz), 129.1, 128.0, 127.5, 127.5, 125.4, 125.2 (d, J=14.8 Hz), 124.9, 124.5, 124.3 (d, J=3.6 Hz), 123.0, 121.0, 115.7, 115.4 (d, J=21.2 Hz), 111.3, 102.1, 68.6, 59.4, 58.5, 45.9, 37.7, 37.4 (d, J=4.2 Hz), 26.7, 23.8, 18.9. HRMS m/z calcd for C.sub.51H.sub.52FN.sub.3O.sub.4SSiNa ([M+Na].sup.+) 872.3330; found 872.3337.

(R)-4-(3-(benzofuran-2-yl)phenyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-3-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (compound 220)

[0434] ##STR00280##

[0435] In a small vial, ((R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (20 mg, 0.0235 mmol, 1.0 equiv) was dissolved in 0.24 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 35 μL, 0.0353 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (80% EtOAc/hexanes) yielded compound 220 as a light yellow foam (12 mg, 85%). TLC: R.sub.f 0.08 (60% EtOAc/hexanes). [α].sub.D.sup.20: +79.5° (c 1.0, CHCl.sub.3). IR (ATR): 3393, 2959, 1671, 1574, 1526, 1491, 1454, 1258, 1230, 1176, 1047, 924, 799, 753. .sup.1H-NMR (600 MHz): δ 8.49 (t, J=6.3 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.64-7.52 (m, 3H), 7.42 (t, J=7.2 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.26-7.23 (m, 1H), 7.15-7.08 (m, 2H), 7.08-7.01 (m, 1H), 5.80-5.69 (m, 1H), 5.22 (d, J=15.6 Hz, 1H), 4.82-4.66 (m, 2H), 4.15 (d, J=15.5 Hz, 1H), 3.55 (ddd, J=10.8, 7.7, 6.0 Hz, 1H), 3.42 (ddd, J=11.2, 6.6, 5.0 Hz, 1H), 1.82-1.71 (m, 1H), 1.71-1.59 (m, 1H), 1.31 (s, 9H), 0.92 (t, J=7.3 Hz, 1H). .sup.13C-NMR (151 MHz): δ 163.9, 161.0 (d, J=246.3 Hz), 155.0, 154.9, 151.8, 151.7, 149.3, 139.0, 137.5, 131.1, 130.0 (d, J=4.2 Hz), 129.3, 129.2 (d, J=8.2 Hz), 129.0, 128.2, 127.7, 125.6, 125.2 (d, J=14.7 Hz), 124.6, 124.3 (d, J=3.6 Hz), 123.1, 121.1, 115.7, 115.4 (d, J=21.2 Hz), 111.3, 102.2, 68.7, 58.5, 58.4, 46.0, 37.5, 37.4 (d, J=4.1 Hz), 23.8. HRMS m/z calcd for C.sub.35H.sub.34FN.sub.3O.sub.4SNa ([M+Na].sup.+) 634.2152; found 634.2154.

Preparation of Compound 226

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0436] ##STR00281##

[0437] To a vial containing ethyl (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (59 mg, 0.0765 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.77 mL, 0.153 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a sticky yellow foam (35 mg, 56%). TLC: R.sub.f 0.52 (30% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +90.7° (c 1.0, CHCl.sub.3). IR (ATR): 3328, 3071, 2958, 2931, 2859, 1688, 1574, 1524, 1473, 1452, 1428, 1391, 1273, 1216, 1162, 1109, 1074, 943, 753, 702. .sup.1H-NMR (600 MHz): δ 8.43 (t, J=6.8 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.45-7.38 (m, 5H), 7.37-7.30 (m, 3H), 7.28-7.24 (m, 5H), 7.08 (s, 1H), 5.78 (d, J=6.5 Hz, 1H), 5.20 (d, J=15.8 Hz, 1H), 4.29 (ddd, J=18.1, 15.9, 8.5 Hz, 1H), 4.04-3.90 (m, 2H), 3.64 (ddd, J=10.4, 8.2, 5.0 Hz, 1H), 3.47 (dt, J=10.6, 5.4 Hz, 1H), 1.83-1.71 (m, 1H), 1.62-1.50 (m, 1H), 1.22 (s, 9H), 0.90 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.3, 155.0, 154.9, 152.0, 151.9, 148.0, 139.3, 139.0, 135.4, 135.4, 133.2, 133.1, 131.2, 129.6, 129.6, 129.3, 129.0, 128.0, 127.6, 127.5, 125.5, 124.8, 124.6, 124.1 (q, J=278.6 Hz), 123.1, 121.1, 116.0, 111.3, 102.2, 68.6, 59.3, 58.5, 45.8, 40.7 (q, J=34.9 Hz), 37.6, 26.6, 23.7, 18.9. HRMS m/z calcd for C.sub.46H.sub.49F.sub.3N.sub.3O.sub.4SSi ([M+H].sup.+) 824.3165; found 824.3143.

(R)-4-(3-(benzofuran-2-yl)phenyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (compound 226)

[0438] ##STR00282##

[0439] In a small vial, (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (18 mg, 0.0215 mmol, 1.0 equiv) was dissolved in 0.22 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 32 μL, 0.0322 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (60% EtOAc/hexanes) yielded compound 226 as a light yellow foam (12 mg, 85%).

[0440] TLC: R.sub.f 0.37 (80% EtOAc/hexanes). [α].sub.D.sup.20: +101.3° (c 1.0, CHCl.sub.3). IR (ATR): 3377, 2960, 1685, 1574, 1526, 1453, 1422, 1400, 1273, 1216, 1162, 1046, 801, 754. .sup.1H-NMR (600 MHz): δ 8.41 (t, J=6.7 Hz, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.64-7.59 (m, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.14 (s, 1H), 5.82-5.68 (m, 1H), 5.24 (d, J=15.8 Hz, 1H), 4.33-4.21 (m, 1H), 4.17 (d, J=15.5 Hz, 1H), 4.10-3.94 (m, 1H), 3.64-3.52 (m, 1H), 3.51-3.38 (m, 1H), 1.81-1.72 (m, 1H), 1.72-1.63 (m, 1H), 1.31 (s, 9H), 1.11 (s, 1H). .sup.13C-NMR (151 MHz): δ 164.2, 154.9, 154.9, 152.1, 152.0, 148.2, 138.8, 138.3, 131.2, 129.4, 129.0, 128.2, 125.8, 124.7, 124.6, 124.1 (q, J=278.6 Hz), 123.2, 121.1, 116.0, 111.3, 102.3, 68.7, 58.5, 46.0, 40.8 (q, J=35.0 Hz), 37.5, 23.8; 1 C not observed. HRMS m/z calcd for C.sub.30H.sub.30F.sub.3N.sub.3O.sub.4SNa ([M+Na].sup.+) 608.1807; found 608.1790.

Preparation of Compound 225

(R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-hydroxyethyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (compound 225)

[0441] ##STR00283##

[0442] In a small vial, (R)-4-(3-(benzofuran-2-yl)phenyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (18 mg, 0.0215 mmol, 1.0 equiv) was dissolved in 0.21 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 16 μL, 0.0644 mmol, 3 equiv) was added dropwise and the mixture was stirred at 0° C. for 5 min, then allowed to warm to room temperature and stirred for 6 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/EtOAc) yielded compound 225 as a light yellow film (5.1 mg, 51%). TLC: R.sub.f 0.06 (80% EtOAc/hexanes). [α].sub.D.sup.20: +147.6° (c 0.53, CHCl.sub.3). IR (ATR): 3332, 3011, 2929, 1684, 1569, 1526, 1452, 1420, 1307, 1272, 1161, 1062, 803, 754. .sup.1H-NMR (600 MHz): δ 8.45 (t, J=6.7 Hz, 1H), 8.21-8.13 (m, 2H), 7.96 (d, J=7.7 Hz, 1H), 7.66-7.57 (m, 3H), 7.54 (d, J=8.2 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.28-7.24 (m, 1H), 7.12 (s, 1H), 5.23 (dd, J=9.9, 3.4 Hz, 1H), 4.41 (d, J=16.3 Hz, 1H), 4.32 (d, J=16.3 Hz, 1H), 4.26-4.15 (m, 1H), 4.15-4.04 (m, 1H), 3.74 (ddd, J=11.3, 9.0, 2.5 Hz, 1H), 3.61 (ddd, J=11.0, 5.4, 3.2 Hz, 1H), 1.59-1.42 (m, 2H). .sup.13C-NMR (151 MHz): δ 164.5, 155.0, 154.9, 154.6, 152.1, 148.0, 141.8, 139.1, 131.1, 129.4, 129.0, 128.0, 125.6, 124.7, 124.5, 124.1 (q, J=278.6 Hz), 123.2, 121.1, 116.2, 111.2, 102.2, 63.9, 62.1, 50.8, 40.8 (q, J=34.9 Hz), 33.6. HRMS m/z calcd for C.sub.26H.sub.23F.sub.3N.sub.3O.sub.3([M+H].sup.+) 482.1692; found 482.1678.

