TRANSCRIPTIONAL ENHANCED ASSOCIATE DOMAIN (TEAD) TRANSCRIPTION FACTOR INHIBITORS AND USES THEREOF

20220402869 · 2022-12-22

Assignee

Dana-Farber Cancer Institute, Inc. (Boston, MA, US)

Inventors

Cpc classification

International classification

Abstract

Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases (e.g., proliferative diseases (e.g., cancers, such as carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)) in a subject. Provided are methods of inhibiting a TEAD transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject.

##STR00001##

Claims

1. A compound of Formula (I): ##STR00785## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein: Ar is an optionally substituted bicyclic or monocyclic aryl, or an optionally substituted bicyclic or monocyclic heteroaryl; R.sup.1 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.f, —N(R.sup.f).sub.2, —SR.sup.f, —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)SR.sup.f, —C(═O)N(R.sup.f).sub.2, —OC(═O)R.sup.f, —OC(═O)OR.sup.f, —OC(═O)SR.sup.f, —OC(═O)N(R.sup.f).sub.2, —N(R.sup.f)C(═O)R.sup.f, —N(R.sup.f)C(═O)OR.sup.f, —N(R.sup.f)C(═O)SR.sup.f, —N(R.sup.f)C(═O)N(R.sup.f).sub.2, —SC(═O)R.sup.f, —SC(═O)OR.sup.f, —SC(═O)SR.sup.f, —SC(═O)N(R.sup.f).sub.2, —C(═NR.sup.f)R.sup.f, —C(═NR.sup.f)OR.sup.f, —C(═NR.sup.f)SR.sup.f, —C(═NR.sup.f)N(R.sup.f).sub.2, —OC(═NR.sup.f) R.sup.f, —OC(═NR.sup.f)OR.sup.f, —OC(═NR.sup.f)SR.sup.f, —OC(═NR.sup.f)N(R.sup.f).sub.2, —NR.sup.fC(═NR.sup.f)R.sup.f, —NR.sup.fC(═NR.sup.f)OR.sup.f, —NR.sup.fC(═NR.sup.f)SR.sup.f, —NR.sup.fC(═NR.sup.f)N(R.sup.f).sub.2, —SC(═NR.sup.f)R.sup.f, —SC(═NR.sup.f)OR.sup.f, —SC(═NR.sup.f)SR.sup.f, —SC(═NR.sup.f)N(R.sup.f).sub.2, —C(═S)R.sup.f, —C(═S)OR.sup.f, —C(═S)SR.sup.f, —C(═S)N(R.sup.f).sub.2, —S(═O)R.sup.f, —SO.sub.2R.sup.f, —NR.sup.fSO.sub.2R.sup.f, —SO.sub.2N(R.sup.f).sub.2, —CN, —SCN, or —NO.sub.2; each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.f, when present, can be joined together with the heteroatom to which they are attached to form an optionally substituted heterocyclic ring; A is an optionally substituted carbocyclic ring, an optionally substituted aryl ring, or an optionally substituted heterocyclic ring; X.sup.1 is a bond, —O—, optionally substituted C.sub.1-6alkyl, —N(R.sup.d)—, —C(R.sup.d).sub.2N(R.sup.d)—, —C(═O)N(R.sup.d)—, —N(R.sup.d)C(═O)—, —C(R.sup.d).sub.2O—, —OC(R.sup.d).sub.2—, —C(═O)—, —C(═O)O—, —C(═O)S—, —C(═O)N(R.sup.d)—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R.sup.d)—, —NR.sup.dC(═O)—, —N(R.sup.d)C(═O)O—, —N(R.sup.d)C(═O)N(R.sup.d)—, —C(═NR.sup.d)—, —C(═NR.sup.d)O—, —C(═NR.sup.d)N(R.sup.d)—, —OC(═NR.sup.d)—, —OC(═NR.sup.d)O—, —OC(═NR.sup.d)S—, —OC(═NR.sup.d)N(R.sup.d)—, —NR.sup.dC(═NR.sup.d)—, —NR.sup.dC(═NR.sup.d)O—, —S—, —S(═O)—, or —SO.sub.2—, wherein R.sup.d is independently a bond, hydrogen, substituted or unsubstituted C.sub.1-6alkyl, or a nitrogen protecting group; X.sup.2 is a bond, —O—, optionally substituted C.sub.1-6alkyl, —N(R.sup.da)—, —C(R.sup.da).sub.2N(R.sup.da)—, —C(═O)N(R.sup.da)—, —N(R.sup.da)C(═O)—, —C(R.sup.da).sub.2O—, —OC(R.sup.da).sub.2—, —C(═O)—, —C(═O)O—, —C(═O)S—, —C(═O)N(R.sup.da)—, —OC(═O)—, —OC(═O)O—, —OC(═O)S—, —OC(═O)N(R.sup.da)—, —NR .sup.daC(═O)—, —N(R.sup.da)C(═O)O—, —N(R.sup.d)C(═O)S—, —N(R.sup.da)C(═O)N(R.sup.da)—, —SC(═O)—, —SC(═O)O—, —SC(═O)S—, —SC(═O)N(R.sup.da)—, —C(═NR.sup.da)—, —C(═NR.sup.da)O—, —C(═NR.sup.da)S—, —C(═NR.sup.da)N(R.sup.da)—, —OC(═NR.sup.da)—, —OC(═NR.sup.da)O—, —OC(═NR.sup.da)S—, —OC(═NR.sup.da)N(R.sup.da)—, —NR.sup.daC(═NR.sup.da)—, —NR.sup.daC(═NR.sup.da)O—, —NR.sup.daC(═NR.sup.da)S—, —NR.sup.daC(═NR.sup.da)N(R.sup.da)—, —SC(═NR.sup.da)—, —SC(═NR.sup.da)O—, —SC(═NR.sup.da)S—, —SC(═NR.sup.da)N(R.sup.da)—, —S—, —S(═O)—, or —SO.sub.2—, wherein R.sup.da is independently a bond, hydrogen, substituted or unsubstituted C.sub.1-6alkyl, or a nitrogen protecting group; D.sup.1 is a warhead of any one of Formulae (i-1) to (i-42): ##STR00786## ##STR00787## ##STR00788## wherein: L.sup.3 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR.sup.L3a—, —NR.sup.L3aC(═O)—, —C(═O)NR.sup.L3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR.sup.L3aC(═S)—, —C(═S)NR.sup.L3a—, trans-CR.sup.L3b═CR.sup.L3b—, cis-CR.sup.L3b═CR.sup.L3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR.sup.L3a—, —NR.sup.L3aS(═O)—, —S(═O).sub.2—, —S(═O).sub.2O—, —OS(═O).sub.2—, —S(═O).sub.2NR.sup.L3a—, or —NR.sup.L3aS(═O).sub.2—, wherein R.sup.L3a is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R.sup.L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; L.sup.4 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain; R.sup.E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E1a, —CH.sub.2N(R.sup.E1a).sub.2, —CH.sub.2SR.sup.E1a, —OR.sup.E1a, —N(R.sup.E1a).sub.2, —Si(R.sup.E1a).sub.3, and —SR.sup.E1a, wherein each occurrence of R.sup.E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E1a groups are joined to form an optionally substituted heterocyclic ring; R.sup.E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E2a, —CH.sub.2N(R.sup.E2a).sub.2, —CH.sub.2SR.sup.E2a, —OR.sup.E2a, —N(R.sup.E2a).sub.2, and —SR.sup.E2a, wherein each occurrence of R.sup.E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E2a groups are joined to form an optionally substituted heterocyclic ring; R.sup.E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E3a, —CH.sub.2N(R.sup.E3a).sub.2, —CH.sub.2SR.sup.E3a, —OR.sup.E3a, —N(R.sup.E3a).sub.2, and —SR.sup.E3a, wherein each occurrence of R.sup.E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E3a groups are joined to form an optionally substituted heterocyclic ring; or R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and R.sup.E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.E4 is a leaving group; R.sup.E5 is halogen; Y is —O—, —S—, or —NR.sup.E6, wherein R.sup.E6 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; a is 1 or 2; and each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1, wherein Ar is an optionally substituted monocyclic aryl.

