COMPOSITIONS AND METHODS FOR INHIBITING RETICULON 4
20200062696 ยท 2020-02-27
Inventors
- Daniel K. Nomura (Berkeley, CA, US)
- James A. Olzmann (Oakland, CA, US)
- Leslie A. Bateman (Boston, MA, US)
- Truc B. Nguyen (Albany, CA, US)
- David K. Miyamoto (Cambridge, MA, US)
- Tucker R. Huffman (El Dorado Hills, CA, US)
- Allison M. Roberts (Kensington, CA, US)
Cpc classification
C07C233/09
CHEMISTRY; METALLURGY
A61K31/167
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07C233/27
CHEMISTRY; METALLURGY
C07D295/033
CHEMISTRY; METALLURGY
C07D295/104
CHEMISTRY; METALLURGY
International classification
C07C233/27
CHEMISTRY; METALLURGY
C07C233/09
CHEMISTRY; METALLURGY
C07D295/104
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
Abstract
Disclosed herein, inter alia, are compositions and methods useful for inhibiting reticulon 4 (RTN4).
Claims
1. A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound having the formula: ##STR00190## wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOC.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5; R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
2. The method of claim 1, wherein the compound has the formula: ##STR00191##
3. (canceled)
4. (canceled)
5. The method of claim 1, wherein the compound has the formula: ##STR00192##
6. (canceled)
7. The method of claim 1, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
8. (canceled)
9. The method of claim 1, wherein R.sup.1 is independently Cl.
10. The method of claim 1, wherein two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
11. (canceled)
12. The method of claim 1, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
13. (canceled)
14. The method of claim 1, wherein L.sup.1 is a bond.
15. The method of claim 1, wherein L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.
16. The method of claim 1, wherein L.sup.2 is NR.sup.5.
17. The method of claim 16, wherein R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
18. (canceled)
19. The method of claim 16, wherein R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl.
20. The method of claim 16, wherein R.sup.5 is hydrogen.
21. (canceled)
22. The method of claim 1, wherein E is: ##STR00193## R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B, NHC(O)NHNR.sup.15AR.sup.15B, NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2, CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, ONR.sup.16AR.sup.16B, NHC(O)NHNR.sup.16AR.sup.16B, NHC(O)NR.sup.16AR.sup.16B, N(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B, NHC(O)NHNR.sup.17AR.sup.17B, NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, are independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I; n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and m15, m16, and m17 are independently and integer from 1 to 2.
23. (canceled)
24. The method of claim 22, wherein E is: ##STR00194##
25. The method of claim 1, having the formula: ##STR00195##
26. The method of claim 1, wherein the cancer is colorectal cancer.
27. (canceled)
28. (canceled)
29. A pharmaceutical composition comprising a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient, wherein the Reticulon 4 inhibitor is a compound having the formula: ##STR00196## wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5; R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
30. (canceled)
31. (canceled)
32. A method inhibiting Reticulon 4 protein activity, said method comprising contacting a Reticulon 4 protein with an effective amount of a Reticulon 4 inhibitor, wherein said Reticulon 4 inhibitor is a compound having the formula: ##STR00197## wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5; R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
33. (canceled)
34. A reticulon 4 protein covalently bonded to a compound having the formula: ##STR00198## wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOC.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5; R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I; n1, n2, n4, and n5 are independently an integer from 0 to 4; and m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2; wherein the reticulon 4 protein is covalently bonded to said compound through said reacted electrophilic moiety.
35. (canceled)
36. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0017]
[0018]
[0019]
[0020]
[0021]
[0022]
[0023]
[0024]
[0025]
[0026]
[0027]
[0028]
[0029]
DETAILED DESCRIPTION
I. Definitions
[0030] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0031] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., CH.sub.2O is equivalent to OCH.sub.2.
[0032] The term alkyl, by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C.sub.1-C.sub.10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (O). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
[0033] The term alkylene, by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, CH.sub.2CH.sub.2CH.sub.2CH.sub.2. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A lower alkyl or lower alkylene is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term alkenylene, by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
[0034] The term heteroalkyl, by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, B, As, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2NHCH.sub.3, CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.3, CH.sub.2SCH.sub.2CH.sub.3, CH.sub.2CH.sub.2, S(O)CH.sub.3, CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, CHCHOCH.sub.3, Si(CH.sub.3).sub.3, CH.sub.2CHNOCH.sub.3, CHCHN(CH.sub.3)CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, and CN. Up to two or three heteroatoms may be consecutive, such as, for example, CH.sub.2NHOCH.sub.3 and CH.sub.2OSi(CH.sub.3).sub.3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
[0035] Similarly, the term heteroalkylene, by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, CH.sub.2CH.sub.2SCH.sub.2CH.sub.2 and CH.sub.2SCH.sub.2CH.sub.2NHCH.sub.2. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula C(O).sub.2R represents both C(O).sub.2R and RC(O).sub.2. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as C(O)R, C(O)NR, NRR, OR, SR, and/or SO.sub.2R. Where heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as NRR or the like, it will be understood that the terms heteroalkyl and NRR are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as NRR or the like.
[0036] The terms cycloalkyl and heterocycloalkyl, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of alkyl and heteroalkyl, respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A cycloalkylene and a heterocycloalkylene, alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
[0037] The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as haloalkyl are meant to include monohaloalkyl and polyhaloalkyl. For example, the term halo(C.sub.1-C.sub.4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0038] The term acyl means, unless otherwise stated, C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0039] The term aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An arylene and a heteroarylene, alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be O bonded to a ring heteroatom nitrogen.
[0040] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
[0041] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0042] The term oxo, as used herein, means an oxygen that is double bonded to a carbon atom.
[0043] The term alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:
##STR00002##
[0044] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, N.sub.3, CF.sub.3, CCl.sub.3, CBr.sub.3, CI.sub.3, CN, CHO, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.2CH.sub.3SO.sub.3H, OSO.sub.3H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, substituted or unsubstituted C.sub.1-C.sub.5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkyl aryl ene is unsubstituted.
[0045] Each of the above terms (e.g., alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0046] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, OR, O, NR, NOR, NRR, SR, -halogen, SiRRR, OC(O)R, C(O)R, CO.sub.2R, CONRR, OC(O)NRR, NRC(O)R, NRC(O)NRR, NRC(O).sub.2R, NRC(NRRR)NR, NRC(NRR)NR, S(O)R, S(O).sub.2R, S(O).sub.2NRR, NRSO.sub.2R, NRNRR, ONRR, NRC(O)NRNRR, CN, NO.sub.2, NRSO.sub.2R, NRC(O)R, NRC(O)OR, NROR, in a number ranging from zero to (2m+1), where m is the total number of carbon atoms in such radical. R, R, R, R, and R each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R, R, and R group when more than one of these groups is present. When R and R are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, NRR includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., CF.sub.3 and CH.sub.2CF.sub.3) and acyl (e.g., C(O)CH.sub.3, C(O)CF.sub.3, C(O)CH.sub.2OCH.sub.3, and the like).
[0047] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: OR, NRR, SR, -halogen, SiRRR, OC(O)R, C(O)R, CO.sub.2R, CONRR, OC(O)NRR, NRC(O)R, C(O)NRR, NRC(O).sub.2R, NRC(NRRR)NR, NRC(NRR)NR, S(O)R, S(O).sub.2R, S(O).sub.2NRR, NRSO.sub.2R, NRNRR, ONRR, NRC(O)NRNRR, CN, NO.sub.2, R, N.sub.3, CH(Ph).sub.2, fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, NRSO.sub.2R, NRC(O)R, NRC(O)OR, NROR, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R, R, and R are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R, R, R, and R groups when more than one of these groups is present.
[0048] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
[0049] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.
[0050] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)(CRR).sub.qU, wherein T and U are independently NR, O, CRR, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH.sub.2).sub.rB, wherein A and B are independently CRR, O, NR, S, S(O), S(O).sub.2, S(O).sub.2NR, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula (CRR), X(CRR).sub.d, where s and d are independently integers of from 0 to 3, and X is O, S, S(O), S(O).sub.2, or S(O).sub.2NR. The substituents R, R, R, and R are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
[0051] As used herein, the terms heteroatom or ring heteroatom are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
[0052] A substituent group, as used herein, means a group selected from the following moieties:
(A) oxo,
halogen, CCl.sub.3, CBr.sub.3, CF.sub.3, CI.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCCl.sub.3, OCF.sub.3, OCBr.sub.3, OCl.sub.3, OCHCl.sub.2, OCHBr.sub.2, OCHI.sub.2, OCHF.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.6 cycloalkyl, or C.sub.5-C.sub.6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C.sub.6-C.sub.10 aryl, C.sub.10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(i) oxo,
halogen, CCl.sub.3, CBr.sub.3, CF.sub.3, CI.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCCl.sub.3, OCF.sub.3, OCBr.sub.3, OCl.sub.3, OCHCl.sub.2, OCHBr.sub.2, OCHI.sub.2, OCHF.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.6 cycloalkyl, or C.sub.5-C.sub.6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C.sub.6-C.sub.10 aryl, C.sub.10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(a) oxo, halogen, CCl.sub.3, CBr.sub.3, CF.sub.3, CI.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCCl.sub.3, OCF.sub.3, OCBr.sub.3, OCl.sub.3, OCHCl.sub.2, OCH Br.sub.2, OCHI.sub.2, OCHF.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.6 cycloalkyl, or C.sub.5-C.sub.6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C.sub.6-C.sub.10 aryl, C.sub.10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,
halogen, CCl.sub.3, CBr.sub.3, CF.sub.3, CI.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCCl.sub.3, OCF.sub.3, OCBr.sub.3, OCl.sub.3, OCHCl.sub.2, OCHBr.sub.2, OCHI.sub.2, OCHF.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.6 cycloalkyl, or C.sub.5-C.sub.6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C.sub.6-C.sub.10 aryl, C.sub.10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0053] A size-limited substituent or size-limited substituent group, as used herein, means a group selected from all of the substituents described above for a substituent group, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C.sub.1-C.sub.20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C.sub.6-C.sub.10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[0054] A lower substituent or lower substituent group, as used herein, means a group selected from all of the substituents described above for a substituent group, wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C.sub.1-C.sub.8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C.sub.6-C.sub.10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
[0055] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
[0056] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C.sub.1-C.sub.20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C.sub.6-C.sub.10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C.sub.1-C.sub.20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C.sub.6-C.sub.10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
[0057] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C.sub.1-C.sub.8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C.sub.6-C.sub.10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C.sub.1-C.sub.8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C.sub.3-C.sub.7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C.sub.6-C.sub.10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.
[0058] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
[0059] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
[0060] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.
[0061] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different.
[0062] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R) or (S) or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0063] As used herein, the term isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0064] The term tautomer, as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
[0065] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
[0066] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
[0067] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by .sup.13C- or .sup.14C-enriched carbon are within the scope of this invention.
[0068] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by .sup.13C- or .sup.14C-enriched carbon are within the scope of this invention.