Preparation of Compound 267

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0443] ##STR00284##

[0444] In a vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (64 mg, 0.0997 mmol, 1.0 equiv) was dissolved in 1.0 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 27 μL, 0.107 mmol, 1.1 equiv) was added dropwise and the mixture was stirred at 0° C. for 2.5 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×3 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/hexanes) yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (37 mg, 69%).

[0445] TLC: R.sub.f 0.58 (80% EtOAc/hexanes). [α].sub.D.sup.20: +101.1° (c 1.0, CHCl.sub.3). IR (ATR): 3337, 3071, 2958, 2932, 2857, 1738, 1716, 1571, 1472, 1428, 1392, 1334, 1226, 1110, 757, 702. .sup.1H-NMR (600 MHz): δ 7.97 (s, 1H), 7.76-7.69 (m, 2H), 7.59-7.52 (m, 4H), 7.44-7.37 (m, 5H), 7.37-7.31 (m, 4H), 5.21 (d, J=9.5 Hz, 1H), 4.52 (dq, J=10.8, 7.1 Hz, 1H), 4.44 (dq, J=10.8, 7.1 Hz, 1H), 4.34-4.11 (m, 2H), 3.71 (td, J=9.9, 3.4 Hz, 1H), 3.59 (dt, J=10.3, 4.6 Hz, 1H), 2.66 (s, 1H), 1.78-1.66 (m, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.38-1.22 (m, 1H), 1.03 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.5, 154.0, 153.8, 147.1, 142.0, 138.9, 135.4, 135.4, 133.3, 129.6, 129.6, 128.8, 128.6, 128.5, 127.6, 127.6, 118.1, 61.8, 61.3, 60.7, 51.0, 35.3, 26.8, 19.1, 14.3; 1 C not observed. HRMS m/z calcd for C.sub.34H.sub.39N.sub.2O.sub.3Si ([M+H].sup.+) 551.2730; found 551.2723.

Ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0446] ##STR00285##

[0447] In a vial, ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (96 mg, 0.174 mmol, 1.0 equiv) was dissolved in 1.7 mL of CH.sub.2Cl.sub.2 and cooled to 0° C. NEt.sub.3 (36 μL, 0.261 mmol, 1.5 equiv) was added, followed by 2-isocyanatopropane (21 μL, 0.209 mmol, 1.2 equiv), and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by addition of 2 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×3 mL). The combined organic extracts were washed with brine (1×3 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as an white solid film (48 mg, 43%). TLC: R.sub.f 0.32 (50% EtOAc/hexanes). [α].sub.D.sup.20: +81.3° (c 1.0, CHCl.sub.3). IR (ATR): 3371, 3071, 2965, 2932, 2858, 1724, 1632, 1579, 1534, 1460, 1429, 1388, 1370, 1299, 1235, 1108, 740, 703. .sup.1H-NMR (600 MHz): δ 7.95 (s, 1H), 7.77-7.67 (m, 2H), 7.42-7.35 (m, 9H), 7.33-7.27 (m, 4H), 5.82 (d, J=6.9 Hz, 1H), 5.14 (d, J=12.7 Hz, 1H), 4.95 (bs, 1H), 4.58-4.48 (m, 1H), 4.48-4.38 (m, 2H), 4.07 (dq, J=13.6, 6.8 Hz, 1H), 3.63 (t, J=8.0 Hz, 1H), 3.50 (dt, J=10.4, 4.7 Hz, 1H), 1.90-1.70 (m, 1H), 1.44 (t, J=7.1 Hz, 3H), 1.30-1.22 (m, 1H), 1.17 (dd, J=6.6, 2.5 Hz, 6H), 0.93 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.2, 156.6, 154.0, 149.1, 147.6, 138.9, 138.6, 135.4, 135.3, 135.3, 133.2, 133.0, 129.8, 129.7, 129.1, 128.9, 128.4, 127.7, 117.9, 61.9, 60.3, 50.8, 42.7, 27.1, 23.4, 23.4, 19.1, 14.3. HRMS m/z calcd for C.sub.38H.sub.45N.sub.3O.sub.4SiNa ([M+Na].sup.+) 658.3077; found 658.3049.

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.SUP.2.-isopropyl-4-phenyl-N.SUP.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide

[0448] ##STR00286##

[0449] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-(isopropylcarbamoyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (48 mg, 0.0755 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.75 mL, 0.151 mmol, 2.0 equiv). The mixture was stirred at room temperature for 17 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-phenyl-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide as a sticky yellow foam (34 mg, 66%). TLC: R.sub.f 0.41 (30% EtOAc/CH.sub.2Cl.sub.2). [α].sub.D.sup.20: +64.5° (c 1.0, CHCl.sub.3). IR (ATR): 3376, 3071, 3051, 2963, 2932, 2859, 1686, 1639, 1578, 1521, 1459, 1428, 1383, 1274, 1162, 1111, 987, 758, 742, 702. .sup.1H-NMR (600 MHz): δ 8.40 (t, J=6.8 Hz, 1H), 8.06 (s, 1H), 7.74-7.60 (m, 2H), 7.49-7.33 (m, 9H), 7.33-7.24 (m, 4H), 5.85 (s, 1H), 5.07 (d, J=15.5 Hz, 1H), 4.80 (bs, 1H), 4.45 (d, J=15.4 Hz, 1H), 4.35-4.15 (m, 1H), 4.13-3.94 (m, 2H), 3.69-3.54 (m, 1H), 3.54-3.44 (m, 1H), 1.98-1.80 (m, 1H), 1.40-1.26 (m, 1H), 1.18 (dd, J=6.6, 2.1 Hz, 6H), 0.90 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.3, 156.3, 152.6, 149.8, 147.8, 139.0, 138.3, 135.3, 133.1, 133.0, 129.7, 129.7, 129.3, 128.9, 128.2, 127.7, 127.6, 127.6, 124.1 (q, J=278.6 Hz), 115.6, 60.2, 59.5, 51.0, 42.6, 40.7 (q, J=34.9 Hz), 27.0, 23.4, 23.4, 19.0. HRMS m/z calcd for C.sub.38H.sub.43F.sub.3N.sub.4O.sub.3SiNa ([M+Na].sup.+) 711.2954; found 711.2957.

(R)-3-(2-hydroxyethyl)-N.SUP.2.-isopropyl-4-phenyl-N.SUP.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (Compound 267)

[0450] ##STR00287##

[0451] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N.sup.2-isopropyl-4-phenyl-N.sup.6-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (34 mg, 0.0494 mmol, 1.0 equiv) was dissolved in 0.49 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 74 μL, 0.0740 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (70% EtOAc/hexanes) yielded compound 267 as a light yellow film (10 mg, 47%). TLC: R.sub.f 0.08 (50% EtOAc/hexanes). [α].sub.D.sup.20: +17.1° (c 0.56, CHCl.sub.3). IR (ATR): 3313, 3061, 2971, 2877, 1682, 1627, 1578, 1523, 1458, 1384, 1273, 1158, 1057, 987, 738, 699. .sup.1H-NMR (600 MHz): δ 8.42 (t, J=6.8 Hz, 1H), 8.10 (s, 1H), 7.82-7.70 (m, 2H), 7.57-7.52 (m, 2H), 7.52-7.46 (m, 1H), 5.99 (d, J=10.1 Hz, 1H), 4.88 (d, J=14.7 Hz, 1H), 4.72-4.39 (m, 2H), 4.31-4.16 (m, 1H), 4.14-3.89 (m, 3H), 3.57-3.45 (m, 1H), 3.45-3.33 (m, 1H), 1.79-1.69 (m, 1H), 1.23 (t, J=7.0 Hz, 6H), 1.19-1.10 (m, 1H). .sup.13C-NMR (151 MHz): δ 164.3, 157.3, 152.8, 148.6, 148.0, 139.3, 137.9, 129.6, 129.0, 128.1, 124.1 (q, J=278.6 Hz), 115.5, 59.2, 58.5, 50.9, 43.0, 40.8 (q, J=35.0 Hz), 37.8, 23.4, 23.3. HRMS m/z calcd for C.sub.22H.sub.25F.sub.3N.sub.4O.sub.3Na ([M+Na].sup.+) 473.1776; found 473.1797.