3. The compound of claim 1 or 2, wherein Ar is optionally substituted phenyl.

4. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00789## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein: R.sup.2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, haloalkyl, methyl, optionally substituted heteroalkyl, trifluoromethyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.c, —NO.sub.2, —N(R.sup.c).sub.2, or —SR.sup.c, wherein R.sup.c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, methyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, R.sup.2 can be joined with together with X.sup.1 to form an optionally substituted heterocyclic ring.

5. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00790## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

6. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00791## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

7. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00792## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

8. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00793## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

9. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00794## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

10. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00795## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

11. The compound of any one of claims 1 to 3, wherein Formula (I) is of the formula: ##STR00796## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

12. The compound of claim 1, wherein Ar is an optionally substituted monocyclic heteroaryl.

13. The compound of claim 12, wherein the optionally substituted monocyclic heteroaryl is thiophene, furan, pyrrole, imidazole, pyrazine, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, or pyridazine.

14. The compound of claim 13, wherein the optionally substituted monocyclic heteroaryl is optionally substituted pyridine.

15. The compound of any one of claims 12 to 14, wherein Formula (I) is of the formula: ##STR00797## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

16. The compound of any one of claims 12 to 14, wherein Formula (I) is of the formula: ##STR00798## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

17. The compound of claim 1, wherein Ar is an optionally substituted bicyclic aryl.

18. The compound of claim 1, wherein Ar is an optionally substituted indane.

19. The compound of claim 17 or 18, wherein Formula (I) is of the formula: ##STR00799## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

20. The compound of claim 19, wherein Formula (I) is of the formula: ##STR00800## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

21. The compound of claim 1, wherein Ar is an optionally substituted bicyclic heteroaryl.

22. The compound of claim 20, wherein Ar is benzothiophene.

23. The compound of claim 20 or 21, wherein Formula (I) is of the formula: ##STR00801## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

24. The compound of claim 20 or 21, wherein Formula (I) is of the formula: ##STR00802## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

25. The compound of claim 20 or 21, wherein Formula (I) is of the formula: ##STR00803## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

26. The compound of claim 20 or 21, wherein Formula (I) is of the formula: ##STR00804## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

27. The compound of claim 20 or 21, wherein Formula (I) is of the formula: ##STR00805## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