[0069] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (.sup.3H), iodine-125 (.sup.125I), or carbon-14 (.sup.14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[0070] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0071] Analog, or analogue is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called reference compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
[0072] The terms a or an, as used in herein means one or more. In addition, the phrase substituted with a[n], as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is substituted with an unsubstituted C.sub.1-C.sub.20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl, the group may contain one or more unsubstituted C.sub.1-C.sub.20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
[0073] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as R-substituted. Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R.sup.3 substituents are present, each R.sup.13 substituent may be distinguished as R.sup.13A, R.sup.13B, R.sup.13C, R.sup.13D, etc., wherein each of R.sup.13A, R.sup.13B, R.sup.13C, R.sup.13D, etc. is defined within the scope of the definition of R.sup.3 and optionally differently.
[0074] A covalent cysteine modifier moiety as used herein refers to a substituent that is capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g. cysteine corresponding to C1101 of the human reticulon 4) to form a covalent bond. Thus, the covalent cysteine modifier moiety is typically electrophilic.
[0075] Description of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
[0076] The term pharmaceutically acceptable salts is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0077] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, ()-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
[0078] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0079] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
[0080] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
[0081] Pharmaceutically acceptable excipient and pharmaceutically acceptable carrier refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[0082] The term preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0083] A Reticulon 4 inhibitor and RTN 4 inhibitor is a substance (e.g., oligonucleotide, protein, composition, or compound) that negatively affects (e.g. decreases) the activity or function of reticulon 4 relative to the activity or function of reticulon 4 in the absence of the inhibitor (e.g., wherein the reticulon 4 inhibitor binds reticulon 4). A reticulon 4 inhibitor compound or RTN 4 inhibitor compound or RTN 4 inhibitor compound refers to a compound (e.g. a compound described herein) that reduces the activity of reticulon 4 when compared to a control, such as absence of the compound or a compound with known inactivity. In embodiments, a Reticulon 4 inhibitor is a compound described herein.
[0084] The terms polypeptide, peptide and protein are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
[0085] A polypeptide, or a cell is recombinant when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.
[0086] An amino acid residue in a protein corresponds to a given residue when it occupies the same essential structural and/or spatial position within the protein as the given residue in a reference sequence. For example, a selected residue in a selected protein corresponds to Cys1101 when the selected residue occupies the same essential structural and/or spatial position as Cys1101 in SEQ ID NO:331. In some embodiments, where a selected protein is aligned for maximum homology with the human reticulon 4 protein, the position in the aligned selected protein aligning with Cys1101 is said to correspond to Cys1101. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the three dimensional structure of the selected protein is aligned for maximum correspondence with the human reticulon 4 protein (reference sequence) and the overall structures compared. In this case, the amino acid that occupies the same essential structural position as Cys1101 in the structural model relative to the reference sequence is said to correspond to the Cys1101 residue.
[0087] Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
[0088] The term contacting may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
[0089] As defined herein, the term activation, activate, activating and the like in reference to a protein-inhibitor interaction means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator. In embodiments activation means positively affecting (e.g. increasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the activator. The terms may reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
[0090] As defined herein, the term inhibition, inhibitor, inhibit, inhibiting and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
[0091] The terms reticulon 4 and RTN 4 and RTN4 refer to a protein (including homologs, isoforms, and functional fragments thereof) with reticulon 4 activity. The term includes any recombinant or naturally-occurring form of reticulon 4 or variants thereof that maintain reticulon 4 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype reticulon 4). In embodiments, the reticulon 4 protein encoded by the RTN 4 gene has the amino acid sequence set forth in or corresponding to Entrez 57142, UniProt Q9NQC3, or RefSeq (protein) NP_065393. In embodiments, the reticulon 4 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_020532. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In embodiments, the sequence corresponds to NP_065393.1. In embodiments, the sequence corresponds to NM_020532.4. In embodiments, the reticulon 4 is a human reticulon 4, such as a human cancer causing reticulon 4.
[0092] In embodiments, the RTN4 sequence corresponds to UniProt ID Q9NQC3, and has the sequence:
TABLE-US-00001 (SEQIDNO:331) MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLE ELEVLERKPAAGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPV APERQPSWDPSPVSSTVPAPSPLSAAAVSPSKLPEDDEPPARPPPPPPAS VSPQAEPVWTPPAPAPAAPPSTPAAPKRRGSSGSVDETLFALPAASEPVI RSSAENMDLKEQPGNTISAGQEDFPSVLLETAASLPSLSPLSAASFKEHE YLGNLSTVLPTEGTLQENVSEASKEVSEKAKTLLIDRDLTEFSELEYSEM GSSFSVSPKAESAVIVANPREEIIVKNKDEEEKLVSNNILHNQQELPTAL TKLVKEDEVVSSEKAKDSFNEKRVAVEAPMREEYADFKPFERVWEVKDSK EDSDMLAAGGKIESNLESKVDKKCFADSLEQTNHEKDSESSNDDTSFPST PEGIKDRSGAYITCAPFNPAATESIATNIFPLLGDPTSENKTDEKKIEEK KAQIVTEKNTSTKTSNPFLVAAQDSETDYVTTDNLTKVTEEVVANMPEGL TPDLVQEACESELNEVTGTKIAYETKMDLVQTSEVMQESLYPAAQLCPSF EESEATPSPVLPDIVMEAPLNSAVPSAGASVIQPSSSPLEASSVNYESIK HEPENPPPYEEAMSVSLKKVSGIKEEIKEPENINAALQETEAPYISIACD LIKETKLSAEPAPDFSDYSEMAKVEQPVPDHSELVEDSSPDSEPVDLFSD DSIPDVPQKQDETVMLVKESLTETSFESMIEYENKEKLSALPPEGGKPYL ESFKLSLDNTKDTLLPDEVSTLSKKEKIPLQMEELSTAVYSNDDLFISKE AQIRETETFSDSSPIETIDEFPTLISSKTDSFSKLAREYTDLEVSHKSEI ANAPDGAGSLPCTELPHDLSLKNIQPKVEEKISFSDDFSKNGSATSKVLL LPPDVSALATQAEIESIVKPKVLVKEAEKKLPSDTEKEDRSPSAIFSAEL SKTSVVDLLYWRDIKKTGVVFGASLELLLSLTVESIVSVTAYIALALLSV TISFRIYKGVIQAIQKSDEGHPFRAYLESEVAISEELVQKYSNSALGHVN CTIKELRRLFLVDDLVDSLKFAVLMWVFTYVGALFNGLTLLILALISLFS VPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE
[0093] In embodiments, the RTN4 sequence corresponds to UniProt ID Q6JRV0, and has the following sequence:
TABLE-US-00002 (SEQIDNO:332) MDEQSPDISSSHSGDERREPAQPGERKPWDDLDDVLDLTGGAGQFSQPFS GSHPARDIEEEEEDEEEERGAWKDSLEPSPVEEEPGSIDSISPVSPHSPA VPSAPMEEPERPPAPCTAPSGSVDENLFTLPAASAHLMHASADKIMEPYS TVSTGQEEFASVLLQSTASLSSLPSLSTDSSKEHAETVAFPTGLAATEAL QEPTDNMYSVSRITSHLPLSDNLESKALDQVKEEVIFSEKGYVVDHPTSQ QETISEEHAKLYSQSAKEMFSGMLQSVAPPHEEFTDIKEVYDPYVDFKPF MSSKSGDVGYEVSDVAEKFQVDVGRLNLESAVKHEEKSSEEMEIDSISDD ISPLTPELLPDSTDYDMFATVEQNIPFSFGGGHVAGNKTDEKKIEDIEAQ KTSVGFGLKVATVNPFYNESAQESEYVTTHVATHVSTKPEGPTPDIVQEA YESEAYDTGIPKQKYESNIDLVQTAANSVQEKVSPTAQAPARLEETDSVS SPVLPDIVMEAPLASALETVALKPDISPVGIKPPARVEKTKAEPEKPPSY EEAVTEVLQNQDLAAALGGSKQGAVVEETETPYISIACDLIKGTESVASG FTEFSKLKQNEFESQFMEPSDESSPDSECSEPSYKQWDSEVVQKEAFSIK TESVNAQSIIIPEQKQVFDQKSEESSPSKSYLDSFQPEICVSKATSDLFA KGLTTLLQEKPLQMEELDEGLSLEKIPCTKYSPVSESPEPRPSPVPEDLS SKLGDIQKEVLIAKQPEDKVQKNRSNLDFVPENTEFTPAVQKPDDSGKAV SDTFGGLDTTTKGGSAVHEVKVDKPKPPSKEDDGSKLPKKESKASTVSSS DFMNSVVDLIYWRDIKRSGVVFGASLFLLLSLSVFSIVSVLAYIALALLS VTISLRIYKGILQAIQKSEEGHPFRSILESNLAVPEDLVQKYCNVALNHV NCTVKELRHLFLVEDLVDSLKFAVLMWVFTYIGALFNGLTLLIVALISLF SIPVIYERHQTQVDHYLALVNKNLKSTSDLILSKVPGLKRKAE.