Preparation of Compound 217

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0452] ##STR00288##

[0453] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (31 mg, 0.0473 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.47 mL, 0.0947 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a white foam (35 mg, 97%). TLC: R.sub.f 0.27 (50% EtOAc/hexanes). [α].sub.D.sup.20: +42.5° (c 1.0, CHCl.sub.3). IR (ATR): 3387, 3071, 2958, 2931, 2859, 1673, 1576, 1523, 1503, 1490, 1253, 1239, 1075, 1042, 930, 757, 702. .sup.1H-NMR (600 MHz): δ 8.36 (t, J=6.3 Hz, 1H), 8.06 (s, 1H), 7.72-7.61 (m, 2H), 7.49-7.45 (m, 2H), 7.45-7.36 (m, 7H), 7.33-7.28 (m, 4H), 6.85 (d, J=1.7 Hz, 1H), 6.81 (dd, J=7.9, 1.6 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.94 (d, J=1.6 Hz, 2H), 5.78 (d, J=8.1 Hz, 1H), 5.17 (d, J=15.7 Hz, 1H), 4.62 (dd, J=14.9, 6.4 Hz, 1H), 4.52 (dd, J=14.8, 6.1 Hz, 1H), 4.00 (d, J=15.5 Hz, 1H), 3.75-3.58 (m, 1H), 3.43 (ddd, J=10.4, 6.0, 4.2 Hz, 1H), 1.78-1.66 (m, 1H), 1.51-1.38 (m, 1H), 1.22 (s, 9H), 0.97 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.0, 152.1, 151.7, 149.1, 147.9, 146.9, 138.5, 138.5, 135.5, 135.4, 133.4, 133.3, 132.2, 129.7, 129.6, 129.1, 128.8, 128.3, 127.6, 127.6, 121.0, 115.4, 108.4, 108.3, 101.0, 68.5, 59.4, 58.6, 45.8, 43.2, 37.6, 26.8, 23.8, 19.1. HRMS m/z calcd for C.sub.44H.sub.49N.sub.3O.sub.6SSiNa ([M+Na].sup.+) 782.3060; found 782.3507.

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((R)-tert-butylsulfinyl)-3-(2-hydroxyethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 217)

[0454] ##STR00289##

[0455] In a small vial, (R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (33 mg, 0.0434 mmol, 1.0 equiv) was dissolved in 0.43 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 65 μL, 0.0651 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (75% EtOAc/hexanes) yielded compound 217 as a white solid foam (13 mg, 57%). TLC: R.sub.f 0.24 (80% EtOAc/hexanes). [α].sub.D.sup.20: +23.9° (c 1.0, CHCl.sub.3). IR (ATR): 3389, 2949, 1666, 1576, 1527, 1503, 1491, 1445, 1254, 1239, 1041, 930, 758. .sup.1H-NMR (600 MHz): δ 8.36 (t, J=6.2 Hz, 1H), 8.08 (s, 1H), 7.69-7.60 (m, 2H), 7.55-7.39 (m, 3H), 6.85 (d, J=1.6 Hz, 1H), 6.81 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.93 (d, J=2.0 Hz, 2H), 5.71-5.62 (m, 1H), 5.20 (d, J=15.6 Hz, 1H), 4.60 (dd, J=14.9, 6.3 Hz, 1H), 4.53 (dd, J=14.8, 6.1 Hz, 1H), 4.13 (d, J=15.6 Hz, 1H), 3.59-3.44 (m, 1H), 3.38 (dt, J=11.3, 5.9 Hz, 1H), 1.76-1.63 (m, 1H), 1.63-1.54 (m, 1H), 1.30 (s, 9H), 1.16 (s, 1H). .sup.13C-NMR (151 MHz): δ 163.9, 152.2, 151.6, 149.3, 147.8, 146.9, 138.4, 137.3, 132.1, 129.3, 128.8, 128.2, 121.0, 115.5, 108.4, 108.3, 101.0, 68.7, 58.5, 58.3, 46.0, 43.2, 37.4, 23.8. HRMS m/z calcd for C.sub.28H.sub.31N.sub.305SNa ([M+Na].sup.+) 544.1882; found 544.1864.

Preparation of Compound 218

(R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

[0456] ##STR00290##

[0457] To a vial containing ethyl (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (31 mg, 0.0473 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.47 mL, 0.0947 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (40% EtOAc/hexanes) yielded (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide as a light yellow foam (34 mg, 99%). TLC: R.sub.f 0.38 (50% EtOAc/hexanes). [α].sub.D.sup.21: +80.9° (c 1.0, CHCl.sub.3). IR (ATR): 3394, 3071, 2958, 2931, 2858, 1676, 1577, 1523, 1491, 1473, 1427, 1391, 1230, 1110, 1075, 943, 758, 702. .sup.1H-NMR (600 MHz): δ 8.44 (t, J=6.4 Hz, 1H), 8.05 (s, 1H), 7.73-7.65 (m, 2H), 7.49-7.45 (m, 2H), 7.45-7.35 (m, 8H), 7.32-7.28 (m, 4H), 7.25-7.22 (m, 1H), 7.14-7.03 (m, 2H), 5.79 (d, J=7.6 Hz, 1H), 5.17 (d, J=15.8 Hz, 1H), 4.76 (dd, J=15.2, 6.4 Hz, 1H), 4.70 (dd, J=15.3, 6.3 Hz, 1H), 3.99 (d, J=15.1 Hz, 1H), 3.65 (td, J=9.9, 9.5, 4.8 Hz, 1H), 3.43 (ddd, J=10.4, 6.1, 4.2 Hz, 1H), 1.78-1.69 (m, 1H), 1.50-1.41 (m, 1H), 1.21 (s, 10H), 0.97 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.1, 161.0 (d, J=246.4 Hz), 152.0, 151.7, 149.0, 138.5, 138.5, 135.5, 135.4, 133.4, 133.2, 130.0 (d, J=4.2 Hz), 129.7, 129.6, 129.1 (d, J=7.9 Hz), 129.1, 128.8, 128.3, 127.6, 127.6, 125.3 (d, J=14.7 Hz), 124.3 (d, J=3.6 Hz), 115.4, 115.3 (d, J=21.2 Hz), 68.5, 59.4, 58.6, 45.8, 37.6, 37.3 (d, J=4.2 Hz), 26.8, 23.8, 19.1. HRMS m/z calcd for C.sub.43H.sub.49FN.sub.3O.sub.3SSi ([M+H].sup.+) 734.3248; found 734.3220.

(R)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-3-(2-hydroxyethyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 218)

[0458] ##STR00291##

[0459] In a small vial, (R)-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-((R)-tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (28 mg, 0.0381 mmol, 1.0 equiv) was dissolved in 0.38 mL of THF and cooled to 0° C. n-Bu.sub.4NF solution (1.0 M in THF, 57 μL, 0.0572 mmol, 1.5 equiv) was added dropwise and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature over 4 h. The reaction mixture was diluted with 1 mL EtOAc and 1 mL sat aq NaHCO.sub.3, then the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (75% EtOAc/hexanes) yielded compound 218 as a white solid foam (14 mg, 76%). TLC: R.sub.f 0.32 (80% EtOAc/hexanes). [α].sub.D.sup.21: +28.4° (c 1.0, CHCl.sub.3). IR (ATR): 3393, 2955, 1669, 1577, 1527, 1491, 1457, 1423, 1364, 1230, 1049, 931, 758. .sup.1H-NMR (600 MHz): δ 8.44 (t, J=6.4 Hz, 1H), 8.07 (s, 1H), 7.68 (d, J=6.9 Hz, 2H), 7.53-7.45 (m, 3H), 7.40 (td, J=7.6, 1.7 Hz, 1H), 7.25-7.22 (m, 1H), 7.10 (t, J=7.4 Hz, 1H), 7.08-7.02 (m, 1H), 5.74-5.62 (m, 1H), 5.19 (d, J=15.7 Hz, 1H), 4.79-4.61 (m, 2H), 4.13 (dd, J=15.7, 2.0 Hz, 1H), 3.52 (ddd, J=10.8, 7.6, 6.2 Hz, 1H), 3.38 (ddd, J=11.2, 6.7, 5.2 Hz, 1H), 1.76-1.64 (m, 1H), 1.64-1.53 (m, 1H), 1.30 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.0, 160.9 (d, J=246.3 Hz), 152.2, 151.6, 149.2, 138.4, 137.4, 130.0 (d, J=4.2 Hz), 129.3, 129.2 (d, J=8.1 Hz), 128.8, 128.2, 125.2 (d, J=14.7 Hz), 124.3 (d, J=3.6 Hz), 115.4, 115.3 (d, J=21.2 Hz), 68.7, 58.6, 58.4, 46.0, 37.4, 37.3 (d, J=4.3 Hz), 23.8. HRMS m/z calcd for C.sub.27H.sub.30FN.sub.3O.sub.3SNa ([M+Na].sup.+) 518.1890; found 518.1907.