28. The compound of any one of claims 1 to 27, wherein R.sup.1 is optionally substituted alkyl.

29. The compound of any one of claims 1 to 28, wherein R.sup.1 is optionally substituted C.sub.1-C.sub.6alkyl.

30. The compound of any one of claims 1 to 29, wherein R.sup.1 is Me.

31. The compound of any one of claims 1 to 29, wherein R.sup.1 is —CF.sub.3.

32. The compound of any one of claims 1 to 27, wherein R.sup.1 is —OR.sup.f.

33. The compound of any one of claims 1 to 27, wherein R.sup.1 is SR.sup.f.

34. The compound of any one of claims 1 to 27, wherein R.sup.1 is —N(R.sup.f).sub.2.

35. The compound of any one of claims claim 32 to 34, wherein R.sup.f is optionally substituted alkyl.

36. The compound of claim 34, wherein at least one instance of R.sup.f is -Me.

37. The compound of claim 34, wherein at least one instance of R.sup.f is —CF.sub.3.

38. The compound of claim 34, wherein at least one instance of R.sup.f is —CH.sub.2CF.sub.3.

39. The compound of claim 34, wherein at least one instance of R.sup.f is —CH.sub.2CCH.

40. The compound of claim 34, wherein at least one instance of R.sup.f is —CH.sub.2Ph.

41. The compound of any one of claims claim 32 to 34, wherein R.sup.f is optionally substituted aryl.

42. The compound of claim 41, wherein at least one instance of R.sup.f is -Ph.

43. The compound of claim 34, wherein each instance R.sup.f is optionally substituted alkyl.

44. The compound of claim 43, wherein each instance of R.sup.f is optionally substituted C.sub.1-C.sub.6alkyl.

45. The compound of claim 44, wherein each instance of R.sup.f is -Me.

46. The compound of claim 42, wherein the two instances of R.sup.f is together be together with the heteroatom to which they are attached can form an optionally substituted heterocyclic ring.

47. The compound of claim 46, wherein the optionally substituted heterocyclic ring is an optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, or optionally substituted piperazine.

48. The method of claim 46, wherein the optionally substituted heterocyclic ring is of the formula: ##STR00806##

49. The compound of claim 32 or 33, wherein R.sup.1 is a halogen.

50. The compound of claim 49, wherein R.sup.1 is —F.

51. The compound of claim 49, wherein R.sup.1 is —Cl.

52. The compound of claim 49, wherein R.sup.1 is —Br.

53. The compound of claim 3, wherein Ar is of the formula: ##STR00807## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

54. The compound of claim 4, wherein Formula (I) is of the formula: ##STR00808## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

55. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is —H.

56. The compound of claim 54, wherein R.sup.2 is —H.

57. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl.

58. The compound of claim 57, wherein R.sup.2 is -Me.

59. The compound of claim 57, wherein R.sup.2 is —CF.sub.3.

60. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is alkynyl.

61. The compound of claim 60, wherein R.sup.2 is unsubstituted acetylenyl.

62. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is —OR.sup.c.

63. The compound of claim 62, wherein R.sup.2 is —OMe.

64. The compound of claim 62, wherein R.sup.2 is —OBn.

65. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is —N(R).sub.2.

66. The compound of claim 65, wherein each instance of R.sup.c together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring.

67. The compound of claim 66, wherein the optionally substituted heterocyclic ring is an optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, or optionally substituted piperazine.

68. The compound of claim 65, wherein each instance of R.sup.c is independently optionally substituted alkyl.

69. The compound of claim 68, wherein each instance of R.sup.c is independently optionally substituted C.sub.1-C.sub.6 alkyl.

70. The compound of claim 65, wherein each instance is independently —H.

71. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is a halogen.

72. The compound of claim 71, wherein R.sup.2 is —F.

73. The compound of claim 71, wherein R.sup.2 is —Cl.

74. The compound of claim 71, wherein R.sup.2 is —Br.

75. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is —CN.

76. The compound of any one of claims 4 to 10, 15, 16, 19, 20, or 23 to 54, wherein R.sup.2 is —NO.sub.2.

77. The compound of any one of claims 54 to 76, wherein m is 1.

78. The compound of claim 55, wherein Ar is of the formula: ##STR00809## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

79. The compound of claim 65, wherein Ar is of the formula: ##STR00810## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

80. The compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is a bond.

81. The compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is a bond.

82. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is a bond.

83. The compound of claim 81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —N(R.sup.d)—.

84. The compound of claim 81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —O—.

85. The compound of claim 81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —C(R.sup.d).sub.2O—.

86. The compound of claim 85, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R.sup.d is H.

87. The compound of claim 81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —CH.sub.2N(R.sup.d)—, wherein R.sup.d is joined together with one instance of R.sup.2 to form an optionally substituted heterocyclic ring.

88. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is —N(R.sup.da)—.

89. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is —O—.

90. The compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is —N(R.sup.da)—.

91. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —N(R.sup.d)—.

92. The compound of claim 90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —O—.

93. The compound of any one of claims 83 or 91, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —N(H)—.

94. The compound of any one of claims 83 or 91, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.1 is —N(Me)-.

95. The compound of any one of claims 8 or 90 to 92, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is —N(H)—.

96. The compound of any one of claims 88 or 90 to 92, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein X.sup.2 is —N(Me)-.

97. The compound of claim 83, wherein the compound of Formula (I) is of the formula: ##STR00811## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

98. The compound of claim 97, wherein the compound of Formula (I) is of the formula: ##STR00812## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

99. The compound of claim 97 or 98, wherein R.sup.d is —H.

100. The compound of claim 97 or 98, wherein R.sup.d is C.sub.1-C.sub.6 alkyl.

101. The compound of claim 100, wherein R.sup.d is -Me.

102. The compound of claim 85, wherein the compound of Formula (I) is of the formula: ##STR00813## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

103. The compound of claim 85, wherein the compound of Formula (I) is of the formula: ##STR00814## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

104. The compound of claim 102 or 103, wherein both instances of R.sup.d are —H.

105. The compound of claim 82, wherein the compound of Formula (I) is of the formula: ##STR00815## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

106. The compound of claim 88, wherein the compound of Formula (I) is of the formula: ##STR00816## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

107. The compound of any one of claims 1 to 106, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein A is an optionally substituted heterocyclic ring.