[0094] As observed in
TABLE-US-00003 (SEQIDNO:333) MGQVLPVFAHCKEAPSTASSTPDSTEGGNDDSDFRELHTAREFSEEDEET TSQDWGTPRELTFSYIAFDGVVGSGGRRDSTARRPRPQGRSVSEPRDQHP QPSLGDSLESIPSLSQSPEPGRRGDPDTAPPSERPLEDLRLRLDHLGWVA RGTGSGEDSSTSSSTPLEDEEPQEPNRLETGEAGEELDLRLRLAQPSSPE VLTPQLSPGSGTPQAGTPSPSRSRDSNSGPEEPLLEEEEKQWGPLEREPV RGQCLDSTDQLEFTVEPRLLGTAMEWLKTSLLLAVYKTVPILELSPPLWT AIGWVQRGPTPPTPVLRVLLKWAKSPRSSGVPSLSLGADMGSKVADLLYW KDTRTSGVVFTGLMVSLLCLLHFSIVSVAAHLALLLLCGTISLRVYRKVL QAVHRGDGANPFQAYLDVDLTLTREQTERLSHQITSRVVSAATQLRHFFL VEDLVDSLKLALLFYILTFVGAIFNGLTLLILGVIGLFTIPLLYRQHQAQ IDQYVGLVTNQLSHIKAKIRAKIPGTGALASAAAAVSGSKAKAE
[0095] As observed in
TABLE-US-00004 (SEQIDNO:334) MGQVLPVFAHCKEAPSTASSTPDSTEGGNDDSDFRELHTAREFSEEDEEE TTSQDWGTPRELTESYTAFDGVVGSGGRRDSTARRPRPQGRSVSEPRDQH PQPSLGDSLESIPSLSQSPEPGRRGDPDTAPPSERPLEDLRLRLDHLGWV ARGTGSGEDSSTSSSTPLEDEEPQEPNRLETGEAGEELDLRLRLAQPSSP EVLTPQLSPGSGTPQAGTPSPSRSRDSNSGPEEPLLEEEEKQWGPLEREP VRGQCLDSTDQLEFTVEPRLLVADLLYWKDTRTSGVVETGLMVSLLCLLH FSIVSVAAHLALLLLCGTISLRVYRKVLQAVHRGDGANPFQAYLDVDLTL TREQTERLSHQITSRVVSAATQLRHFELVEDLVDSLKLALLFYILTFVGA IENGLTLLILGVIGLETIPLLYRQHQAQIDQYVGLVTNQLSHIKAKIRAK IPGTGALASAAAAVSGSKAKAE
[0096] As observed in
TABLE-US-00005 (SEQIDNO:335) MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCADSF VSSSSSQPVSLFSTSQEGLSSLCSDEPSSEIMTSSFLSSSEIHNTGLTIL HGEKSHVLGSQPILAKEGKDHLDLLDMKKMEKPQGTSNNVSDSSVSLAAG VHCDRPSIPASFPEHPAFLSKKIGQVEEQIDKETKNPNGVSSREAKTALD ADDRFTLLTAQKPPTEYSKVEGIYTYSLSPSKVSGDDVIEKDSPESPFEV IIDKAAFDKEFKDSYKESTDDFGSWSVHTDKESSEDISETNDKLFPLRNK EAGRYPMSALLSRQFSHTNAALEEVSRCVNDMHNFTNEILTWDLVPQVKQ QTDKSSDCITKTTGLDMSEYNSEIPVVNLKTSTHQKTPVCSIDGSTPITK STGDWAEASLQQENAITGKPVPDSLNSTKEESIKGVQGNMQKQDDTLAEL PGSPPEKCDSLGSGVATVKVVLPDDHLKDEMDWQSSALGEITEADSSGES DDTVIEDITADTSFENNKIQAEKPVSIPSAVVKTGEREIKEIPSCEREEK TSKNFEELVSDSELHQDQPDILGRSPASEAACSKVPDTNVSLEDVSEVAP EKPITTENPKLPSTVSPNVFNETEFSLNVTTSAYLESLHGKNVKHIDDSS PEDLIAAFTETRDKGIVDSERNAFKAISEKMTDFKTTPPVEVLHENESGG SEIKDIGSKYSEQSKETNGSEPLGVFPTQGTPVASLDLEQEQLTIKALKE LGERQVEKSTSAQRDAELPSEEVLKQTFTFAPESWPQRSYDILERNVKNG SDLGISQKPITIRETTRVDAVSSLSKTELVKKHVLARLLTDFSVHDLIFW RDVKKTGFVFGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIYKSVI QAVQKSEEGHPFKAYLDVDITLSSEAFHNYMNAAMVHINRALKLIIRLFL VEDLVDSLKLAVFMWLMTYVGAVFNGITLLILAELLIFSVPIVYEKYKTQ IDHYVGIARDQTKSIVEKIQAKLPGIAKKKAE
[0097] As observed in
TABLE-US-00006 (SEQIDNO:336) MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCAEGL SSLCSDEPSSEIMTSSELSSSEIHNTGLTILHGEKSHVLGSQPILAKEGK DHLDLLDMKKMEKPQGTSNNVSDSSVSLAAGVHCDRPSIPASEPEHPAEL SKKIGQVEEQIDKETKNPNGVSSREAKTALDADDRFTLLTAQKPPTEYSK VEGIYTYSLSPSKVSGDDVIEKDSPESPFEVIIDKAAFDKEFKDSYKEST DDEGSWSVHTDKESSEDISETNDKLEPLRNKEAGRYPMSALLSRQFSHTN AALEEVSRCVNDMHNFTNEILTWDLVPQVKQQTDKSSDCITKTTGLDMSE YNSEIPVVNLKTSTHQKTPVCSIDGSTPITKSTGDWAEASLQQENAITGK PVPDSLNSTKEFSIKGVQGNMQKQDDTLAELPGSPPEKCDSLGSGVATVK VVLPDDHLKDEMDWQSSALGEITEADSSGESDDTVIEDITADTSFENNKI QAEKPVSIPSAVVKTGEREIKEIPSCEREEKTSKNFEELVSDSELHQDQP DILGRSPASEAACSKVPDTNVSLEDVSEVAPEKPITTENPKLPSTVSPNV FNETEFSLNVITSAYLESLHGKNVKHIDDSSPEDLIAAFTETRDKGIVDS ERNAFKAISEKMTDEKTIPPVEVLHENESGGSEIKDIGSKYSEQSKETNG SEPLGVEPTQGTPVASLDLEQEQLTIKALKELGERQVEKSTSAQRDAELP SEEVLKQTFTFAPESWPQRSYDILERNVKNGSDLGISQKPITIRETTRVD AVSSLSKTELVKKHVLARLLTDFSVHDLIFWRDVKKTGFVFGTTLIMLLS LAAFSVISVVSYLILALLSVTISFRIYKSVIQAVQKSEEGHPFKAYLDVD ITLSSEAFHNYMNAAMVHINRALKLIIRLFLVEDLVDSLKLAVFMWLMTY VGAVENGITLLILAELLIFSVPIVYEKYKTQIDHYVGIARDQTKSIVEKI QAKLPGIAKKKAE
[0098] As observed in
TABLE-US-00007 (SEQIDNO:337) MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCAVHD LIFWRDVKKTGFVFGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIY KSVIQAVQKSEEGHPFKAYLDVDITLSSEAFHNYMNAAMVHINRALKLII RLFLVEDLVDSLKLAVFMWLMTYVGAVFNGITLLILAELLIFSVPIVYEK YKTQIDHYVGIARDQTKSIVEKIQAKLPGIAKKKAE
[0099] As observed in
TABLE-US-00008 (SEQIDNO:338) MAAPGDPQDELLPLAGPGSQWLRHRGEGENEAVTPKGATPAPQAGEPSPG LGARAREAASREAGSGPARQSPVAMETASTGVAGVSSAMDHTFSTTSKDG EGSCYTSLISDICYPPQEDSTYFTGILQKENGHVTISESPEELGTPGPSL PDVPGIESRGLFSSDSGIEMTPAESTEVNKILADPLDQMKAEAYKYIDIT RPEEVKHQEQHHPELEDKDLDFKNKDTDISIKPEGVREPDKPAPVEGKII KDHLLEESTFAPYIDDLSEEQRRAPQITTPVKITLTEIEPSVETTTQEKT PEKQDICLKPSPDTVPTVTVSEPEDDSPGSITPPSSGTEPSAAESQGKGS ISEDELITAIKEAKGLSYETAENPRPVGQLADRPEVKARSGPPTIPSPLD HEASSAESGDSEIELVSEDPMAAEDALPSGYVSFGHVGGPPPSPASPSIQ YSILREEREAELDSELIIESCDASSASEESPKREQDSPPMKPSALDAIRE ETGVRAEERAPSRRGLAEPGSFLDYPSTEPQPGPELPPGDGALEPETPML PRKPEEDSSSNQSPAATKGPGPLGPGAPPPLLFLNKQKAIDLLYWRDIKQ TGIVEGSFLLLLFSLTQFSVVSVVAYLALAALSATISFRIYKSVLQAVQK TDEGHPFKAYLELEITLSQEQIQKYTDCLQFYVNSTLKELRRLFLVQDLV DSLKFAVLMWLLTYVGALFNGLTLLLMAVVSMFTLPVVYVKHQAQIDQYL GLVRTHINAVVAKIQAKIPGAKRHAE
[0100] As observed in
TABLE-US-00009 (SEQIDNO:339) MAAEDALPSGYVSFGHVGGPPPSPASPSIQYSILREEREAELDSELIIES CDASSASEESPKREQDSPPMKPSALDAIREETGVRAEERAPSRRGLAEPG SFLDYPSTEPQPGPELPPGDGALEPETPMLPRKPEEDSSSNQSPAATKGP GPLGPGAPPPLLFLNKQKAIDLLYWRDIKQTGIVEGSFLLLLFSLTQFSV VSVVAYLALAALSATISFRIYKSVLQAVQKTDEGHPFKAYLELEITLSQE QIQKYTDCLQFYVNSTLKELRRLFLVQDLVDSLKFAVLMWLLTYVGALFN GLTLLLMAVVSMFTLPVVYVKHQAQIDQYLGLVRTHINAVVAKIQAKIPG AKRHAE
[0101] As observed in
TABLE-US-00010 (SEQIDNO:340) MQATADSTKMDCVWSNWKSQATDLLYWRDIKQTGIVFGSFLLLLFSLTQF SVVSVVAYLALAALSATISFRIYKSVLQAVQKTDEGHPFKAYLELEITLS QEQIQKYTDCLQFYVNSTLKELRRLFLVQDLVDSLKFAVLMWLLTYVGAL FNGLTLLLMAVVSMFTLPVVYVKHQAQIDQYLGLVRTHINAVVAKIQAKI PGAKRHAE
[0102] As observed in
TABLE-US-00011 (SEQIDNO:341) MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLE ELEVLERKPAAGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPV APERQPSWDPSPVSSTVPAPSPLSAAAVSPSKLPEDDEPPARPPPPPPAS VSPQAEPVWTPPAPAPAAPPSTPAAPKRRGSSGSVDETLFALPAASEPVI RSSAENMDLKEQPGNTISAGQEDFPSVLLETAASLPSLSPLSAASEKEHE YLGNLSTVLPTEGTLQENVSEASKEVSEKAKTLLIDRDLTEFSELEYSEM GSSFSVSPKAESAVIVANPREEIIVKNKDEEEKLVSNNILHNQQELPTAL TKLVKEDEVVSSEKAKDSFNEKRVAVEAPMREEYADFKPFERVWEVKDSK EDSDMLAAGGKIESNLESKVDKKCFADSLEQTNHEKDSESSNDDTSFPST PEGIKDRSGAYITCAPFNPAATESIATNIFPLLGDPTSENKTDEKKIEEK KAQIVTEKNTSTKTSNPFLVAAQDSETDYVTTDNLTKVTEEVVANMPEGL TPDLVQEACESELNEVTGTKIAYETKMDLVQTSEVMQESLYPAAQLCPSF EESEATPSPVLPDIVMEAPLNSAVPSAGASVIQPSSSPLEASSVNYESIK HEPENPPPYEEAMSVSLKKVSGIKEEIKEPENINAALQETEAPYISIACD LIKETKLSAEPAPDFSDYSEMAKVEQPVPDHSELVEDSSPDSEPVDLFSD DSIPDVPQKQDETVMLVKESLTETSFESMIEYENKEKLSALPPEGGKPYL ESFKLSLDNTKDTLLPDEVSTLSKKEKIPLQMEELSTAVYSNDDLFISKE AQIRETETESDSSPIEIIDEFPTLISSKTDSFSKLAREYTDLEVSHKSEI ANAPDGAGSLPCTELPHDLSLKNIQPKVEEKISFSDDFSKNGSATSKVLL LPPDVSALATQAEIESIVKPKVLVKEAEKKLPSDTEKEDRSPSAIFSAEL SKTSVVDLLYWRDIKKTGVVFGASLELLLSLTVESIVSVTAYIALALLSV TISFRIYKGVIQATQKSDEGHPFRAYLESEVAISEELVQKYSNSALGHVN CTIKELRRLFLVDDLVDSLKFAVLMWVETYVGALENGLTLLILALISLFS VPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE
[0103] As observed in
TABLE-US-00012 (SEQIDNO:342) MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPEDEEEEEEEEEEDEDEDLE ELEVLERKPAAGLSAAPVPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPV APERQPSWDPSPVSSTVPAPSPLSAAAVSPSKLPEDDEPPARPPPPPPAS VSPQAEPVWTPPAPAPAAPPSTPAAPKRRGSSGSVVVDLLYWRDIKKTGV VFGASLFLLLSLIVESIVSVTAYIALALLSVTISFRIYKGVIQAIQKSDE GHPFRAYLESEVAISEELVQKYSNSALGHVNCTIKELRRLFLVDDLVDSL KFAVLMWVFTYVGALFNGLTLLILALISLFSVPVIYERHQAQIDHYLGLA NKNVKDAMAKIQAKIPGLKRKAE
[0104] As observed in
TABLE-US-00013 (SEQIDNO:343) MDGQKKNWKDKVVDLLYWRDIKKTGVVFGASLFLLLSLTVFSIVSVTAYI ALALLSVTISFRIYKGVIQAIQKSDEGHPFRAYLESEVAISEELVQKYSN SALGHVNCTIKELRRLFLVDDLVDSLKFAVLMWVFTYVGALFNGLTLLIL ALISLFSVPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE
[0105] The term expression includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
[0106] The terms disease or condition refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a cancer. The disease may be stroke. The disease may be an inflammatory disease. In some further instances, cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
[0107] As used herein, the term cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
[0108] The term leukemia refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.