Preparation of Compound 223

Ethyl (S)-4-(3-(benzofuran-2-yl)phenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0460] ##STR00292##

[0461] To a vial was added ethyl (S)-4-(3-bromophenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (57 mg, 0.126 mmol, 1.0 equiv), benzofuran-2-ylboronic acid (51 mg, 0.316 mmol, 2.0 equiv), and Na.sub.2CO.sub.3 (47 mg, 0.442 mmol, 3.0 equiv). Degassed ethanol (1.3 mL) was added, and the whole solution purged with argon for ˜10 minutes. Bis(triphenylphosphine)palladium dichloride (4.4 mg, 0.00631 mmol, 0.05 equiv) was quickly added to the reaction, then it was capped with a teflon-lined cap and stirred at 60° C. After 16 h, the reaction was cooled to room temperature, then diluted with EtOAc, filtered through Celite, and concentrated by rotary evaporation. Purification by silica flash chromatography (30% EtOAc/hexanes) yielded ethyl (S)-4-(3-(benzofuran-2-yl)phenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (49 mg, 80%). TLC: R.sub.f 0.31 (40% EtOAc/hexanes). [α].sub.D.sup.20: +71.0° (c 1.0, CHCl.sub.3). IR (ATR): 2981, 2860, 1740, 1716, 1575, 1452, 1419, 1391, 1369, 1335, 1302, 1258, 1224, 1068, 1021, 937, 796, 750. .sup.1H-NMR (600 MHz): δ 8.26 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.26-7.23 (m, 1H), 7.11 (s, 1H), 5.14 (d, J=15.0 Hz, 1H), 5.02 (d, J=15.2 Hz, 1H), 4.77 (d, J=14.9 Hz, 1H), 4.58-4.41 (m, 3H), 1.47 (t, J=7.1 Hz, 3H), 1.28 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 155.3, 154.9, 152.9, 150.5, 147.7, 139.0, 135.6, 131.0, 129.2, 129.1, 128.2, 125.7, 124.7, 124.5, 123.0, 121.0, 118.0, 111.2, 101.9, 62.0, 58.2, 23.3, 14.3. HRMS m/z calcd for C.sub.28H.sub.28N.sub.2O.sub.4SNa ([M+Na].sup.+) 511.1667; found 511.1686.

Ethyl 4-(3-(benzofuran-2-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0462] ##STR00293##

[0463] In a vial, ethyl (S)-4-(3-(benzofuran-2-yl)phenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (46 mg, 0.0941 mmol, 1.0 equiv) was dissolved in 0.94 mL of anhyd MeOH and cooled to 0° C. HCl solution (4.0 M in dioxane, 47 μL, 0.188 mmol, 2 equiv) was added dropwise and the mixture was stirred at 0° C. for 3 h. The reaction was quenched by addition of sat. aq. NaHCO.sub.3 and then diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×3 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (10% MeOH/EtOAc) yielded ethyl 4-(3-(benzofuran-2-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (26 mg, 73%). TLC: R.sub.f0.22 (5% MeOH/CH.sub.2Cl.sub.2). IR (ATR): 3327, 2983, 2850, 1733, 1571, 1451, 1391, 1371, 1335, 1309, 1287, 1258, 1223, 1169, 1023, 798, 750. .sup.1H-NMR (600 MHz): δ 8.27 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.57-7.50 (m, 2H), 7.30 (t, J=8.1 Hz, 1H), 7.24 (t, J=7.4 Hz, 1H), 7.09 (s, 1H), 4.54 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 4.37 (s, 2H), 2.79 (bs, 1H), 1.47 (t, J=7.1 Hz, 3H). .sup.13C-NMR (151 MHz): δ 165.4, 155.4, 154.9, 154.1, 152.5, 147.2, 139.3, 139.1, 130.8, 129.1, 129.1, 128.3, 125.4, 124.7, 124.4, 123.0, 121.0, 118.1, 111.2, 101.8, 61.9, 52.7, 14.3; 1 C not observed. HRMS m/z calcd for C.sub.24H.sub.21N.sub.2O.sub.3 ([M+H].sup.+) 385.1552; found 385.1552.

Ethyl 4-(3-(benzofuran-2-yl)phenyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0464] ##STR00294##

[0465] In a vial, ethyl 4-(3-(benzofuran-2-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (25 mg, 0.0650 mmol, 1.0 equiv) was dissolved in 0.65 mL of CH.sub.2Cl.sub.2 and cooled to 0° C. NEt.sub.3 (23 μL, 0.163 mmol, 1.5 equiv) was added, followed by 2-isocyanatopropane (7 μL, 0.0715 mmol, 1.1 equiv), and the mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched by addition of 1 mL saturated aqueous NaHCO.sub.3, then the aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×3 mL). The combined organic extracts were washed with brine (1×1 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (100% CH.sub.2Cl.sub.2.fwdarw.50% EtOAc/CH.sub.2Cl.sub.2) and filtration of insoluble byproducts with Et.sub.2O yielded ethyl 4-(3-(benzofuran-2-yl)phenyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as an white solid film (15 mg, 51%). TLC: R.sub.f 0.81 (10% MeOH/EtOAc). IR (ATR): 3386, 3093, 2964, 2950, 2908, 2860, 1722, 1650, 1580, 1522, 1463, 1382, 1296, 1236, 1108, 789, 751. .sup.1H-NMR (600 MHz): δ 8.26 (s, 1H), 8.03 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.30 (t, J=7.2 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.11 (s, 1H), 4.94 (s, 1H), 4.82 (d, J=2.5 Hz, 2H), 4.50 (q, J=7.1 Hz, 2H), 4.22 (d, J=7.6 Hz, 1H), 4.06 (dq, J=13.4, 6.7 Hz, 1H), 1.47 (t, J=7.1 Hz, 3H), 1.21 (d, J=6.5 Hz, 6H). .sup.13C-NMR (151 MHz): δ 165.0, 155.6, 155.2, 154.9, 153.3, 149.0, 147.9, 138.8, 134.4, 131.0, 129.2, 129.0, 128.1, 125.7, 124.7, 124.5, 123.0, 121.0, 118.3, 111.2, 102.0, 62.1, 51.7, 51.3, 42.7, 23.6, 14.3. HRMS m/z calcd for C.sub.28H.sub.27N.sub.3O.sub.4Na ([M+Na].sup.+) 492.1899; found 492.1889.

4-(3-(benzofuran-2-yl)phenyl)-N.SUB.2.-isopropyl-N.SUB.6.-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,6-dicarboxamide (Compound 223)

[0466] ##STR00295##

[0467] To a vial containing ethyl 4-(3-(benzofuran-2-yl)phenyl)-2-(isopropylcarbamoyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (14 mg, 0.0300 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum 2,2,2-trifluoroethylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.30 mL, 0.0601 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (60% EtOAc/hexanes) yielded compound 223 as a sticky yellow foam (13 mg, 81%).

[0468] TLC: R.sub.f 0.26 (30% EtOAc/CH.sub.2Cl.sub.2). IR (ATR): 3320, 2966, 2924, 2854, 1678, 1639, 1578, 1528, 1456, 1385, 1274, 1260, 1164, 749. .sup.1H-NMR (600 MHz): δ 8.47 (t, J=6.7 Hz, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.64-7.59 (m, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.32 (t, J=7.2 Hz, 1H), 7.29-7.21 (m, 4H), 7.12 (s, 1H), 4.97 (s, 2H), 4.81 (s, 2H), 4.24-4.11 (m, 3H), 4.06 (h, J=6.7 Hz, 1H), 1.21 (d, J=6.5 Hz, 6H). .sup.13C-NMR (151 MHz): δ 164.3, 155.6, 154.9, 154.9, 152.0, 149.7, 148.2, 138.4, 134.5, 131.2, 129.4, 129.0, 127.8, 125.9, 124.7, 124.5, 124.1 (q, J=278.7 Hz), 123.2, 121.1, 116.0, 111.2, 102.2, 51.6, 51.4, 42.7, 40.8 (q, J=34.9 Hz), 23.6. HRMS m/z calcd for C.sub.28H.sub.25F.sub.3N.sub.4O.sub.3Na ([M+Na].sup.+) 545.1776; found 545.1763.

Preparation of Compound 212

Ethyl (R)-2-(tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

[0469] ##STR00296##

[0470] To a vial was added ethyl (R)-4-(3-bromophenyl)-2-(tert-butylsulfinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (53 mg, 0.117 mmol, 1.0 equiv), pyridin-3-ylboronic acid (29 mg, 0.235 mmol, 2.0 equiv), and Na.sub.2CO.sub.3 (37 mg, 0.352 mmol, 3.0 equiv). Degassed ethanol (1.2 mL) was added, and the whole solution purged with argon for −10 minutes. Bis(triphenylphosphine)palladium dichloride (4.1 mg, 0.00587 mmol, 0.05 equiv) was quickly added to the reaction, then it was capped with a teflon-lined cap and stirred at 60° C. After 21 h, the reaction was cooled to room temperature, then diluted with EtOAc, filtered through Celite, and concentrated by rotary evaporation. Purification by silica flash chromatography (2.5% MeOH/CH.sub.2Cl.sub.2) yielded ethyl (R)-2-(tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate as a light yellow foam (43 mg, 82%). TLC: R.sub.f 0.19 (2.5% MeOH/CH.sub.2Cl.sub.2). [α].sub.D.sup.19: −67.1° (c 1.0, CHCl.sub.3). IR (ATR): 3404, 2982, 2866, 1738, 1718, 1576, 1473, 1392, 1369, 1333, 1301, 1271, 1067, 1022, 752. .sup.1H-NMR (600 MHz): δ 8.90 (d, J=1.5 Hz, 19H), 8.63 (d, J=4.1 Hz, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.93 (dt, J=7.9, 1.8 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.40 (dd, J=7.8, 4.8 Hz, 1H), 5.12 (d, J=15.3 Hz, 1H), 5.01 (d, J=15.4 Hz, 1H), 4.74 (d, J=14.9 Hz, 1H), 4.53 (d, J=15.2 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.27 (s, 9H). .sup.13C-NMR (151 MHz): δ 165.1, 152.9, 150.6, 148.8, 148.4, 147.8, 139.3, 138.5, 136.3, 135.6, 134.6, 129.4, 128.1, 127.7, 127.3, 123.6, 118.0, 62.0, 58.2, 23.2, 14.3; 2 C not observed. HRMS m/z calcd for C.sub.25H.sub.28N.sub.3O.sub.3S ([M+H].sup.+) 450.1851; found 450.1834.