108. The compound of claim 107, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof wherein A is of formula: ##STR00817## ##STR00818## wherein: R.sup.3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —C(═O)OR.sup.e, —C(═O)N(R.sup.e).sub.2, —OR.sup.e, —N(R.sup.e).sub.2, —SR.sup.e, or —N(R.sup.e)SO.sub.2R.sup.e wherein R.sup.e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, two instances of R.sup.3 can be joined together to form an optionally substituted carbocyclic or heterocyclic fused ring; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

109. The compound of claim 107, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein A is of formula: ##STR00819##

110. The compound of claim 108, wherein ring ##STR00820## is of the formula: ##STR00821##

111. The compound of claim 110, wherein the compound of Formula (I) is of the formula: ##STR00822## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

112. The compound of claim 108, wherein the compound of Formula (I) is of the formula: ##STR00823## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

113. The compound of claim 108, wherein the compound of Formula (I) is of the formula: ##STR00824## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

114. The compound of any one of claims 108 to 113, wherein R.sup.3 is hydrogen.

115. The compound of any one of claims 108 to 113, wherein R.sup.3 is optionally substituted alkyl.

116. The compound of claim 115, wherein R.sup.3 is optionally substituted methyl.

117. The compound of claim 115, wherein R.sup.3 is -Me.

118. The compound of claim 115, wherein R.sup.3 is -Et.

119. The compound of claim 115, wherein R.sup.3 is —CF.sub.3.

120. The compound of any one of claims 108 to 113, wherein R.sup.3 is optionally substituted carbocyclyl.

121. The compound of any one of claims 108 to 113, wherein R.sup.3 is optionally substituted heterocyclyl.

122. The compound of claim 121, wherein R.sup.3 is optionally substituted azirdinyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, dioxolanyl, oxathiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, pyridazinonyl, tetrahydropyranyl, dihydropyridinyl, piperazinyl, morpholinyl, dithianyl, and dioxanyl, triazinyl, azepanyl, or oxepanyl.

123. The compound of claim 122, wherein R.sup.3 is optionally substituted morpholinyl, piperazinyl, pyrrolidinyl, or pyridazinonyl.

124. The compound of any one of claims 108 to 113, wherein R.sup.3 is optionally substituted aryl.

125. The compound of claim 113, wherein R.sup.3 is optionally substituted or unsubstituted phenyl.

126. The compound of any one of claims 108 to 113, wherein R.sup.3 is optionally substituted heteroaryl.

127. The compound of claim 126, wherein the heteroaryl is an optionally substituted thiophene, benzothiophene, furan, isobenzofuran, pyrrole, imidazole, pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, triazole, tetrazole, oxazole, isoxazole, thiazole, or oxazole.

128. The compound of claim 127, wherein the heteroaryl is an optionally substituted pyrazole, triazole, tetrazole, pyridine, or pyrimidine.

129. The compound of any one of claims 108 to 113, wherein R.sup.3 is —OR.sup.e.

130. The compound of claim 129, wherein R.sup.3 is —OH.

131. The compound of claim 129, wherein R.sup.3 is —OMe.

132. The compound of any one of claims 1 to 106, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or mixture thereof, wherein A is an optionally substituted carbocyclic ring.

133. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein A is a six-membered ring.

134. The compound of any one of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein A is an aromatic ring.

135. The compound of claim 134, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein A is phenyl.

136. The compound of claim 135, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof wherein A is of Formula (IV): ##STR00825##

137. The compound of any one of claims 108, 109, 114, 117, or 118 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R.sup.3 is hydrogen.

138. A compound of Formula (I-e): ##STR00826## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: R.sup.1 is hydrogen, trifluoromethyl or N(R.sup.a)(R.sup.b), wherein R.sup.a is selected from optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; R.sup.b is selected from optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form a heterocycle; R.sup.2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, haloalkyl, methyl, optionally substituted heteroalkyl, trifluoromethyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.c, —NO.sub.2, —N(R.sup.c).sub.2, or —SR.sup.c, wherein R.sup.c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, methyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, R.sup.2 can be joined with together with X.sup.1 to form an optionally substituted heterocyclic ring; A is an optionally substituted carbocyclic ring, an optionally substituted aryl ring, or an optionally substituted heterocyclic ring; V.sup.1 is N or —C(R.sup.2)—; X.sup.1 is a bond or O, S, —CH.sub.2N(R.sup.d)—, or —N(R.sup.d)—, wherein R.sup.d is a bond, hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally R.sup.d can be joined together with one instance of R.sup.2 to form an optionally substituted heterocyclic ring; X.sup.2 is a bond or O, S, or N(R.sup.d); m is 0, 1, 2, 3 or 4; D.sup.1 is a warhead of any one of Formulae (i-1) to (i-42): ##STR00827## ##STR00828## ##STR00829## wherein: L.sup.3 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR.sup.L3a—, —NR.sup.L3aC(═O)—, —C(═O)NR.sup.L3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR.sup.L3aC(═S), —C(═S)NR.sup.L3a trans —CR.sup.L3b═CR.sup.L3b—, cis-CR.sup.L3b═CR.sup.L3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR.sup.L3a—, —NR.sup.L3aS(═O)—, —S(═O).sub.2—, —S(═O).sub.2O—, —OS(═O).sub.2—, —S(═O).sub.2NR.sup.L3a—, or —NR.sup.L3aS(═O).sub.2—, wherein R.sup.L3a is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R.sup.L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; L.sup.4 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain; R.sup.E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E1a, —CH.sub.2N(R.sup.E1a).sub.2, —CH.sub.2SR.sup.E1a, —OR.sup.E1a, —N(R.sup.E1a).sub.2, —Si(R.sup.E1a).sub.3, and —SR.sup.E1a, wherein each occurrence of R.sup.E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E1a groups are joined to form an optionally substituted heterocyclic ring; R.sup.E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E2a, —CH.sub.2N(R.sup.E2a).sub.2, —CH.sub.2SR.sup.E2a, —OR.sup.E2a, —N(R.sup.E2a).sub.2, and —SR.sup.E2a, wherein each occurrence of R.sup.E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E2a groups are joined to form an optionally substituted heterocyclic ring; R.sup.E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E3a, —CH.sub.2N(R.sup.E3a).sub.2, —CH.sub.2SR.sup.E3a, —OR.sup.E3a, —N(R.sup.E3a).sub.2, and —SR.sup.E3a, wherein each occurrence of R.sup.E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E3a groups are joined to form an optionally substituted heterocyclic ring; or R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and R.sup.E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.E4 is a leaving group; R.sup.E5 is halogen; Y is O, S, or NR.sup.E6, wherein R.sup.E6 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; a is 1 or 2; and each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