[0109] The term sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
[0110] The term melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
[0111] The term carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.
[0112] As used herein, the term neurodegenerative disease refers to a disease or condition in which the function of a subject's nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Strussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff s disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or Tabes dorsalis.
[0113] The terms treating, or treatment refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term treating and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.
[0114] Patient or subject in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.
[0115] A effective amount is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an effective amount is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a therapeutically effective amount. A reduction of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A prophylactically effective amount of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An activity decreasing amount, as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A function disrupting amount, as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
[0116] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
[0117] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0118] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0119] As used herein, the term administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent.
[0120] Co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[0121] A cell as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
[0122] Control or control experiment is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
[0123] The term modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule. In some embodiments, a reticulon 4 associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with reticulon 4 (e.g. cancer). A reticulon 4 modulator is a compound that increases or decreases the activity or function or level of activity or level of function of reticulon 4.
[0124] The term modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. Modulation refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
[0125] The term associated or associated with in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease, a cancer associated with reticulon 4 activity, reticulon 4 associated cancer, reticulon 4 associated disease) means that the disease (e.g. cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or inpart) the substance or substance activity or function. For example, a cancer associated with reticulon 4 activity or function may be a cancer that results (entirely or partially) from aberrant reticulon 4 function (e.g. enzyme activity, protein-protein interaction, signaling pathway) or a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant reticulon 4 activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a cancer associated with reticulon 4 activity or function or a reticulon 4 associated cancer, may be treated with a reticulon 4 modulator or reticulon 4 inhibitor, in the instance where reticulon 4 activity or function (e.g. signaling pathway activity) causes the cancer.
[0126] The term aberrant as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
[0127] The term signaling pathway as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components. For example, binding of a reticulon 4 protein with a compound as described herein may reduce the interactions between the reticulon 4 protein and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival.
[0128] The term electrophilic chemical moiety is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is electrophilic.
[0129] The term nucleophilic chemical moiety is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is nucleophilic.
[0130] Nucleic acid refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof. The terms polynucleotide, oligonucleotide, oligo or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term nucleotide refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term duplex in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.
[0131] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide through a covalent, non-covalent or other interaction.
[0132] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, O
[0133] Nucleic acids can include nonspecific sequences. As used herein, the term nonspecific sequence refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.
[0134] An antisense nucleic acid as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g. single stranded morpholino oligo), or interfering with the endogenous activity of the target nucleic acid. See, e.g., Weintraub, Scientific American, 262:40 (1990). Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) are generally between 15 and 25 bases in length. Thus, antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331). In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in vitro. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in a cell. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) in an organism. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) under physiological conditions. Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides.
[0135] In the cell, the antisense nucleic acids hybridize to the corresponding RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) forming a double-stranded molecule. The antisense nucleic acids interfere with the endogenous behavior of the RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331) and inhibit its function relative to the absence of the antisense nucleic acid. Furthermore, the double-stranded molecule may be degraded via the RNAi pathway. The use of antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)). Further, antisense molecules which bind directly to the DNA may be used. Antisense nucleic acids may be single or double stranded nucleic acids. Non-limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre-cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors.
[0136] The term complement, as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.
[0137] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).
[0138] The term antibody refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
[0139] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one light (about 25 kDa) and one heavy chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable heavy chain, V.sub.H, or VH refer to the variable region of an immunoglobulin heavy chain, including an Fv, scFv, dsFv or Fab; while the terms variable light chain, V.sub.L or VL refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv, dsFv or Fab.
[0140] Examples of antibody functional fragments include, but are not limited to, complete antibody molecules, antibody fragments, such as Fv, single chain Fv (scFv), complementarity determining regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2 and any combination of those or any other functional portion of an immunoglobulin peptide capable of binding to target antigen (see, e.g., F
[0141] Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
[0142] The terms identical or percent identity, in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like). Such sequences are then said to be substantially identical. This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
[0143] The term irreversible covalent bond is used in accordance with its plain ordinary meaning in the art and refers to the resulting association between atoms or molecules of (e.g., electrophilic chemical moiety and nucleophilic moiety) wherein the probability of dissociation is low. In embodiments, the irreversible covalent bond does not easily dissociate under normal biological conditions. In embodiments, the irreversible covalent bond is formed through a chemical reaction between two species (e.g., electrophilic chemical moiety and nucleophilic moiety).
[0144] Anti-cancer agent and anticancer agent are used in accordance with their plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; top sentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II, or r1L.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol (i.e. paclitaxel), Taxotere, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, ()-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Gurin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to .sup.111In, .sup.90Y or .sup.131I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa), erlotinib (Tarceva), cetuximab (Erbitux), lapatinib (Tykerb), panitumumab (Vectibix), vandetanib (Caprelsa), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like.
[0145] The term reticulon 4 activity as used herein refers to the biological activity of the protein. In embodiments, reticulon 4 activity includes endoplasmic reticulum (ER) tubule formation. Reticulon 4 activity may be quantified by measuring tubular ER network formation, ER morphology, mitosis rate, nuclear envelope assembly, nuclear envelope disassembly, or cell death.
[0146] The term reticulon 4 protein-reticulon 4 inhibitor complex as used herein refers to a reticulon 4 protein bonded (e.g., covalently bonded) to a Reticulon 4 inhibitor (e.g., a compound described herein).
II. Compounds
[0147] In an aspect is provided a compound having the formula:
##STR00003##
[0148] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0149] Two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0150] The symbol z1 is an integer from 0 to 5.
[0151] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(OR.sup.2CC(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0152] Two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0153] The symbol z2 is an integer from 0 to 4.
[0154] L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene.
[0155] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0156] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene.
[0157] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0158] E is an electrophilic moiety.
[0159] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0160] R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0161] Each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I.
[0162] The symbols n1, n2, n4, and n5 are independently an integer from 0 to 4.
[0163] The symbols m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
[0164] In embodiments, the compound has the formula:
##STR00004##
R.sup.1, R.sup.2, L.sup.1, L.sup.2, E, z1 and z2 are as described herein.
[0165] In embodiments, the compound has the formula:
##STR00005##
R.sup.1, R.sup.2, L.sup.1, L.sup.2, and E are as described herein.
[0166] In embodiments, the compound has the formula:
##STR00006##
R.sup.1, L.sup.1, L.sup.2, and E are as described herein.
[0167] In embodiments, the compound has the formula:
##STR00007##
R.sup.1, L.sup.1, L.sup.2, and E are as described herein.
[0168] In embodiments, the compound has the formula:
##STR00008##
R.sup.1, R.sup.4, L.sup.2, and E are as described herein.
[0169] In embodiments, the compound has the formula:
##STR00009##
R.sup.4, L.sup.2, and E are as described herein.
[0170] In embodiments, the compound has the formula:
##STR00010##
R.sup.1, R.sup.4, L.sup.2, and E are as described herein.
[0171] In embodiments, the compound has the formula:
##STR00011##
R.sup.1, R.sup.5, L.sup.1, and E are as described herein.
[0172] In embodiments, the compound has the formula:
##STR00012##
R.sup.5, L.sup.1, and E are as described herein.
[0173] In embodiments, the compound has the formula:
##STR00013##
R.sup.1, L.sup.2, and E are as described herein.
[0174] In embodiments, the compound has the formula:
##STR00014##
wherein R.sup.20, L.sup.1, L.sup.2, and E are as described herein; two adjacent R.sup.1 substituents form Ring A, wherein Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. The symbol z20 is an integer from 0 to 8.
[0175] In embodiments, the compound has the formula:
##STR00015##
wherein R.sup.20, z20, L.sup.1, L.sup.2, and E are as described herein.
[0176] In embodiments, the compound has the formula:
##STR00016##
wherein R.sup.20, z20, L.sup.1, L.sup.2, and E are as described herein.
[0177] In embodiments, the compound has the formula:
##STR00017##
wherein R.sup.20, z20, L.sup.1, L.sup.2, and E are as described herein.
[0178] In embodiments, the compound has the formula:
##STR00018##
L.sup.1, L.sup.2, and E are as described herein.
[0179] In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SR.sup.1D, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0180] In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
[0181] In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0182] In embodiments, two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
[0183] In embodiments, R.sup.1 is independently Cl. In embodiments, R.sup.1 is independently halogen. In embodiments, R.sup.1 is independently unsubstituted methyl. In embodiments, R.sup.1 is independently unsubstituted ethyl. In embodiments, R.sup.1 is independently unsubstituted propyl. In embodiments, R.sup.1 is independently unsubstituted isopropyl. In embodiments, R.sup.1 is independently unsubstituted n-propyl. In embodiments, R.sup.1 is independently unsubstituted butyl. In embodiments, R.sup.1 is independently unsubstituted n-butyl. In embodiments, R.sup.1 is independently unsubstituted t-butyl. In embodiments, R.sup.1 is independently unsubstituted pentyl. In embodiments, R.sup.1 is independently unsubstituted n-pentyl. In embodiments, R.sup.1 is independently unsubstituted hexyl. In embodiments, R.sup.1 is independently unsubstituted n-hexyl. In embodiments, R.sup.1 is independently unsubstituted heptyl. In embodiments, R.sup.1 is independently unsubstituted n-heptyl. In embodiments, R.sup.1 is independently unsubstituted octyl. In embodiments, R.sup.1 is independently unsubstituted n-octyl. In embodiments, R.sup.1 is independently unsubstituted benzyl. In embodiments, R.sup.1 is independently unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.1 is independently halo-substituted methyl. In embodiments, R.sup.1 is independently halo-substituted ethyl. In embodiments, R.sup.1 is independently halo-substituted isopropyl. In embodiments, R.sup.1 is independently halo-substituted n-propyl. In embodiments, R.sup.1 is independently halo-substituted n-butyl. In embodiments, R.sup.1 is independently halo-substituted t-butyl. In embodiments, R.sup.1 is independently halo-substituted n-pentyl. In embodiments, R.sup.1 is independently halo-substituted benzyl. In embodiments, R.sup.1 is independently halo-substituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 7 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted 7 to 9 membered heteroalkyl.