(R)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 212)

[0471] ##STR00297##

[0472] To a vial containing ethyl (R)-2-(tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (20 mg, 0.0445 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum piperonylamide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.44 mL, 0.0890 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/CH.sub.2Cl.sub.2) yielded compound 212 as a white foam (18 mg, 74%). TLC: R.sub.f 0.33 (3% MeOH/EtOAc). [α].sub.D.sup.20: −49.1° (c 1.0, CHCl.sub.3). IR (ATR): 3387, 2979, 1669, 1575, 1524, 1504, 1490, 1445, 1362, 1335, 1253, 1189, 1040, 935, 757. .sup.1H-NMR (600 MHz): δ 8.88 (s, 1H), 8.65 (s, 1H), 8.36 (t, J=6.1 Hz, 1H), 8.14 (s, 1H), 7.95-7.83 (m, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 6.82 (dd, J=7.9, 1.7 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.93 (s, 2H), 5.10 (d, J=14.9 Hz, 1H), 5.00 (d, J=15.4 Hz, 1H), 4.70 (d, J=14.8 Hz, 1H), 4.60 (d, J=6.2 Hz, 2H), 4.55 (d, J=15.3 Hz, 1H), 1.26 (s, 9H). .sup.13C-NMR (151 MHz): δ 163.9, 151.3, 151.2, 149.3, 148.9, 148.3, 147.9, 146.9, 139.2, 138.5, 136.1, 135.0, 134.5, 132.1, 129.5, 128.1, 127.6, 126.9, 123.7, 121.0, 115.5, 108.4, 108.3, 101.0, 58.2, 43.3, 23.2; 2 C not observed. HRMS m/z calcd for C.sub.31H.sub.31N.sub.4O.sub.4S ([M+H].sup.+) 555.2066; found 555.2043.

Preparation of Compound 213

(R)-2-(tert-butylsulfinyl)-N-(2-fluorobenzyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (Compound 213)

[0473] ##STR00298##

[0474] To a vial containing ethyl (R)-2-(tert-butylsulfinyl)-4-(3-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (20 mg, 0.0445 mmol, 1.0 equiv, azeotroped 3× with toluene) at room temperature was slowly added a pre-stirred (>2 h) stock solution of dimethylaluminum (2-fluorobenzyl)amide (0.2 M solution in CH.sub.2Cl.sub.2/toluene, 0.44 mL, 0.0890 mmol, 2.0 equiv). The mixture was stirred at room temperature for 15 h, then carefully quenched by addition of a few drops of MeOH followed by dilution with 1 mL of CH.sub.2Cl.sub.2 and careful addition of 1 mL saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc (3×1 mL), then the combined organic layers were dried (Na.sub.2SO.sub.4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50% EtOAc/CH.sub.2Cl.sub.2) yielded compound 213 as a light yellow foam (18 mg, 76%). TLC: R.sub.f 0.39 (3% MeOH/EtOAc). [α].sub.D.sup.20: −57.6° (c 1.0, CHCl.sub.3). IR (ATR): 3388, 2960, 1672, 1575, 1524, 1491, 1456, 1422, 1363, 1335, 1230, 1178, 1064, 1022, 937, 758. .sup.1H-NMR (600 MHz): δ 8.92 (s, 1H), 8.67 (s, 1H), 8.50 (t, J=6.2 Hz, 1H), 8.12 (s, 1H), 7.95-7.89 (m, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.45-7.39 (m, 2H), 7.26-7.24 (m, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.08-7.04 (m, 1H), 5.12 (d, J=14.8 Hz, 1H), 5.00 (d, J=15.4 Hz, 1H), 4.75 (d, J=6.3 Hz, 2H), 4.71 (d, J=14.9 Hz, 1H), 4.55 (d, J=15.3 Hz, 1H), 1.26 (s, 9H). .sup.13C-NMR (151 MHz): δ 164.0, 161.0 (d, J=246.1 Hz), 151.2, 151.2, 149.2, 148.7, 148.2, 139.1, 138.5, 136.2, 135.0, 134.6, 130.0 (d, J=4.2 Hz), 129.5, 129.2 (d, J=8.1 Hz), 128.1, 127.5, 126.9, 125.1 (d, J=14.7 Hz), 124.3 (d, J=3.6 Hz), 123.7, 115.4 (d, J=21.3 Hz), 115.33, 58.2, 37.5 (d, J=4.0 Hz), 23.2; 2 C not observed. HRMS m/z calcd for C.sub.30H.sub.30FN.sub.4O.sub.2S ([M+H].sup.+) 529.2074; found 529.2090.

[0475] Select compounds described herein were evaluated for structure-activity analyses in vitro. The IC.sub.50 value was measured after infection with Trypanosoma cruzi parasites for 72 hours and treatment with the compound for 72 hours.

TABLE-US-00001 TABLE 1 IC.sub.50 values and cytotoxicity data of exemplary compounds described herein. Compound # IC.sub.50 (μM) Cytotoxicity (μM) 21 0.054 >10 37 0.048 >10 49 0.862 >10 50 0.230 >10 51 >10 >10 57 0.495 >10 58 0.301 >10 77 >10 >10 78 >10 >10 79 1.40 >10 84 1.51 >10 85 0.0437 >10 86 2.85 >10 87 7.18 >10 88 1.51 >10 89 0.028 >10 90 8.50 >10 91 >10 >10

Example 1. In Vivo Efficacy Assay of Exemplary Compounds Described Herein

[0476] The efficacy of compounds on T. cruzi infection in a mouse model (T. cruzi strain CA-I/72 grown in mouse C2C12 myoblast cells) was determined. Exemplary results for compounds 21 (2015-FoleyC-021) and 37 (2015-FoleyC-037) are shown in FIG. 1, and exemplary results for compounds 50, 57, 58, and 89 are shown in FIG. 2.

[0477] 6-week old female BALB/c mice were infected with 2×10.sup.6 Trypanosoma cruzi (T. cruzi) Brazil strain parasites expressing luciferase. Each tested group had five individual mice. Three days post-infection with T. cruzi parasites, the mice were treated with the compounds for four consecutive days, with two doses per day (bid) with approximately a 12 hour difference between the doses. Compounds were administered intraperitoneally at 50 mg/kg diluted in 10% DMSO in water. On the seventh day after infection (12 hours after the last dose), 2.5 mg of luciferin (intraperitoneal) was administered, followed by a reading of the luminescence using an In Vivo Imaging System (IVIS, Perkin Elmer). The average luminescence signal per group was compared and normalized to the control groups: treated with reference drug (50 mg/kg Benznidazole (Bz), 100% efficacy) and compared with the vehicle alone (10% DMSO in water or 20% Solutol, 0% efficacy).

Example 2. In Vitro Assay

[0478] Select compounds described herein were evaluated for structure-activity analyses for anti-trypanosomal activity, plasma stability, microsomal stability, Parallel artificial membrane permeability assay (PAMPA) Permeability, Caco-2 Bi-directional Permeability, plasma protein binding, cytotoxicity, pharmacokinetics assays, and relative bioavailability, in vitro and in vivo. Exemplary results for compounds 21 (2015-FoleyC-021) and 37 (2015-FoleyC-037) are shown in Table 2.