139. The compound of claim 138, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is a bond.

140. The compound of claim 138, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is a bond.

141. The compound of claim 139, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is a bond.

142. The compound of claim 140, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is N(R.sup.d).

143. The compound of claim 140, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is O.

144. The compound of claim 140, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is —CH.sub.2N(R.sup.d)—, wherein R.sup.d is joined together with one instance of R.sup.2 to form an optionally substituted heterocyclic ring.

145. The compound of claim 139, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is N(R.sup.d).

146. The compound of claim 139, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is O.

147. The compound of claim 138, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is N(R.sup.d).

148. The compound of claim 146, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is N(R.sup.d).

149. The compound of claim 146, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is O.

150. The compound of any one of claims 138-149, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is N—H.

151. The compound of any one of claims 138-149, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.1 is N-Me.

152. The compound of any one of claims 138-149, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is N—H.

153. The compound of any one of claims 138-149, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X.sup.2 is N-Me.

154. The compound of any one of claims 138-153, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is an optionally substituted heterocyclic ring.

155. The compound of any one of claims 141-144, wherein A is of the Formula (II): ##STR00830## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)OH, OR.sup.e, N(R.sup.e).sub.2, or SR.sup.e, wherein R.sup.e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

156. The compound of any one of claims 145 or 146, wherein A is of the Formula (III): ##STR00831## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)OH, OR.sup.e, N(R.sup.e).sub.2, or SR.sup.e, wherein R.sup.e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

157. The compound of any one of claims 138-153, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is an optionally substituted carbocyclic ring.

158. The compound of claim 157, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is a six-membered ring.

159. The compound of any one of claim 157, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is an aromatic ring.

160. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is phenyl.

161. The compound of claim 157, wherein A is of Formula (IV): ##STR00832## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)OH, OR.sup.e, N(R.sup.e).sub.2, or SR.sup.e, wherein R.sup.e is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

162. The compound of any one of claims 138-161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.1 is trifluoromethyl.

163. The compound of any one of claims 138-161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.1 is hydrogen.

164. The compound of any one of claims 138-161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.1 is N(R.sup.a)(R.sup.b), wherein R.sup.a is selected from optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.b is selected from optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form a heterocycle.

165. The compound of claim 164, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.1 of Formula (V): ##STR00833##

166. The compound of any one of claims 138-165, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein V.sup.1 is N.

167. The compound of any one of claims 138-165, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein V.sup.1 is C(R.sup.2).

168. The compound of any one of claims 155, 156, or 161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.3 is hydrogen.

169. The compound of any one of claims 138-168, wherein the compound is of Formula (VI): ##STR00834##

170. The compound of claim 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is optionally substituted alkyl.

171. The compound of claim 170, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is methyl.

172. The compound of claim 170, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is trifluoromethyl.

173. The compound of claim 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is optionally substituted alkynyl.

174. The compound of claim 173, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is —N(R.sup.c).sub.2, wherein R.sup.c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, methyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.c together with the nitrogen atom to which they are attached can be joined to form a heterocyclic ring.

175. The compound of claim 174, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is of formula: ##STR00835##

176. The compound of any one of claim 174, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is —NH.sub.2.

177. The compound of any one of claim 174, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is —NO.sub.2.

178. The compound of any one of claim 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is —OR.sup.c, wherein R.sup.c is selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, methyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

179. The compound of claim 178, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is —OMe.

180. The compound of any one of claim 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is a halogen.

181. The compound of any one of claim 180, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is Cl.

182. The compound of any one of claim 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R.sup.2 is hydrogen.

183. The compound of any one of claims 1 to 182, wherein the compound is of formula: ##STR00836## ##STR00837## ##STR00838## ##STR00839## ##STR00840## ##STR00841## ##STR00842## ##STR00843## ##STR00844## ##STR00845## ##STR00846## ##STR00847## ##STR00848## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

184. A pharmaceutical composition comprising a compound of any one of claims 1 to 138, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, and optionally a pharmaceutically acceptable excipient.

185. The pharmaceutical composition of claim 139, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for use in treating a proliferative disease in a subject in need thereof.

186. A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 183, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 184 or 185.

187. The method of claim 186, wherein the proliferative disease is cancer.

188. The method of claim 187, wherein the cancer is a sarcoma.

189. The method of claim 188, wherein the cancer is Kaposi's Sarcoma.

190. The method of claim 187, wherein the cancer is lung cancer.

191. The method of claim 187, wherein the cancer is a thyroid cancer.

192. The method of claim 187, wherein the cancer is breast cancer.

193. The method of claim 187, wherein the cancer is liver cancer.

194. The method of claim 187, wherein the cancer is prostate cancer.

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

196. The method of claim 187, wherein the cancer is colorectal cancer.

197. The method of claim 187, wherein the cancer is ovarian cancer.

198. The method of claim 187, wherein the cancer is skin cancer.

199. The method of claim 187, wherein the cancer is esophageal cancer.

200. The method of claim 187, wherein the cancer is carcinoma.

201. The method of claim 187, wherein the cancer is fallopian tube carcinoma.

202. A method of inhibiting a transcription factor in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 138, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 139 or 140.