[0184] In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.4-C.sub.6 cycloalkyl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.5 cycloalkyl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.5-C.sub.6 cycloalkyl. In embodiments, two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.4 cycloalkyl.
[0185] In embodiments, R.sup.1 is independently unsubstituted 5 membered heteroaryl. In embodiments, R.sup.1 is independently unsubstituted 6 membered heteroaryl. In embodiments, R.sup.1 is independently unsubstituted pyridyl. In embodiments, R.sup.1 is independently unsubstituted 2-pyridyl. In embodiments, R.sup.1 is independently unsubstituted 3-pyridyl. In embodiments, R.sup.1 is independently unsubstituted 4-pyridyl. In embodiments, R.sup.1 is independently unsubstituted pyridazinyl. In embodiments, R.sup.1 is independently unsubstituted pyrimidinyl. In embodiments, R.sup.1 is independently unsubstituted pyrazinyl. In embodiments, R.sup.1 is independently unsubstituted triazinyl. In embodiments, R.sup.1 is independently unsubstituted pyrrolyl. In embodiments, R.sup.1 is independently unsubstituted 2-pyrrolyl. In embodiments, R.sup.1 is independently unsubstituted 3-pyrrolyl. In embodiments, R.sup.1 is independently unsubstituted furanyl. In embodiments, R.sup.1 is independently unsubstituted 2-furanyl. In embodiments, R.sup.1 is independently unsubstituted 3-furanyl. In embodiments, R.sup.1 is independently unsubstituted thienyl. In embodiments, R.sup.1 is independently unsubstituted 2-thienyl. In embodiments, R.sup.1 is independently unsubstituted 3-thienyl. In embodiments, R.sup.1 is independently unsubstituted pyrazolyl. In embodiments, R.sup.1 is independently unsubstituted isoxazolyl. In embodiments, R.sup.1 is independently unsubstituted isothiazolyl. In embodiments, R.sup.1 is independently unsubstituted imidazolyl. In embodiments, R.sup.1 is independently unsubstituted oxazolyl. In embodiments, R.sup.1 is independently unsubstituted thiazolyl. In embodiments, R.sup.1 is independently unsubstituted phenyl. In embodiments, R.sup.1 is independently unsubstituted biphenyl. In embodiments, R.sup.1 is independently unsubstituted 2-biphenyl. In embodiments, R.sup.1 is independently unsubstituted 3-biphenyl. In embodiments, R.sup.1 is independently unsubstituted 4-biphenyl.
[0186] In embodiments, R.sup.1 is independently CX.sup.1.sub.3. In embodiments, R.sup.1 is independently CHX.sup.1.sub.2. In embodiments, R.sup.1 is independently CH.sub.2X.sup.1. In embodiments, R.sup.1 is independently OCX.sup.1.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2X.sup.1. In embodiments, R.sup.1 is independently OCHX.sup.1.sub.2. In embodiments, R.sup.1 is independently CN. In embodiments, R.sup.1 is independently SO.sub.n1R.sup.1D. In embodiments, R.sup.1 is independently SO.sub.v1NR.sup.1AR.sup.1B. In embodiments, R.sup.1 is independently NHC(O)NR.sup.1AR.sup.1B. In embodiments, R.sup.1 is independently N(O).sub.m1. In embodiments, R.sup.1 is independently NR.sup.1AR.sup.1B. In embodiments, R.sup.1 is independently C(O)R.sup.1C. In embodiments, R.sup.1 is independently C(O)OR.sup.1C. In embodiments, R.sup.1 is independently C(O)NR.sup.1AR.sup.1B. In embodiments, R.sup.1 is independently OR.sup.1D. In embodiments, R.sup.1 is independently NR.sup.1ASO.sub.2R.sup.1D. In embodiments, R.sup.1 is independently NR.sup.1AC(O)R.sup.1C. In embodiments, R.sup.1 is independently NR.sup.1AC(O)OR.sup.1C. In embodiments, R.sup.1 is independently NR.sup.1AOR.sup.1C. In embodiments, R.sup.1 is independently OH. In embodiments, R.sup.1 is independently NH.sub.2. In embodiments, R.sup.1 is independently COOH. In embodiments, R.sup.1 is independently CONH.sub.2. In embodiments, R.sup.1 is independently NO.sub.2. In embodiments, R.sup.1 is independently SH. In embodiments, R.sup.1 is independently halogen. In embodiments, R.sup.1 is independently F. In embodiments, R.sup.1 is independently Cl. In embodiments, R.sup.1 is independently Br. In embodiments, R.sup.1 is independently I. In embodiments, R.sup.1 is independently CF.sub.3. In embodiments, R.sup.1 is independently CHF.sub.2. In embodiments, R.sup.1 is independently CH.sub.2F. In embodiments, R.sup.1 is independently OCF.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2F. In embodiments, R.sup.1 is independently OCHF.sub.2. In embodiments, R.sup.1 is independently OCH.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently OCH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently OC(CH.sub.3).sub.3. In embodiments, R.sup.1 is independently SCH.sub.3. In embodiments, R.sup.1 is independently SCH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently SCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently SCH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently SC(CH.sub.3).sub.3. In embodiments, R.sup.1 is independently CH.sub.3. In embodiments, R.sup.1 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently C(CH.sub.3).sub.3.
[0187] In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0188] In embodiments, R.sup.1 is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1 is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1 is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1 is independently unsubstituted methyl. In embodiments, R.sup.1 is independently unsubstituted ethyl. In embodiments, R.sup.1 is independently unsubstituted propyl. In embodiments, R.sup.1 is independently unsubstituted isopropyl. In embodiments, R.sup.1 is independently unsubstituted tert-butyl. In embodiments, R.sup.1 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1 is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1 is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1 is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1 is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1 is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0189] In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0190] In embodiments, R.sup.1A is independently hydrogen. In embodiments, R.sup.1A is independently CX.sup.1A.sub.3. In embodiments, R.sup.1A is independently CHX.sup.1A.sub.2. In embodiments, R.sup.1A is independently CH.sub.2X.sup.1A. In embodiments, R.sup.1A is independently CN. In embodiments, R.sup.1A is independently COOH. In embodiments, R.sup.1A is independently CONH.sub.2. In embodiments, X.sup.1A is independently F, Cl, Br, or I.
[0191] In embodiments, R.sup.1A is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1A is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1A is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1A is independently unsubstituted methyl. In embodiments, R.sup.1A is independently unsubstituted ethyl. In embodiments, R.sup.1A is independently unsubstituted propyl. In embodiments, R.sup.1A is independently unsubstituted isopropyl. In embodiments, R.sup.1A is independently unsubstituted tert-butyl. In embodiments, R.sup.1A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1A is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1A is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1A is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1A is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1A is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0192] In embodiments, R.sup.1B is independently hydrogen. In embodiments, R.sup.1B is independently CX.sup.1B.sub.3. In embodiments, R.sup.1B is independently CHX.sup.1B.sub.2. In embodiments, R.sup.1B is independently CH.sub.2X.sup.1B. In embodiments, R.sup.1B is independently CN. In embodiments, R.sup.1B is independently COOH. In embodiments, R.sup.1B is independently CONH.sub.2. In embodiments, X.sup.1B is independently F, Cl, Br, or I.
[0193] In embodiments, R.sup.1B is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1B is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1B is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1B is independently unsubstituted methyl. In embodiments, R.sup.1B is independently unsubstituted ethyl. In embodiments, R.sup.1B is independently unsubstituted propyl. In embodiments, R.sup.1B is independently unsubstituted isopropyl. In embodiments, R.sup.1B is independently unsubstituted tert-butyl. In embodiments, R.sup.1B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1B is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1B is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1B is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1B is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1B is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0194] In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0195] In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0196] In embodiments, R.sup.1C is independently hydrogen. In embodiments, R.sup.1C is independently CX.sup.1C.sub.3. In embodiments, R.sup.1C is independently CHX.sup.1C.sub.2. In embodiments, R.sup.1C is independently CH.sub.2X.sup.1C. In embodiments, R.sup.1C is independently CN. In embodiments, R.sup.1C is independently COOH. In embodiments, R.sup.1C is independently CONH.sub.2. In embodiments, X.sup.1C is independently F, Cl, Br, or I.
[0197] In embodiments, R.sup.1C is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1C is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1C is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1C is independently unsubstituted methyl. In embodiments, R.sup.1C is independently unsubstituted ethyl. In embodiments, R.sup.1C is independently unsubstituted propyl. In embodiments, R.sup.1C is independently unsubstituted isopropyl. In embodiments, R.sup.1C is independently unsubstituted tert-butyl. In embodiments, R.sup.1C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1C is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1C is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1C is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1C is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1C is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0198] In embodiments, R.sup.1D is independently hydrogen. In embodiments, R.sup.1D is independently CX.sup.1D.sub.3. In embodiments, R.sup.1D is independently CHX.sup.1D.sub.2. In embodiments, R.sup.1D is independently CH.sub.2X.sup.1D. In embodiments, R.sup.1D is independently CN. In embodiments, R.sup.1D is independently COOH. In embodiments, R.sup.1D is independently CONH.sub.2. In embodiments, X.sup.1C is independently F, Cl, Br, or I.
[0199] In embodiments, R.sup.1D is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1D is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1D is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.1D is independently unsubstituted methyl. In embodiments, R.sup.1D is independently unsubstituted ethyl. In embodiments, R.sup.1D is independently unsubstituted propyl. In embodiments, R.sup.1D is independently unsubstituted isopropyl. In embodiments, R.sup.1D is independently unsubstituted tert-butyl. In embodiments, R.sup.1D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.1D is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1D is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1D is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.1D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1D is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1D is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.1D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0200] In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.20-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.1 is independently F, Cl, Br, or I. In embodiments, R.sup.1 is independently hydrogen. In embodiments, R.sup.1 is independently unsubstituted methyl. In embodiments, R.sup.1 is independently unsubstituted ethyl. In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.20-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0201] In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form a R.sup.20-substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.1 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0202] R.sup.20 is independently oxo,
halogen, CX.sup.20.sub.3, CHX.sup.20.sub.2, CH.sub.2X.sup.20, OCX.sup.20.sub.3, OCH.sub.2X.sup.20, OCHX.sup.20.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.21-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.21-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.21-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.21-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.21-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.21-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.20 is independently oxo,
halogen, CX.sup.20.sub.3, CHX.sup.20.sub.2, CH.sub.2X.sup.20, OCX.sup.20.sub.3, OCH.sub.2X.sup.20, OCHX.sup.20.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O) NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.20 is independently F, Cl, Br, or I. In embodiments, R.sup.20 is independently unsubstituted methyl. In embodiments, R.sup.20 is independently unsubstituted ethyl.