TABLE-US-00002 TABLE 2 IC.sub.50 and EC.sub.50, values, logS data, permeability data, plasma stability, protein binding, toxicity, and microsomal stability data of exemplary compounds described herein. Compound # [00299] embedded image [00300] In Vitro Assays plasma stability (t.sub.1/2, mouse) >4 h >4 h microsomal stability (t.sub.1/2, mouse): 1 mg/mL hepatic microsomes 3.9 min 1.3 min 0.25 mg/mL hepatic microsomes 46 min 13 min Parallel artificial membrane −7.26 −5.24 permeability assay (PAMPA) Permeability (log Pe [cm/s]) Caco-2 Bi-directional Permeability 24.9 13.2 (Efflux ratio) plasma protein binding (mouse) 95.5 % 91.9 % Cytotoxicity Screening HepG2 IC.sub.50 (μM) Cellular ATP 52.5 54.2 Membrane Integrity 62.1 90.6 Cell Count 51.3 56.2 MRC5 IC.sub.50 (μM) Cellular ATP 44.7 54.1 Membrane Integrity 24.4 13.4 Cell Count 63.7 64.2 In Vivo Pharmacokinetic (PK) Studies PK (ip, 50 mg/kg) t.sub.l/2 2.8 h 6.3 h C.sub.max 19.8 μM 6.8 μM Area under the curve (AUC) 50.1 μM.Math.h 11.1 μM.Math.h PK (po, 50 mg/kg) t.sub.l/2 3.5 h 4.3 h C.sub.max 11.8 uM 1.7 uM AUC 24.3 μM.Math.h 5.2 μM.Math.h Relative Bioavailability, F.sub.rel (po/ip) 48 % 47 %

[0479] To evaluate the hepatic microsomal stability of selected compounds, 1 μM of each selected compound was incubated with 1 mg/mL hepatic microsomes in 100 mM KPi, pH 7.4. The microsomes were obtained from C57BL/6 mice. The reaction was initiated by adding NADPH (1 mM final concentration). Aliquots were removed at 0, 5, 10, 20, 40, and 60 minutes and added to acetonitrile (5× v:v) to stop the reaction and precipitate the protein. NADPH dependence of the reaction is evaluated with -NADPH samples. At the end of the assay, the samples were centrifuged through a Millipore Multiscreen Solvinter 0.45 micron low binding PTFE hydrophilic filter plate and analyzed by LC-MS/MS. Data was log transformed and represented as half-life.

[0480] To evaluate the plasma stability of selected compounds, 10 μM of each selected compound was incubated with undiluted plasma. Plasma was freshly obtained from C57BB1\6 mice drawn in the vivarium and used immediately. Plasma was brought to 37° C. within a 96-well plate and then the compound is introduced via a DMSO stock solution. The sample was continually shaken at 37° C. and aliquots are removed at multiple time points out to four hours. Aliquots were added to acetonitrile (5× v:v) to stop any enzymatic activity and held on ice. At the end of the assay, the samples were centrifuged through a Millipore Multiscreen Solvinter 0.45 micron low binding PTFE hydrophilic filter plate and analyzed by LC-MS/MS. Data was log transformed and represented as half-life.

[0481] To evaluate the plasma protein binding of selected compounds, equilibrium dialysis was used. All samples of the selected compounds were tested in triplicate using the RED Rapid Equilibrium Dialysis Device (Thermo Scientific). The initial drug concentration in the plasma chamber was 5 μM and phosphate buffered saline was added to the receiver chamber. The plate was covered and allowed to shake in a 37° C. incubator for 6 hours. 25 μl was sampled from the plasma and PBS chambers which were then diluted with either blank PBS or plasma to achieve a 1:1 ratio or plasma:PBS for all samples. The concentration of drug in the plasma and PBS chambers were determined by LC-MS/MS. The fraction bound was calculated as ([plasma]−[PBS])/[plasma].

[0482] To evaluate the Parallel Artificial Membrane Permeability Assay (PAMPA) of selected compounds, an assessment of permeability was done using a commercial PAMPA kit. Selected compounds were evaluated over a range of concentrations by 300 μl of PBS containing the compound to the bottom donor plate. Selected compounds were from DMSO stocks and the final DMSO concentration in the donor wells was one percent. 200 μl of blank PBS was added to the top receiver plate. The plates were allowed to incubate at room temperature. After 5 hours, aliquots were taken from the donor and receiver plates and the concentration of drug was determined. Compound permeability was calculated using the equation

[00001] $P_{e} = - \frac{\ln [1 - \frac{C_{A} (t)}{C_{e q}}]}{(A * (\frac{1}{V_{D}} + \frac{1}{V_{A}}) * t)}$

where P.sub.e is expressed in units of cm/s, C.sub.A(t) is drug concentration in the acceptor at time t, V.sub.D is donor well volume, V.sub.A is acceptor well volume, A is the area of the filter (0.3 cm.sup.2), t is time in seconds, and C.sub.eq=[C.sub.D(t)*V.sub.D+C.sub.A(t)*V.sub.A]/(V.sub.D+V.sub.A).

[0483] To evaluate the plasma pharmacokinetics of selected compounds, a group of eighteen female mice were administered divided into two groups; Group 1 (intraperitoneal (i.p.)) and Group 2 (oral administration (p.o.)) with compound 21 or compound 37 solution formulation at a dose of 50 mg/kg by both the routes in 5% NMP, 5% Solutol and 90% Normal saline. Blood samples (approximately 60 mL) were collected from retro orbital plexus of each mouse under light isoflurane anesthesia such that the samples were obtained at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours (i.p.); and pre-dose, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hour (p.o.). The blood samples were collected from a set of three mice at each time point in labeled micro centrifuge tube containing K2EDTA as anticoagulant. Plasma samples were separated by centrifugation at 4000 rpm for 10 min and stored below −70° C. until bioanalysis. After collection of blood sample, animals were humanely euthanized by carbon dioxide asphyxiation to collect liver and heart from Group 1 and Group 2 at 1, 8 and 24 hours. The collected tissues were rinsed in PBS and were homogenized with cold phosphate buffer saline (pH 7.4) of nine times the weight of liver and two times the weight of heart tissue and stored below −70° C. until bio-analysis. Total volume was ten and three times the tissue weights of liver and heart, respectively. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed with fit-for-purpose LC-MS/MS method (LLOQ: 1.01 ng/mL for plasma; 20.20 ng/g for liver and 6.06 ng/g for heart tissue). Following a single intraperitoneal dose administration to female BALB/c mice, plasma concentrations of compound 21 or compound 37 were quantifiable till 24 hours with T.sub.max at 0.25 hour. Following a single oral dose administration to female BALB/c mice, plasma concentrations of compound 21 or compound 37 were quantifiable till 24 hours with T.sub.max at 1.00 hour. Exemplary results for compounds 21 (2015-FoleyC-021) and 37 (2015-FoleyC-037) are shown above in Table 2.

[0484] To evaluate the metabolic stability of compounds 21 and 37 in mice liver microsomes (MLM), a 1120 μL aliquot of potassium phosphate buffer (50 mM, pH 7.4) containing mice liver microsomes (0.357 mg/mL) was added to individual 2 mL tubes (final concentration 0.25 mg/mL). Imipramine in MLM was run as positive controls. Test compounds (compound 21 or compound 37) and positive control compounds (1 mM DMSO stocks) were directly spiked into respective tubes to prepare a concentration of 1.428 μM (final concentration 1 μM). From the above mix, 70 μL was added to individual wells of 96 well reaction plates and pre-incubated in a 37° C. water bath for 5 min. All the reactions were initiated by adding 30 μL of 3.33 mM NADPH (final concentration 1 mM). Reactions without NADPH and heat inactivated microsomes minus NADPH (0 min and 60 min) were also incubated to rule out non-NADPH metabolism or chemical instability in the incubation buffer. All reactions were terminated using 100 μL of ice-cold acetonitrile containing internal standard (glipizide—2 μM) at 0, 5, 15 and 60 min. The plates were centrifuged at 4000 RPM for 15 min and 100 μL aliquots were submitted for analysis by LC-M/MS. Samples were monitored for parent compound disappearance in Multiple reaction monitoring (MRM) mode using LC-MS/MS.

[0485] To evaluate the bi-directional Caco-2 permeability of compounds 21 and 37, Caco-2 cells were grown in Dulbecco's Modified Eagle Medium (DMEM) (20% Fetal bovine serum (FBS)) until 85-90% confluence. After attaining required confluence, cells were trypsinized and seeded into 24 well millcell plates at a density of 0.6×105 cells/insert. The plates were maintained for 21 days at 37° C. in CO2 incubator with change of medium every alternative day. Monolayer integrity was monitored by measuring Trans-epithelial electrical resistance (TEER) from day 15. Caco-2 cell monolayer was washed twice with HBSS and incubated for 30 min in CO2 incubator. TEER values were measured and wells showing TEER values above 230 ohms.Math.cm2 were taken for experiments. Bi-directional permeability study was initiated by adding appropriate volume of HBSS containing the test compounds or probe P-gp substrate loperamide to either the apical (A-B transport) or basal side (B-A transport) of the monolayer. At selected time points (0, 15, 30, 60 and 90 mins) an aliquot of 50 μL was collected from the receiver compartment for determination of test compound concentrations. The volume withdrawn was replaced immediately with plain HBSS buffer (pH 7.4). TEER was measure at the end of the experiment to test the post experiment monolayer integrity. A 50 μL sample of loperamide, compound 21 and compound 37 were mixed with 100 μL internal standard followed by mixing. Finally samples were vortexed for 5 minutes and transferred to 96-well plates for LC MS/MS analysis.