203. A method of inhibiting a transcription factor in a biological sample, the method comprising: contacting the biological sample with an effective amount of a compound of any one of claims 1 to 183, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 184 or 185.

204. The method of claim 191 or 193, wherein the transcription factor is TEAD1, TEAD2, TEAD3, or TEAD4.

205. The method of any one of claims 186 to 201 further comprising administering to the subject a therapeutically effective amount of an additional pharmaceutical agent in combination with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or the pharmaceutical composition.

206. The method of claim 203 further comprising contacting the biological sample with an additional pharmaceutical agent in combination with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or the pharmaceutical composition.

207. The method of claim 203, wherein the biological sample is a cell or tissue.

208. The method of claim 202 or 203, wherein the additional pharmaceutical agent is an anti-proliferative agent.

209. Use of a compound of any one of claims 1 to 183, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 184 or 185, for treating a disease in a subject in need thereof.

210. A compound of any one of claims 1 to 183, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 184 or 185, for use in treating a disease in a subject in need thereof.

211. A kit comprising: a compound of any one of claims 1 to 183, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 184 or 185; and instructions for administering to a subject or contacting a biological sample with the compound, or the pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or the pharmaceutical composition.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0158] FIG. 1 shows the NSAID starting point-flufenamic acid.

[0159] FIG. 2 shows preliminary data for the lead compound, including the TEAD transcription reporter assay and endogenous TEAD transcription targets.

[0160] FIG. 3 shows relative TEAD transcriptional activity for MDA-MB-231/8×G TIIC-luc.

[0161] FIG. 4 shows pulldown from MB-231 cell lysates.

[0162] FIG. 5 shows mass spectrometry labeling of TEAD2 with 1-34.

[0163] FIG. 6 shows the in vitro inhibition of palmitoylation of TEAD2 protein using the disclosed compounds.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0164] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Compounds

[0165] In certain embodiments, a compound described herein is of Formula (I):

##STR00012##

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

[0166] Ar is an optionally substituted bicyclic or monocyclic aryl, or an optionally substituted bicyclic or monocyclic heteroaryl;

[0167] R.sup.1 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.f, —N(R.sup.f).sub.2, —SR.sup.f, —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)SR.sup.f, —C(═O)N(R.sup.f).sub.2, —OC(═O)R.sup.f, —OC(═O)OR.sup.f, —OC(═O)SR.sup.f, —OC(═O)N(R.sup.f).sub.2, —N(R.sup.f)C(═O)R.sup.f, —N(R.sup.f)C(═O)OR.sup.f, —N(R.sup.f)C(═O)SR.sup.f, —N(R.sup.f)C(═O)N(R.sup.f).sub.2, —SC(═O)R.sup.f, —SC(═O)OR.sup.f, —SC(═O)SR.sup.f, —SC(═O)N(R.sup.f).sub.2, —C(═NR.sup.f)R.sup.f, —C(═NR.sup.f)OR.sup.f, —C(═NR.sup.f)SR.sup.f, —C(═NR.sup.f)N(R.sup.f).sub.2, —OC(═NR.sup.f) R.sup.f, —OC(═NR.sup.f)OR.sup.f, —OC(═NR.sup.f)SR.sup.f, —OC(═NR.sup.f)N(R.sup.f).sub.2, —NR.sup.fC(═NR.sup.f)R.sup.f, —NR.sup.fC(═NR.sup.f)OR.sup.f, —NR.sup.fC(═NR.sup.f)SR.sup.f, —NR.sup.fC(═NR.sup.f)N(R.sup.f).sub.2, —SC(═NR.sup.f)R.sup.f, —SC(═NR.sup.f)OR.sup.f, —SC(═NR.sup.f)SR.sup.f, —SC(═NR.sup.f)N(R.sup.f).sub.2, —C(═S)R.sup.f, —C(═S)OR.sup.f, —C(═S)SR.sup.f, —C(═S)N(R.sup.f).sub.2, —S(═O)R.sup.f, —SO.sub.2R.sup.f, —NR.sup.fSO.sub.2R.sup.f, —SO.sub.2N(R.sup.f).sub.2, —CN, —SCN, or —NO.sub.2;

[0168] each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.f, when present, can be joined together with the heteroatom to which they are attached to form an optionally substituted heterocyclic ring;

[0169] A is an optionally substituted carbocyclic ring, an optionally substituted aryl ring, or an optionally substituted heterocyclic ring;

[0170] X.sup.1 is a bond, —O—, optionally substituted C.sub.1-6alkyl, —N(R.sup.d)—, —C(R.sup.d).sub.2N(R.sup.d)—, —C(═O)N(R.sup.d)—, —N(R.sup.d)C(═O)—, —C(R.sup.d).sub.2O—, —OC(R.sup.d).sub.2—, —C(═O)—, —C(═O)O—, —C(═O)S—, —C(═O)N(R.sup.d)—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R.sup.d)—, —NR.sup.dC(═O)—, —N(R.sup.d)C(═O)O—, —N(R.sup.d)C(═O)N(R.sup.d)—, —C(═NR.sup.d)—, —C(═NR.sup.d)O—, —C(═NR.sup.d)N(R.sup.d)—, —OC(═NR.sup.d)—, —OC(═NR.sup.d)O—, —OC(═NR.sup.d)S—, —OC(═NR.sup.d)N(R.sup.d)—, —NR.sup.dC(═NR.sup.d)—, —NR.sup.dC(═NR.sup.d)O—, —S—, —S(═O)—, or —SO.sub.2—, wherein R.sup.d is independently a bond, hydrogen, substituted or unsubstituted C.sub.1-6alkyl, or a nitrogen protecting group;