[0203] R.sup.21 is independently oxo,
halogen, CX.sup.21.sub.3, CHX.sup.21.sub.2, CH.sub.2X.sup.21, OCX.sup.21.sub.3, OCH.sub.2X.sup.21, OCHX.sup.21.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.22-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.22-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.22-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.22-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.22-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.22-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.21 is independently oxo,
halogen, CX.sup.21.sub.3, CHX.sup.21.sub.2, CH.sub.2X.sup.21, OCX.sup.21.sub.3, OCH.sub.2X.sup.21, OCHX.sup.21.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.21 is independently F, Cl, Br, or I. In embodiments, R.sup.21 is independently unsubstituted methyl. In embodiments, R.sup.21 is independently unsubstituted ethyl.
[0204] R.sup.22 is independently oxo,
halogen, CX.sup.22.sub.3, CHX.sup.22.sub.2, CH.sub.2X.sup.22, OCX.sup.22.sub.3, OCH.sub.2X.sup.22, OCHX.sup.22.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.22 is independently F, Cl, Br, or I. In embodiments, R.sup.22 is independently unsubstituted methyl. In embodiments, R.sup.22 is independently unsubstituted ethyl.
[0205] In embodiments, R.sup.1A is independently
hydrogen, CX.sup.1A.sub.3, CHX.sup.1A.sub.2, CH.sub.2X.sup.1A, CN, COOH, CONH.sub.2, R.sup.20A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A is independently hydrogen, CX.sup.1A.sub.3, CHX.sup.1A.sub.2, CH.sub.2X.sup.1A, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.1A is independently F, Cl, Br, or I. In embodiments, R.sup.1A is independently hydrogen. In embodiments, R.sup.1A is independently unsubstituted methyl. In embodiments, R.sup.1A is independently unsubstituted ethyl.
[0206] In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.20A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.20A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.20A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0207] R.sup.20A is independently oxo,
halogen, CX.sup.20A.sub.3, CHX.sup.20A.sub.2, CH.sub.2X.sup.20A, OCX.sup.20A.sub.3, OCH.sub.2X.sup.20A, OCHX.sup.20A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.21A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.21A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.21A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.21A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.21A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.21A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.20A is independently oxo, halogen, CX.sup.20A.sub.3, CHX.sup.20A.sub.2, CH.sub.2X.sup.20A, OCX.sup.20A.sub.3, OCH.sub.2X.sup.20A, OCHX.sup.20A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.20A is independently F, Cl, Br, or I. In embodiments, R.sup.20A is independently unsubstituted methyl. In embodiments, R.sup.20A is independently unsubstituted ethyl.
[0208] R.sup.21A is independently oxo,
halogen, CX.sup.21A.sub.3, CHX.sup.21A.sub.2, CH.sub.2X.sup.21A, OCX.sup.21A.sub.3, OCH.sub.2X.sup.21A, OCHX.sup.21A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.22A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.22A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.22A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.22A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.22A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.22A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.21A is independently oxo,
halogen, CX.sup.21A.sub.3, CHX.sup.21A.sub.2, CH.sub.2X.sup.21A, OCX.sup.21A.sub.3, OCH.sub.2X.sup.21A, OCHX.sup.21A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.21A is independently F, Cl, Br, or I. In embodiments, R.sup.21A is independently unsubstituted methyl. In embodiments, R.sup.21A is independently unsubstituted ethyl.
[0209] R.sup.22A is independently oxo,
halogen, CX.sup.22A.sub.3, CHX.sup.22A.sub.2, CH.sub.2X.sup.22A, OCX.sup.22A.sub.3, OCH.sub.2X.sup.22A, OCHX.sup.22A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.22A is independently F, Cl, Br, or I. In embodiments, R.sup.22A is independently unsubstituted methyl. In embodiments, R.sup.22A is independently unsubstituted ethyl.
[0210] In embodiments, R.sup.1B is independently hydrogen, CX.sup.1B.sub.3, CHX.sup.1B.sub.2, CH.sub.2X.sup.1B, CN, COOH, CONH.sub.2, R.sup.20B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1B is independently hydrogen, CX.sup.1B.sub.3, CHX.sup.1B.sub.2, CH.sub.2X.sup.1B, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.1B is independently F, Cl, Br, or I. In embodiments, R.sup.1B is independently hydrogen. In embodiments, R.sup.1B is independently unsubstituted methyl. In embodiments, R.sup.1B is independently unsubstituted ethyl.
[0211] In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.20B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.20B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.20B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0212] R.sup.20B is independently oxo,
halogen, CX.sup.20B.sub.3, CHX.sup.20B.sub.2, CH.sub.2X.sup.20B, OXC.sup.20B.sub.3, OCH.sub.2X.sup.20B.sub.3, OCHX.sup.20B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.21B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.21B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.21B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.21B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.21B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.21B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.20B is independently oxo,
halogen, CX.sup.20B.sub.3, CHX.sup.20B.sub.2, CH.sub.2X.sup.20B, OCX.sup.20B.sub.3, OCH.sub.2X.sup.20B, OCHX.sup.20B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.20B is independently F, Cl, Br, or I. In embodiments, R.sup.20B is independently unsubstituted methyl. In embodiments, R.sup.20B is independently unsubstituted ethyl.
[0213] R.sup.21B is independently oxo,
halogen, CX.sup.21B.sub.3, CHX.sup.21B.sub.2, CH.sub.2X.sup.21B, OCX.sup.21B.sub.3, OCH.sub.2X.sup.21B, OCHX.sup.21B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.22B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.22B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.22B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.22B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.22B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.22B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.21B is independently oxo,
halogen, CX.sup.21B.sub.3, CHX.sup.21B.sub.2, CH.sub.2X.sup.21B, OCX.sup.21B.sub.3, OCH.sub.2X.sup.21B, OCHX.sup.21B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.21B is independently F, Cl, Br, or I. In embodiments, R.sup.21B is independently unsubstituted methyl. In embodiments, R.sup.21B is independently unsubstituted ethyl.
[0214] R.sup.22B is independently oxo,
halogen, CX.sup.22B.sub.3, CHX.sup.22B.sub.2, CH.sub.2X.sup.22B, OCX.sup.22B.sub.3, OCH.sub.2X.sup.22B, OCHX.sup.22B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.22B is independently F, Cl, Br, or I. In embodiments, R.sup.22B is independently unsubstituted methyl. In embodiments, R.sup.22B is independently unsubstituted ethyl.
[0215] In embodiments, R.sup.1C is independently hydrogen, CX.sup.1C.sub.3, CHX.sup.1C.sub.2, CH.sub.2X.sup.1C, CN, COOH, CONH.sub.2, R.sup.20C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1C is independently hydrogen, CX.sup.1C.sub.3, CHX.sup.1C.sub.2, CH.sub.2X.sup.1C, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.1C is independently F, Cl, Br, or I. In embodiments, R.sup.1C is independently hydrogen. In embodiments, R.sup.1C is independently unsubstituted methyl. In embodiments, R.sup.1C is independently unsubstituted ethyl.
[0216] R.sup.20C is independently oxo,
halogen, CX.sup.20C.sub.3, CHX.sup.2n, CH.sub.2X.sup.20C, OCX.sup.2n, OCH.sub.2X.sup.20C, OCHX.sup.20C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.21C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.21C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.21C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.21C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.21C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.21C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.20C is independently oxo,
halogen, CX.sup.20C.sub.3, CHX.sup.20C.sub.2, CH.sub.2X.sup.20C, OCX.sup.20C.sub.3, OCH.sub.2X.sup.20C, OCHX.sup.20C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.20C is independently F, Cl, Br, or I. In embodiments, R.sup.20C is independently unsubstituted methyl. In embodiments, R.sup.20C is independently unsubstituted ethyl.
[0217] R.sup.21C is independently oxo,
halogen, CX.sup.21C.sub.3, CHX.sup.21C.sub.2, CH.sub.2X.sup.21C, OCX.sup.21C.sub.3, OCH.sub.2X.sup.21C, OCHX.sup.21C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.22C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.22C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.22C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.22C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.22C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.22C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.21C is independently oxo,
halogen, CX.sup.21C.sub.3, CHX.sup.21C.sub.2, CH.sub.2X.sup.21C, OCX.sup.21C.sub.3, OCH.sub.2X.sup.21C, OCHX.sup.21C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.21C is independently F, Cl, Br, or I. In embodiments, R.sup.21C is independently unsubstituted methyl. In embodiments, R.sup.21C is independently unsubstituted ethyl.
[0218] R.sup.22C is independently oxo,
halogen, CX.sup.22C.sub.3, CHX.sup.22C.sub.2, CH.sub.2X.sup.22C, OCX.sup.22C.sub.3, OCH.sub.2X.sup.22C, OCHX.sup.22C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.22C is independently F, Cl, Br, or I. In embodiments, R.sup.22C is independently unsubstituted methyl. In embodiments, R.sup.22C is independently unsubstituted ethyl.
[0219] In embodiments, R.sup.1D is independently hydrogen, CX.sup.1D.sub.3, CHX.sup.1D.sub.2, CH.sub.2X.sup.1D, CN, COOH, CONH.sub.2, R.sup.20D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.20D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.20D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.20D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.20D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.20D-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.1D is independently hydrogen, CX.sup.1D.sub.3, CHX.sup.1D.sub.2, CH.sub.2X.sup.1D, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.1D is independently F, Cl, Br, or I. In embodiments, R.sup.1D is independently hydrogen. In embodiments, R.sup.1D is independently unsubstituted methyl. In embodiments, R.sup.1D is independently unsubstituted ethyl.
[0220] R.sup.20D is independently oxo,
halogen, CX.sup.20D.sub.3, CHX.sup.20D.sub.2, CH.sub.2X.sup.20D, OCX.sup.20D.sub.3, OCH.sub.2X.sup.20D, OCHX.sup.20D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.21D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.21D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.21D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.21D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.21D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.21D substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.20D is independently oxo,
halogen, CX.sup.20D.sub.3, CHX.sup.20D.sub.2, CH.sub.2X.sup.20D, OCX.sup.20D.sub.3, OCH.sub.2X.sup.20D, OCHX.sup.20D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.20D is independently F, Cl, Br, or I. In embodiments, R.sup.20D is independently unsubstituted methyl. In embodiments, R.sup.20D is independently unsubstituted ethyl.