[0486] To evaluate the cytotoxicity of selected compounds, cell viability assays (CellTiter Glo) were conducted. Each compound (compound 21 or compound 37) was plated in triplicate starting at their respective stock concentration. They were serially diluted column-wise for ten 3× dilutions using DMSO as the diluent. Staurosporine was used as positive control for DRC (dose response curve), and was plated starting at 1.25 mM. This plate was used as a source plate to make the assay plates by transferring 0.1 μl into 25 μl assay volume to reach the right working concentration for each compound. HepG2 and MRC5 were plated at a density of 1500 cells/25 μl in well in the assay plate and allowed to settle overnight. 0.1 μL of compounds was then transferred from the source plate, into the cell assay plates. The cells were left to incubate with the compounds for 48 hours, after which, 25 μL of Promega Cell Titer-Glo was added to each well, and allowed to incubate at room temperature with shaking for 20 minutes. RLU's (Relative Light Units) for each well were then recorded on a BioTek Synergy NEO. Fluorescence microscopy was also used to evaluate the cytotoxicity of selected compounds. Cells were plated at a density of 1500 cells/25 μl in well in a 384 wells plate the day before incubation with the drugs. The following day, 0.1 μl of the source plate are added to the assay plate. Then, 25 μl of a fluorophores mixture containing Hoechst 33342, Sytol7 diluted in Eagle's Minimum Essential Medium (EMEM) was added to each well. Plates are read after 48 hours of incubation in the ImageXpress instrument (Molecular Devices) using the appropriate filters.

Example 3. In Vitro Assay of Exemplary Compounds Described Herein

[0487] Select compounds described herein were evaluated for structure-activity analyses for anti-plasmodial activity in vitro. For Dd2 EC50 (M), calculations were for n=3. For HepG2 EC50 (M), calculations were for n=1. For the human microsomal stability determination, t was 60 minutes.

TABLE-US-00003 TABLE 3 IC.sub.50 and EC.sub.50, values, logS data, permeability data, and microsomal stability data of exemplary compounds described herein. Solubility Hep LogS, at Permeability Human Dd2 G2 pH 1.2; (log microsomal Compound EC.sub.50 EC.sub.50 pH 6.5; Predicted Predicted Pe, in stability # Compound Structure (μM) (μM) or pH 7.4 logS logD [cm/s]) (%) Tan003- M03 [00301] embedded image 0.24 ± 0.07 45 5.1; −5.2; −5.1 −4.37 3.94 −5.40 61.5 ent- Tan003- M03 [00302] 0.20 ± 0.02 — −5.2 (at pH 7.4) — — — 62.7 Tan003- 008 [00303] 0.53 ± 0.11 41 3.8; −5.0; −4.9 −4.20 3.59 −5.74 < 1 ent- Tan003- 008 [00304] 0.86 ± 0.08 — — — — — — ent- Tan003- D20 [00305] embedded image 0.38 ± 0.09 60 — — — — — Tan003- D20 [00306] 0.38 ± 0.02 — 3.8; −5.2; −5.1 −4.57 4.05 −5.62 <1 Tan002- O12; 2015- foleyc- 216 [00307] 0.89 ± 0.13 >100 — −3.06 2.75 — — 2015- foleyc- 223 [00308] >25 57 — −4.44 4.51 — — 2015- foleyc- 212 [00309] >25 >100 — −4.30 4.21 — — 2015- foleyc- 213 [00310] embedded image >25 >100 — −4.59 4.67 — — 2015- foleyc- 225 [00311] 4.92 ± 0.62 >100 — −4.37 2.44 — — 2015- foleyc- 264 [00312] >25 >100 — −4.82 1.54 — — 2015- foleyc- 265 [00313] 6.69 ± 0.35 77 — −5.01 2.05 — — 2015- foleyc- 226 [00314] >25 >100 — −3.91 4.46 — — 2015- foleyc- 253 [00315] embedded image 5.73 ± 0.33 62 — −4.52 3.04 — — 2015- foleyc- 254 [00316] 9.95 ± 0.89 71 — −4.75 3.56 — — 2015- foleyc- 267 [00317] 3.50 ± 0.97 >100 — −3.98 2.22 — — 2015- foleyc- 217 [00318] 2.19 ± 0.32 63 3.73 3.22 2015- foleyc- 218 [00319] 1.45 ± 0.28 >100 — −4.09 3.68 — — 2015- foleyc- 255 [00320] embedded image 15.50 ± 0.75 >100 — −4.44 2.65 — — 2015- foleyc- 219 [00321] 1.39 ± 0.13 >100 — −3.90 4.95 — — 2015- foleyc- 220 [00322] >25 >100 — −4.09 5.40 — — 2015- foleyc- 248 [00323] >25 >100 — −3.96 2.76 — — 2015- foleyc- 247 [00324] 1.48 ± 0.14 >100 — −3.57 1.89 — — 2015- foleyc- 241 [00325] embedded image 4.99 ± 0.59 >100 — −4.21 4.34 — — 2015- foleyc- 268 [00326] 10.2 ± 0.94 >100 — −4.45 4.85 — — 2015- foleyc- 237 [00327] 5.84 ± 0.94 >100 — −3.99 3.11 — —

[0488] To determine EC.sub.50 for selected compounds, P. falciparum Dd2 and 3D7 strains were maintained at 37° C. in 5% CO.sub.2 and 95% air using a modified Trager and Jensen (Trager et al., 1976, Science, 193, 673-675) method in RPMI media with L-glutamine (Invitrogen) and supplemented with 25 mM HEPES, 26 mM NaHCO.sub.3, 2% dextrose, 15 mg/L hypoxanthine (Sigma-Aldrich), 25 mg/L gentamicin (Life Technologies), and 0.5% Albumax II (Life Technologies). Different dilutions of the compound in RPMI 1640 (Life Technologies) from a stock of 10 mM in dimethyl sulfoxide (DMSO) were added to the culture at a 1% parasitemia and 2% hematocrit in 96-well black plates (Santa Cruz Biotechnology). Maximum DMSO concentration in the culture never exceeded 0.25%. Chloroquine at 1 μM was used as a positive control to determine the baseline value. Following 72 h incubation at 37° C., the ability of the compounds to inhibit growth of the parasite was determined by a SYBR green I-based DNA quantification assay (See Bennett et al., 2004, Chemother. 48, 1807-1810; see also Johnson et al., 2007, Antimicrob. Agents. Chemother. 51, 1926-1933; Smilkstein et al., 2004, Antimicrob. Agents. Chemother. 48, 1803-1806). EC.sub.50 was calculated (n=3) from a dose response curve that was generated from a concentration range of 0-20 μM using GraphPad Prism v5.0.

[0489] To determine microsomal stability for selected compounds, a reaction plate was prepared by adding 691.25 μL, pre-warmed (37° C.) microsomal solution (0.63 mg/mL protein in 100 mM KPO4 with 1.3 mM EDTA) to an empty well of a 96 well plate and maintained at 37° C. The diluted 0.1 mM compound (8.75 μL) is added to the microsomal solution in the reaction plate and mixed thoroughly by repeated pipetting. The resulting solutions were pre-incubated for 5 minutes at 37° C. before preparing the T=0 plates. For the T=0 plates, an aliquot (160 μL) of each reaction solution was added to an empty well of a 96 well plate, as an exact replicate of the Reaction Plate. Cold (4° C.) MeOH (400 μL) is added to each well and mixed thoroughly by repeated pipetting. NADPH Regeneration solution (40 μL) is added to each well and mixed thoroughly by repeated pipetting. For the T=60 minute Incubation Plates (without NADPH), an aliquot (160 μL) of each reaction solution was added to an empty well of a 96 well plate, as an exact replicate of the Reaction Plate. LC-MS grade H2O (40 μL) is added to each well and mixed thoroughly by repeated pipetting. The plate was sealed and incubated at 37° C. for the incubation period. After incubation, cold (4° C.) MeOH (400 μL) is added to each well and mixed thoroughly by repeated pipetting. For the T=60 minute Incubation Plates, NADPH (95 μL) was added to the remaining solution (microsomes+test compound) in each well in the previously-prepared reaction plate to initiate the reaction. The plate was sealed and incubated at 37° C. for the incubation period. An aliquot (100 μL) was removed from each well at the desired time point and dispensed into a well of a 96-well plate. 200 μL of cold (4° C.) MeOH was ato quench the reaction.

[0490] For selected compounds (Tan003-M03, ent-Tan003-M03, Tan003-O08, and Tan003-D20, kinetic solubility assays were performed. The selected compound samples were supplied as DMSO dissolved stocks for analysis in SGF pH1.2, 50 mM NaPO4 pH6.5 and 1×PBS pH7.4 buffers. A final DMSO concentration of 2.0% and maximum theoretical compound concentrations of 200 M (assuming a 10 mM DMSO stock) was achieved by diluting a 6 μl aliquot of DMSO stock with 294 μl of the appropriate buffer using Hamilton Starlet liquid handling and incubated directly in a Millipore solubility filter plate. Following 24 hour incubation at ambient temperature (23.3-24.2° C.), the samples were vacuum filtered.