[0171] X.sup.2 is a bond, —O—, optionally substituted C.sub.1-6alkyl, —N(R.sup.da)—, —C(R.sup.da).sub.2N(R.sup.da)—, —C(═O)N(R.sup.da)—, —N(R.sup.da)C(═O)—, —C(R.sup.da).sub.2O—, —OC(R.sup.da).sub.2—, —C(═O)—, —C(═O)O—, —C(═O)S—, —C(═O)N(R.sup.da), —OC(═O)—, —OC(═O)O—, —OC(═O)S—, —OC(═O)N(R.sup.da)—, —NR.sup.daC(═O)—, —N(R.sup.da)C(═O)O—, —N(R.sup.d)C(═O)S—, —N(R.sup.da)C(═O)N(R.sup.da)—, —SC(═O)—, —SC(═O)O—, —SC(═O)S—, —SC(═O)N(R.sup.da)—, —C(═NR.sup.da)—, —C(═NR.sup.da)O—, —C(═NR.sup.da)S—, —C(═NR.sup.da)N(R.sup.da)—, —OC(═NR.sup.da)—, —OC(═NR.sup.da)O—, —OC(═NR.sup.da)S—, —OC(═NR.sup.da)N(R.sup.da), —NR.sup.daC(═NR.sup.da)—, —NR.sup.daC(═NR.sup.da)O—, —NR.sup.daC(═NR.sup.da)S—, —NR.sup.daC(═NR.sup.da)N(R.sup.da)—, —SC(═NR.sup.da)—, —SC(═NR.sup.da)O—, —SC(═NR.sup.da)S—, —SC(═NR.sup.da)N(R.sup.da)—, —S—, —S(═O)—, or —SO.sub.2—, wherein R.sup.da is independently a bond, hydrogen, substituted or unsubstituted C.sub.1-6alkyl, or a nitrogen protecting group;

[0172] D.sup.1 is a warhead of any one of Formulae (i-1) to (i-42):

##STR00013## ##STR00014## ##STR00015##

wherein:

[0173] L.sup.3 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR.sup.L3a—, —NR.sup.L3aC(═O)—, —C(═O)NR.sup.L3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O—, —NR.sup.L3aC(═S)—, —C(═S)NR.sup.L3a—, trans-CR.sup.L3b═CR.sup.L3b—, cis-CR.sup.L3b═CR.sup.L3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR.sup.L3a—, —NR.sup.L3aS(═O)—, —S(═O).sub.2—, —S(═O).sub.2O—, —OS(═O).sub.2—, —S(═O).sub.2NR.sup.L3a—, or —NR.sup.L3aS(═O).sub.2—, wherein R.sup.L3a is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R.sup.L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

[0174] L.sup.4 is a bond or an optionally substituted C.sub.1-4 hydrocarbon chain;

[0175] R.sup.E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E1a, —CH.sub.2N(R.sup.E1a).sub.2, —CH.sub.2SR.sup.E1a, —OR.sup.E1a, —N(R.sup.E1a).sub.2, —Si(R.sup.E1a).sub.3, and —SR.sup.E1a, wherein each occurrence of R.sup.E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E1a groups are joined to form an optionally substituted heterocyclic ring;

[0176] R.sup.E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E2a, —CH.sub.2N(R.sup.E2a).sub.2, —CH.sub.2SR.sup.E2a, —OR.sup.E2a, —N(R.sup.E2a).sub.2, and —SR.sup.E2a, wherein each occurrence of R.sup.E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E2a groups are joined to form an optionally substituted heterocyclic ring;

[0177] R.sup.E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH.sub.2OR.sup.E3a, —CH.sub.2N(R.sup.E3a).sub.2, —CH.sub.2SR.sup.E3a, —OR.sup.E3a, —N(R.sup.E3a).sub.2, and —SR.sup.E3a, wherein each occurrence of R.sup.E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.E3a groups are joined to form an optionally substituted heterocyclic ring;

[0178] or R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and R.sup.E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

[0179] R.sup.E4 is a leaving group;

[0180] R.sup.E5 is halogen;

[0181] Y is —O—, —S—, or —NR.sup.E6, wherein R.sup.E6 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

[0182] a is 1 or 2; and

[0183] each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

[0184] Formula (I) contains the substituent R.sup.1. In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is haloalkyl. In certain embodiments, R.sup.1 is trihalomethyl. In certain embodiments, R.sup.1 is trifluoromethyl. In certain embodiments, R.sup.1 is trichloromethyl. In certain embodiments, R.sup.1 is dihalomethyl. In certain embodiments, R.sup.1 is difluoromethyl. In certain embodiments, R.sup.1 is halomethyl. In certain embodiments, R.sup.1 is fluoromethyl. In certain embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is —F. In certain embodiments, R.sup.1 is —Cl. In certain embodiments, R.sup.1 is —Br. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-C.sub.6alkyl. In certain embodiments, R.sup.1 is -Me. In certain embodiments, R.sup.1 is

##STR00016##

In certain embodiments, R.sup.1 is optionally substituted alkenyl. In certain embodiments, R.sup.1 is optionally substituted alkynyl. In certain embodiments, R.sup.1 is optionally substituted carbocyclyl. In certain embodiments, R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted aryl. In certain embodiments, R.sup.1 is optionally substituted heteroaryl. In certain embodiments, R.sup.1 is —OR.sup.f, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.f, when present, can be joined together with the heteroatom to which they are attached to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.f is

##STR00017##

In certain embodiments, R.sup.f is optionally substituted C.sub.1-C.sub.6alkyl. In certain embodiments, R.sup.f is C.sub.1-C.sub.6 haloalkyl. In certain embodiments, R.sup.1 is —OCF.sub.3. In certain embodiments, R.sup.1 is —OMe. In certain embodiments, R.sup.1 is —OCH.sub.2CF.sub.3. In certain embodiments, R.sup.1 is —OCH.sub.2CCH. In certain embodiments, R.sup.1 is —OPh.