[0221] R.sup.21D is independently oxo,
halogen, CX.sup.21D.sub.3, CHX.sup.21D.sub.2, CH.sub.2X.sup.21D, OCX.sup.21D.sub.3, OCH.sub.2X.sup.21D, OCHX.sup.21D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.22D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.22D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.22D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.22D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.22D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.22D-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.21D is independently oxo,
halogen, CX.sup.21D.sub.3, CHX.sup.21D.sub.2, CH.sub.2X.sup.21D, OCX.sup.21D.sub.3, OCH.sub.2X.sup.21D, OCHX.sup.21D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.21D is independently F, Cl, Br, or I. In embodiments, R.sup.21D is independently unsubstituted methyl. In embodiments, R.sup.21D is independently unsubstituted ethyl.
[0222] R.sup.22D is independently oxo,
halogen, CX.sup.22D.sub.3, CHX.sup.22D.sub.2, CH.sub.2X.sup.22D, OCX.sup.22D.sub.3, OCH.sub.2X.sup.22D, OCHX.sup.22D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.22D is independently F, Cl, Br, or I. In embodiments, R.sup.22D is independently unsubstituted methyl. In embodiments, R.sup.22D is independently unsubstituted ethyl.
[0223] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5.
[0224] In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SR.sup.2D, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0225] In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
[0226] In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0227] In embodiments, two adjacent R.sup.2 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R.sup.2 substituents are joined to form an unsubstituted cycloalkyl. In embodiments, two adjacent R.sup.2 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
[0228] In embodiments, R.sup.2 is independently CX.sup.2.sub.3. In embodiments, R.sup.2 is independently CHX.sup.2.sub.2. In embodiments, R.sup.2 is independently CH.sub.2X.sup.2. In embodiments, R.sup.2 is independently OCX.sup.2.sub.3. In embodiments, R.sup.2 is independently OCH.sub.2X.sup.2. In embodiments, R.sup.2 is independently OCHX.sup.2.sub.2. In embodiments, R.sup.2 is independently CN. In embodiments, R.sup.2 is independently SO.sub.n2R.sup.2D. In embodiments, R.sup.2 is independently SO.sub.v2NR.sup.2AR.sup.2B. In embodiments, R.sup.2 is independently NHC(O)NR.sup.2AR.sup.2B. In embodiments, R.sup.2 is independently N(O).sub.m2. In embodiments, R.sup.2 is independently NR.sup.2AR.sup.2B. In embodiments, R.sup.2 is independently C(O)R.sup.2C. In embodiments, R.sup.2 is independently C(O)OR.sup.2C. In embodiments, R.sup.2 is independently C(O)NR.sup.2AR.sup.2B. In embodiments, R.sup.2 is independently OR.sup.2D. In embodiments, R.sup.2 is independently NR.sup.2ASO.sub.2R.sup.2D. In embodiments, R.sup.2 is independently NR.sup.2AC(O)R.sup.2C. In embodiments, R.sup.2 is independently NR.sup.2AC(O)OR.sup.2C. In embodiments, R.sup.2 is independently NR.sup.2AOR.sup.2C. In embodiments, R.sup.2 is independently OH. In embodiments, R.sup.2 is independently NH.sub.2. In embodiments, R.sup.2 is independently COOH. In embodiments, R.sup.2 is independently CONH.sub.2. In embodiments, R.sup.2 is independently NO.sub.2. In embodiments, R.sup.2 is independently SH. In embodiments, R.sup.2 is independently halogen. In embodiments, R.sup.2 is independently F. In embodiments, R.sup.2 is independently Cl. In embodiments, R.sup.2 is independently Br. In embodiments, R.sup.2 is independently I. In embodiments, R.sup.2 is independently CF.sub.3. In embodiments, R.sup.2 is independently CHF.sub.2. In embodiments, R.sup.2 is independently CH.sub.2F. In embodiments, R.sup.2 is independently OCF.sub.3. In embodiments, R.sup.2 is independently OCH.sub.2F. In embodiments, R.sup.2 is independently OCHF.sub.2. In embodiments, R.sup.2 is independently OCH.sub.3. In embodiments, R.sup.2 is independently OCH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently OCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently OCH(CH.sub.3).sub.2. In embodiments, R.sup.2 is independently OC(CH.sub.3).sub.3. In embodiments, R.sup.2 is independently SCH.sub.3. In embodiments, R.sup.2 is independently SCH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently SCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently SCH(CH.sub.3).sub.2. In embodiments, R.sup.2 is independently SC(CH.sub.3).sub.3. In embodiments, R.sup.2 is independently CH.sub.3. In embodiments, R.sup.2 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.2 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.2 is independently C(CH.sub.3).sub.3.
[0229] In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2CC, R.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0230] In embodiments, R.sup.2 is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2 is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2 is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2 is independently unsubstituted methyl. In embodiments, R.sup.2 is independently unsubstituted ethyl. In embodiments, R.sup.2 is independently unsubstituted propyl. In embodiments, R.sup.2 is independently unsubstituted isopropyl. In embodiments, R.sup.2 is independently unsubstituted tert-butyl. In embodiments, R.sup.2 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2 is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2 is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2 is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2 is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2 is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0231] In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0232] In embodiments, R.sup.2A is independently hydrogen. In embodiments, R.sup.2A is independently CX.sup.2A3. In embodiments, R.sup.2A is independently CHX.sup.2A.sub.2. In embodiments, R.sup.2A is independently CH.sub.2X.sup.2A. In embodiments, R.sup.2A is independently CN. In embodiments, R.sup.2A is independently COOH. In embodiments, R.sup.2A is independently CONH.sub.2. In embodiments, X.sup.2A is independently F, Cl, Br, or I.
[0233] In embodiments, R.sup.2A is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2A is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2A is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2A is independently unsubstituted methyl. In embodiments, R.sup.2A is independently unsubstituted ethyl. In embodiments, R.sup.2A is independently unsubstituted propyl. In embodiments, R.sup.2A is independently unsubstituted isopropyl. In embodiments, R.sup.2A is independently unsubstituted tert-butyl. In embodiments, R.sup.2A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2A is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2A is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2A is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2A is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2A is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0234] In embodiments, R.sup.2B is independently hydrogen. In embodiments, R.sup.2B is independently CX.sup.2B3. In embodiments, R.sup.2B is independently CHX.sup.2B.sub.2. In embodiments, R.sup.2B is independently CH.sub.2X.sup.2B. In embodiments, R.sup.2B is independently CN. In embodiments, R.sup.2B is independently COOH. In embodiments, R.sup.2B is independently CONH.sub.2. In embodiments, X.sup.2B is independently F, Cl, Br, or I.
[0235] In embodiments, R.sup.2B is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2B is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2B is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2B is independently unsubstituted methyl. In embodiments, R.sup.2B is independently unsubstituted ethyl. In embodiments, R.sup.2B is independently unsubstituted propyl. In embodiments, R.sup.2B is independently unsubstituted isopropyl. In embodiments, R.sup.2B is independently unsubstituted tert-butyl. In embodiments, R.sup.2B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2B is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2B is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2B is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2B is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2B is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0236] In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0237] In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0238] In embodiments, R.sup.2C is independently hydrogen. In embodiments, R.sup.2C is independently CX.sup.2C.sub.3. In embodiments, R.sup.2C is independently CHX.sup.2C.sub.2. In embodiments, R.sup.2C is independently CH.sub.2X.sup.2C. In embodiments, R.sup.2C is independently CN. In embodiments, R.sup.2C is independently COOH. In embodiments, R.sup.2C is independently CONH.sub.2. In embodiments, X.sup.2C is independently F, Cl, Br, or I.
[0239] In embodiments, R.sup.2C is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2C is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2C is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2C is independently unsubstituted methyl. In embodiments, R.sup.2C is independently unsubstituted ethyl. In embodiments, R.sup.2C is independently unsubstituted propyl. In embodiments, R.sup.2C is independently unsubstituted isopropyl. In embodiments, R.sup.2C is independently unsubstituted tert-butyl. In embodiments, R.sup.2C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2C is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2C is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2C is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2C is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2C is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0240] In embodiments, R.sup.2D is independently hydrogen. In embodiments, R.sup.2D is independently CX.sup.2D.sub.3. In embodiments, R.sup.2D is independently CHX.sup.2D.sub.2. In embodiments, R.sup.2D is independently CH.sub.2X.sup.2D. In embodiments, R.sup.2D is independently CN. In embodiments, R.sup.2D is independently COOH. In embodiments, R.sup.2D is independently CONH.sub.2. In embodiments, X.sup.2D is independently F, Cl, Br, or I.
[0241] In embodiments, R.sup.2D is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2D is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2D is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.2D is independently unsubstituted methyl. In embodiments, R.sup.2D is independently unsubstituted ethyl. In embodiments, R.sup.2D is independently unsubstituted propyl. In embodiments, R.sup.2D is independently unsubstituted isopropyl. In embodiments, R.sup.2D is independently unsubstituted tert-butyl. In embodiments, R.sup.2D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.2D is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2D is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2D is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.2D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2D is independently substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2D is independently unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, R.sup.2D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0242] In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.23-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.2 is independently F, Cl, Br, or I. In embodiments, R.sup.2 is independently unsubstituted methyl. In embodiments, R.sup.2 is independently unsubstituted ethyl. In embodiments, R.sup.2 is independently
halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.23-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0243] In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form a R.sup.23-substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R.sup.2 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0244] R.sup.23 is independently oxo,
halogen, CX.sup.23.sub.3, CHX.sup.23.sub.2, CH.sub.2X.sup.23, OCX.sup.23.sub.3, OCH.sub.2X.sup.23, OCHX.sup.23.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.24-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.24-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.24-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.24-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.24-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.24-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.23 is independently oxo,
halogen, CX.sup.23.sub.3, CHX.sup.23.sub.2, CH.sub.2X.sup.23, OCX.sup.23.sub.3, OCH.sub.2X.sup.23, OCHX.sup.23.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.23 is independently F, Cl, Br, or I. In embodiments, R.sup.23 is independently unsubstituted methyl. In embodiments, R.sup.23 is independently unsubstituted ethyl.
[0245] R.sup.24 is independently oxo,
halogen, CX.sup.24.sub.3, CHX.sup.24.sub.2, CH.sub.2X.sup.24, OCX.sup.24.sub.3, OCH.sub.2X.sup.24, OCHX.sup.24.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.25-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.25-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.25-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.25-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.25-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.25-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.24 is independently oxo,
halogen, CX.sup.24.sub.3, CHX.sup.24.sub.2, CH.sub.2X.sup.24, OCX.sup.24.sub.3, OCH.sub.2X.sup.24, OCHX.sup.24.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.24 is independently F, Cl, Br, or I. In embodiments, R.sup.24 is independently unsubstituted methyl. In embodiments, R.sup.24 is independently unsubstituted ethyl.
[0246] R.sup.25 is independently oxo,
halogen, CX.sup.25.sub.3, CHX.sup.25.sub.2, CH.sub.2X.sup.25, OCX.sup.25.sub.3, OCH.sub.2X.sup.25, OCHX.sup.25.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.25 is independently F, Cl, Br, or I. In embodiments, R.sup.25 is independently unsubstituted methyl. In embodiments, R.sup.25 is independently unsubstituted ethyl.