[0491] For selected compounds, a Parallel artificial membrane permeability assay (PAMPA) analysis was conducted. The 10 mM DMSO stock solutions for selected compounds (Tan003-M03, ent-Tan003-M03, Tan003-O08, and Tan003-D20) were diluted 50 fold with 1×PBS, pH 7.4, for a dose concentration of 200 M and a volume of 300 μL in the Donor compartment of the Corning Gentest Pre-coated PAMPA plate. After preparation of the Donor plate, any precipitation was noted. The Acceptor compartment was filled with 1×PBS (200 μL), pH 7.4. After careful assembly of the PAMPA plate, it was left to incubate for five hours in the dark at ambient temperature. The previously prepared solubility assay was used to measure the initial concentration of the sample in buffer (C0). After the incubation was complete, the PAMPA plate was disassembled, and the samples were transferred from the Donor and Acceptor plates to 96-well plates for analysis by chemiluminescent nitrogen detection (CLND. The C0 plate was filtered prior to analysis by CLND.

[0492] Selected compounds were evaluated for cytotoxicity using HepG2 human hepatoma cells. A 384-well clear bottom plate was seeded with 2,500 cells/well and incubated for 24 h. Serial dilutions of the compound (were added to the plate and plates were incubated for an additional 48 h. Viability of cells were assessed by MTS [(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell proliferation assay (CellTiter 96® Aqueous non-radioactive cell proliferation assay, Promega) (See Cory et al., Cancer Communications, 3, 1991, p. 207-212).

Example 4. In Vivo Assay of Exemplary Compounds Described Herein

[0493] Select Compounds Described Herein were Evaluated for Structure-Activity Analyses for Anti-Plasmodial Activity In Vivo.

TABLE-US-00004 TABLE 4 In vivo PK and liver distribution data for exemplary compounds described herein. Compound # [00328] embedded image [00329] [00330] PK (ip, (Dose: 50 mg/kg) (Dose: l00 mg/kg) (Dose: l00 mg/kg) plasma/ 1.2 h / 2.2 h 2.4 h / 3.5 h 1.9 h / 4.6 h liver) t.sub.l/2 1.0 h / 0.1 h 0.5 h / 0.5 h 1.0 h / 0.25 h T.sub.max 14.0 μM / 58.6 μM 33.4 μM / 87.6 μM 72.6 μM / 111.3 μM C.sub.max 52.7 μM.Math.h / 186.0 μM.Math.h 157.9 μM.Math.h / 666.8 μM.Math.h 167.9 μM.Math.h / 306.4 AUCin μM.Math.h PK(po, (Dose: 50 mg/kg) (Dose: 100 mg/kg) (Dose: 100 mg/kg) plasma/ 8.2 h / 3.1 h 1.1 h / 16.9 h 2.1 h / 6.4 h liver) t.sub.l/2 0.25 h / 0.25 h 1.0 h / 4.0 h 0.5 h / 0.5 h T.sub.max 10.9 μM / 53.8 μM 27.6 μM / 39.6 μM 56.4 μM / 49.2 μM Cmax 29.9 μM.Math.h / 107.9 μM.Math.h 77.1 μM.Math.h / 238.1 μM.Math.h 36.7 μM.Math.h /124.9 μM.Math.h Area under the curve (AUC.sub.inf) Relative 57% 49% 22% Bio- availability, F.sub.rel (AUC.sub.inf po / AUC.sub.inf ip)

[0494] A plasma pharmacokinetics and liver distribution study of selected compounds, including Pyrrolopyridine-008 (2015-foleyc-216), Pyrrolopyridine-D20-ent (2015-foleyc-217), and Pyrrolopyridine-M03 (2015-foleyc-218), in female BALB/c mice was conducted following a single intraperitoneal and oral administration. To determine in vivo PK data for selected compounds, a group of fifty four female mice were divided into two groups as; Group 1 (100 mg/kg; intraperitoneal (i.p.)) and Group 2 (100 mg/kg; oral administration (p.o.)). Following a single intraperitoneal dose administration to female BALB/c mice, plasma concentrations of the selected compound (2015-foleyc-216, 2015-foleyc-217, or 2015-foleyc-218) were quantifiable till 12 hours with T.sub.max at 1.00 hour. Following a single oral dose administration to female BALB/c mice, plasma concentrations of the selected compound ((2015-foleyc-216, 2015-foleyc-217, or 2015-foleyc-218) were quantifiable till 12 hours with T.sub.max at 0.50 hour. Animals in Group 1 and Group 2 were administered with solution formulation of the selected compound ((2015-foleyc-216, 2015-foleyc-217, or 2015-foleyc-218) in 5% NMP, 5% Solutol HS, 30% PEG-400 and 60% HPβCD (20% w/v) at 100 mg/kg dose by intraperitoneal and oral route respectively. Blood samples (approximately 60 μL) were collected from retro orbital plexus of each mouse under light isoflurane anesthesia such that the samples were obtained at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours (i.p.); and pre-dose, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours (p.o.). The blood samples were collected from a set of thoursee mice at each time point in labeled micro centrifuge tube containing K2EDTA as anticoagulant. Plasma samples were separated by centrifugation at 4000 rpm for 10 min and stored below −70° C. until bioanalysis. After collection of blood sample, animals were humanely euthanized by carbon dioxide asphyxiation to collect liver from Group 1 and Group 2 at all the time points. The collected tissues were rinsed in PBS and were homogenized with nine times of liver weight in ice cold phosphate buffer saline (pH 7.4) and stored below −70° C. until bio-analysis. Total homogenate volume was ten times the tissue weight. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed with fit-for-purpose LC-MS/MS method (LLOQ: 2.01 ng/mL for plasma and 50.30 ng/g for liver). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool of Phoenix WinNonlin® (Version 6.3). Mean pharmacokinetic parameters are summarized in Table 4.

Example 5. Assessment of Stage Specific Parasite Inhibition by Exemplary Compounds Described Herein

[0495] Select compounds described herein were evaluated for stage specific inhibition of parasite development. Tightly synchronized parasite cultures (Dd2) were treated with 3×IC.sub.50 concentrations of compound Tan003-M03 (“M03”), compound ent-Tan003-D20 (“D20-ent”), compound Tan003-O08 (“008”) or compound Tan002-O12 (“012”) at early ring, late ring, trophozoite, and schizont stages. Every 12 hours, Giemsa smears were made for treated cultures and samples were also collected and fixed for flow cytometry. Giemsa staining revealed All exemplary compounds predominantly inhibit parasite stage development prior to egress when treated at Ring (FIG. 3), Trophozoite or Schizont stages (not shown). These results were also confirmed via flow cytometry (FIGS. 4A-4D). Prior to flow analysis, fixed samples were permeabilized, RNase treated, and stained with YoYo-I as described in Bouillon et al., 2013. As seen in FIG. 4, at 18 hours post invasion (late ring) in the control culture the peaks represent singly, and multiple-infected cells based on DNA content. As the parasite matures, the DNA content increases and peaks start to spread to the right because of schizogony. Following reinvasion parasitemia increases in the next growth cycle, which is represented by an increase in peak height. At 54 hpi, parasites are at the early ring stage of the next cycle, parasitemia is significantly higher, and three distinct peaks reappear. In contrast, exposure to all exemplary compounds at the late ring stage the maturation is blocked and as a result parasitemia does not increase. This suggests a block of intraerythrocytic maturation of parasite late in schizont stages of development just prior to egress when treated with any of these exemplary compounds.

Example 6. Parasitocidal or Parasitostatic Determination of Exemplary Compounds Described Herein

[0496] Asynchronous cultures were grown and treated with compounds, vehicle control or Dihydroartemisinin at 3×IC.sub.50 to determine their respective rate of killing curves. Cultures were treated for 12, 24, 48, or 72 hours with compound, washed several times to remove any inhibitor, and monitored for continued growth for several days. As shown in FIG. 5, compounds Tan003-M03 and ent-Tan003-D20 are parasitocidal and prevent any parasite development beyond the schizont stage when treated for at least 48 hours. Compound Tan003-O08 demonstrates potent parasitocidal activity beginning at 72 hours of treatment (FIG. 6), and compound Tan002-O12 did not show any parasitocidal activity in this study. Overall, the exemplary compounds including, but not limited to, Tan003-M03 and ent-Tan003-D20 are parasitocidal agents blocking parasite maturation at the segmenter stage preventing egress, a novel mechanism of action absent among current antimalarials.

EQUIVALENTS AND SCOPE

[0497] In the claims 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. Claims 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 invention 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 invention 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.

[0498] Furthermore, the invention 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 claim 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 invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention 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 invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0499] 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 invention that falls within the prior art may be explicitly excluded from any one or more of the claims. 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 invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0500] 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 claims. 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 invention, as defined in the following claims.

REFERENCES

[0501] 1. Bouillon, A., Gorgette, O., Mercereau-Puijalon, O., Barale, J. C., 2013. Screening and evaluation of inhibitors of Plasmodium falciparum merozoite egress and invasion using cytometry.

ANTI-PARASITIC COMPOUNDS AND USES THEREOF

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Y02A50/30

GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

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A61P33/06

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C07D471/04

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Abstract

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Description