[0185] In certain embodiments, R.sup.1 is —N(R.sup.f).sub.2, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two instances of R.sup.f, when present, can be joined together with the heteroatom to which they are attached to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.1 is —SR.sup.f. In certain embodiments, R.sup.1 is —SCF.sub.3. In certain embodiments, R.sup.1 is —C(═O)R.sup.f. In certain embodiments, R.sup.1 is —C(═O)OR.sup.f. In certain embodiments, R.sup.1 is —C(═O)SR.sup.f. In certain embodiments, R.sup.1 is —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —OC(═O)R.sup.f. In certain embodiments, R.sup.1 is —OC(═O)OR.sup.f. In certain embodiments, R.sup.1 is —OC(═O)SR.sup.f. In certain embodiments, R.sup.1 is —OC(═O)N(R.sup.ff).sub.2. In certain embodiments, R.sup.1 is —N(R.sup.f)C(═O)R.sup.f. In certain embodiments, R.sup.1 is —N(R.sup.f)C(═O)OR.sup.f. In certain embodiments, R.sup.1 is —N(R.sup.f)C(═O)SR.sup.f. In certain embodiments, R.sup.1 is —N(R.sup.f)C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —SC(═O)R.sup.f. In certain embodiments, R, is —SC(═O)OR.sup.f. In certain embodiments, R.sup.1 is —SC(═O)SR.sup.f. In certain embodiments, R.sup.1 is —SC(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —C(═NR.sup.f)R.sup.f. In certain embodiments, R.sup.1 is —C(═NR.sup.f)OR.sup.f. In certain embodiments, R.sup.1 is —C(═NR.sup.f)SR.sup.f. In certain embodiments, R.sup.1 is —C(═NR.sup.f)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —OC(═NR.sup.f)R.sup.f. In certain embodiments, R.sup.1 is —OC(═NR.sup.f)OR.sup.f. In certain embodiments, R.sup.1 is —OC(═NR.sup.ff)SR.sup.f. In certain embodiments, R.sup.1 is —OC(═NR.sup.f)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —NR.sup.fC(═NR.sup.f)R.sup.f. In certain embodiments, R.sup.1 is —NR.sup.fC(═NR.sup.f)OR.sup.f. In certain embodiments, R.sup.1 is —NR.sup.fC(═NR.sup.f)SR.sup.f. In certain embodiments, R.sup.1 is —NR.sup.fC(═NR.sup.f)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —SC(═NR.sup.f)R.sup.f. In certain embodiments, R.sup.1 is —SC(═NR.sup.f)OR.sup.f. In certain embodiments, R.sup.1 is —SC(═NR.sup.f)SR.sup.f. In certain embodiments, R.sup.1 is —SC(═NR.sup.f)N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —S(═O)R.sup.f. In certain embodiments, R.sup.1 is —SO.sub.2R.sup.f. In certain embodiments, R.sup.1 is —NR.sup.fSO.sub.2R.sup.f. In certain embodiments, R.sup.1 is —SO.sub.2N(R.sup.f).sub.2. In certain embodiments, R.sup.1 is —CN. In certain embodiments, R.sup.1 is —SCN. In certain embodiments, R.sup.1 is —NO.sub.2. In certain embodiments, R.sup.f is substituted or unsubstituted acyl. In certain embodiments, R.sup.f contains a biotin-derivative. In certain embodiments, R.sup.1 is

##STR00018##

In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.f is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.f is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.f is substituted or unsubstituted aryl. In certain embodiments, R.sup.f is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.f is hydrogen. In certain embodiments, R.sup.f is substituted or unsubstituted acyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.1_s alkyl and R.sup.f is substituted or unsubstituted acyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.f is substituted or unsubstituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.f is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.f is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.f is substituted or unsubstituted aryl. In certain embodiments, R.sup.f is substituted or unsubstituted heteroaryl. In certain embodiments, there are two instances of R.sup.f and each is alkyl. In certain embodiments, there are two instances of R.sup.f and each is methyl. In certain embodiments, R.sup.1 is dimethylamine. In certain embodiments, two instances of R.sup.f are joined to form a substituted or unsubstituted heterocycle. In certain embodiments, R.sup.1 is a substituted or unsubstituted piperidine ring. In certain embodiments, R.sup.1 is a substituted or unsubstituted piperazine ring. In certain embodiments, R.sup.1 is a substituted or unsubstituted morpholine ring.

[0186] In certain embodiments, R.sup.1 is of Formula (V):

##STR00019##

In certain embodiments, R.sup.1 is —NH.sub.2. In certain embodiments, R.sup.1 is

##STR00020##

In certain embodiments, R.sup.1 is

##STR00021##

In certain embodiments, R.sup.1 is

##STR00022##

In certain embodiments, R.sup.1 is

##STR00023##

In certain embodiments, R.sup.1 is

##STR00024##

[0187] Formula (I) includes an aryl ring (Ar). In certain embodiments, the aryl ring is bicyclic or monocyclic aryl, or bicyclic or monocyclic heteroaryl. In certain embodiments, the aryl ring is monocyclic aryl. In certain embodiments, the aryl ring is substituted phenyl. In certain embodiments, the aryl ring is of the formula:

##STR00025##

wherein R.sup.2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, haloalkyl, methyl, optionally substituted heteroalkyl, trifluoromethyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.c, —NO2, —N(R.sup.c).sub.2, or —SR.sup.c, wherein R.sup.c is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, methyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or optionally, R.sup.2 can be joined with together with X1 to form an optionally substituted heterocyclic ring. In certain embodiments, the aryl ring is of the formula:

##STR00026##