[0247] In embodiments, R.sup.2A is independently hydrogen, CX.sup.2A.sub.3, CHX.sup.2A.sub.2, CH.sub.2X.sup.2A, CN, COOH, CONH.sub.2, R.sup.23A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A is independently hydrogen, CX.sup.2A.sub.3, CHX.sup.2A.sub.2, CH.sub.2X.sup.2A, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.2A is independently F, Cl, Br, or I. In embodiments, R.sup.2A is independently hydrogen. In embodiments, R.sup.2A is independently unsubstituted methyl. In embodiments, R.sup.2A is independently unsubstituted ethyl.
[0248] In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.23A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.23A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.23A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0249] R.sup.23A is independently oxo,
halogen, CX.sup.23A.sub.3, CHX.sup.23A.sub.2, CH.sub.2X.sup.23A, OCX.sup.23A.sub.3, OCH.sub.2X.sup.23A, OCHX.sup.23A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.24A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.24A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.24A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.24A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.24A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.24A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.23A is independently oxo,
halogen, CX.sup.23A.sub.3, CHX.sup.23A.sub.2, CH.sub.2X.sup.23A, OCX.sup.23A.sub.3, OCH.sub.2X.sup.23A, OCHX.sup.23A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.23A is independently F, Cl, Br, or I. In embodiments, R.sup.23A is independently unsubstituted methyl. In embodiments, R.sup.23A is independently unsubstituted ethyl.
[0250] R.sup.24A is independently oxo,
halogen, CX.sup.24A.sub.3, CHX.sup.24A.sub.2, CH.sub.2X.sup.24A, OCX.sup.24A.sub.3, OCH.sub.2X.sup.24A, OCHX.sup.24A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.25A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.25A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.25A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.25A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.25A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.25A-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.24A is independently oxo,
halogen, CX.sup.24A.sub.3, CHX.sup.24A.sub.2, CH.sub.2X.sup.24A, OCX.sup.24A.sub.3, OCH.sub.2X.sup.24A, OCHX.sup.24A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.24A is independently F, Cl, Br, or I. In embodiments, R.sup.24A is independently unsubstituted methyl. In embodiments, R.sup.24A is independently unsubstituted ethyl.
[0251] R.sup.25A is independently oxo,
halogen, CX.sup.25A.sub.3, CHX.sup.25A.sub.2, CH.sub.2X.sup.25A, OCX.sup.25A.sub.3, OCH.sub.2X.sup.25A, OCHX.sup.25A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.25A is independently F, Cl, Br, or I. In embodiments, R.sup.25A is independently unsubstituted methyl. In embodiments, R.sup.25A is independently unsubstituted ethyl.
[0252] In embodiments, R.sup.2B is independently hydrogen, CX.sup.2B.sub.3, CHX.sup.2B.sub.2, CH.sub.2X.sup.2B, CN, COOH, CONH.sub.2, R.sup.23B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2B is independently hydrogen, CX.sup.2B.sub.3, CHX.sup.2B.sub.2, CH.sub.2X.sup.2B, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.2B is independently F, Cl, Br, or I. In embodiments, R.sup.2B is independently hydrogen. In embodiments, R.sup.2B is independently unsubstituted methyl. In embodiments, R.sup.2B is independently unsubstituted ethyl.
[0253] In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.23B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.23B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.23B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0254] R.sup.23B is independently oxo,
halogen, CX.sup.23B.sub.3, CHX.sup.23B.sub.2, CH.sub.2X.sup.23B, OCX.sup.23B.sub.3, OCH.sub.2X.sup.23B, OCHX.sup.23B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.24B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.24B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.24B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.24B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.24B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.24B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.23B is independently oxo,
halogen, CX.sup.23B.sub.3, CHX.sup.23B.sub.2, CH.sub.2X.sup.23B, OCX.sup.23B.sub.3, OCH.sub.2X.sup.23B, OCHX.sup.23B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.23B is independently F, Cl, Br, or I. In embodiments, R.sup.23B is independently unsubstituted methyl. In embodiments, R.sup.23B is independently unsubstituted ethyl.
[0255] R.sup.24B is independently oxo,
halogen, CX.sup.24B.sub.3, CHX.sup.24B.sub.2, CH.sub.2X.sup.24B, OCX.sup.24B.sub.3, OCH.sub.2X.sup.24B, OCHX.sup.24B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.25B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.25B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.25B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.25B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.25B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.25B-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.24B is independently oxo,
halogen, CX.sup.24B.sub.3, CHX.sup.24B.sub.2, CH.sub.2X.sup.24B, OCX.sup.24B.sub.3, OCH.sub.2X.sup.24B, OCHX.sup.24B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.24B is independently F, Cl, Br, or I. In embodiments, R.sup.24B is independently unsubstituted methyl. In embodiments, R.sup.24B is independently unsubstituted ethyl.
[0256] R.sup.25B is independently oxo,
halogen, CX.sup.25B.sub.3, CHX.sup.25B.sub.2, CH.sub.2X.sup.25B, OCX.sup.25B.sub.3, OCH.sub.2X.sup.25B, OCHX.sup.25B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.25B is independently F, Cl, Br, or I. In embodiments, R.sup.25B is independently unsubstituted methyl. In embodiments, R.sup.25B is independently unsubstituted ethyl.
[0257] In embodiments, R.sup.2C is independently hydrogen, CX.sup.2C.sub.3, CHX.sup.2C.sub.2, CH.sub.2X.sup.2C, CN, COOH, CONH.sub.2, R.sup.23C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2C is independently hydrogen, CX.sup.2C.sub.3, CHX.sup.2C.sub.2, CH.sub.2X.sup.2C, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.2C is independently F, Cl, Br, or I. In embodiments, R.sup.2C is independently hydrogen. In embodiments, R.sup.2C is independently unsubstituted methyl. In embodiments, R.sup.2C is independently unsubstituted ethyl.
[0258] R.sup.23C is independently oxo,
halogen, CX.sup.23C.sub.3, CHX.sup.23C.sub.2, CH.sub.2X.sup.23C, OCX.sup.23C.sub.3, OCH.sub.2X.sup.23C, OCHX.sup.23C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.24C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.24C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.24C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.24C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.24C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.24C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.23C is independently oxo,
halogen, CX.sup.23C.sub.3, CHX.sup.23C.sub.2, CH.sub.2X.sup.23C, OCX.sup.23C.sub.3, OCH.sub.2X.sup.23C, OCHX.sup.23C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.23C is independently F, Cl, Br, or I. In embodiments,
[0259] R.sup.23C is independently unsubstituted methyl. In embodiments, R.sup.23C is independently unsubstituted ethyl.
[0260] R.sup.24C is independently oxo,
halogen, CX.sup.24C.sub.3, CHX.sup.24C.sub.2, CH.sub.2X.sup.24C, OCX.sup.24C.sub.3, OCH.sub.2X.sup.24C, OCHX.sup.24C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.25C-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.25C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.25C-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.25C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.25C-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.25C-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.24C is independently oxo,
halogen, CX.sup.24C.sub.3, CHX.sup.24C.sub.2, CH.sub.2X.sup.24C, OCX.sup.24C.sub.3, OCH.sub.2X.sup.24C, OCHX.sup.24C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2H.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.24C is independently F, Cl, Br, or I. In embodiments,
[0261] R.sup.24C is independently unsubstituted methyl. In embodiments, R.sup.24C is independently unsubstituted ethyl.
[0262] R.sup.25C is independently oxo,
halogen, CX.sup.25C.sub.3, CHX.sup.25C.sub.2, CH.sub.2X.sup.25C, OCX.sup.25C.sub.3, OCH.sub.2X.sup.25C, OCHX.sup.25C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.25C is independently F, Cl, Br, or I. In embodiments, R.sup.25C is independently unsubstituted methyl. In embodiments, R.sup.25C is independently unsubstituted ethyl.
[0263] In embodiments, R.sup.2D is independently hydrogen, CX.sup.2D.sub.3, CHX.sup.2D.sub.2, CH.sub.2X.sup.2D, CN, COOH, CONH.sub.2, R.sup.23D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.23D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.23D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.23D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.23D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.23D-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.2D is independently hydrogen, CX.sup.2D.sub.3, CHX.sup.2D.sub.2, CH.sub.2X.sup.2D, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.2D is independently F, Cl, Br, or I. In embodiments, R.sup.2D is independently hydrogen. In embodiments, R.sup.2D is independently unsubstituted methyl. In embodiments, R.sup.2D is independently unsubstituted ethyl.
[0264] R.sup.23D is independently oxo,
halogen, CX.sup.23D.sub.3, CHX.sup.23D.sub.2, CH.sub.2X.sup.23D, OCX.sup.23D.sub.3, OCH.sub.2X.sup.23D, OCHX.sup.23D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.24D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.24D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.24D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.24D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.24D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.24D-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.23D is independently oxo,
halogen, CX.sup.23D.sub.3, CHX.sup.23D.sub.2, CH.sub.2X.sup.23D, OCX.sup.23D.sub.3, OCH.sub.2X.sup.23D, OCHX.sup.23D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.23D is independently F, Cl, Br, or I. In embodiments,
[0265] R.sup.23D is independently unsubstituted methyl. In embodiments, R.sup.23D is independently unsubstituted ethyl.
[0266] R.sup.24D is independently oxo,
halogen, CX.sup.24D.sub.3, CHX.sup.24D.sub.2, CH.sub.2X.sup.24D, OCX.sup.24D.sub.3, OCH.sub.2X.sup.24D, OCHX.sup.24D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.25D-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.25D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.25D-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.25D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.25D-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or R.sup.25D-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.24D is independently oxo,
halogen, CX.sup.24D.sub.3, CHX.sup.24D.sub.2, CH.sub.2X.sup.24D, OCX.sup.24D.sub.3, OCH.sub.2X.sup.24D, OCHX.sup.24D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.24D is independently F, Cl, Br, or I. In embodiments, R.sup.24D is independently unsubstituted methyl. In embodiments, R.sup.24D is independently unsubstituted ethyl.
[0267] R.sup.25D is independently oxo,
halogen, CX.sup.25D.sub.3, CHX.sup.25D.sub.2, CH.sub.2X.sup.25D, OCX.sup.25D.sub.3, OCH.sub.2X.sup.25D, OCHX.sup.25D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.12, C.sub.6-C.sub.10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.25D is independently F, Cl, Br, or I. In embodiments, R.sup.25D is independently unsubstituted methyl. In embodiments, R.sup.25D is independently unsubstituted ethyl.
[0268] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4.
[0269] In embodiments, L.sup.1 is a bond, substituted or unsubstituted C.sub.1-C.sub.8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L.sup.1 is a bond.
[0270] In embodiments, 12 is a bond. In embodiments, L.sup.1 is S(O).sub.2. In embodiments, L.sup.1 is NR.sup.4. In embodiments, L.sup.1 is O. In embodiments, L.sup.1 is S. In embodiments, L.sup.1 is C(O). In embodiments, L.sup.1 is C(O)NR.sup.4. In embodiments, L.sup.1 is NR.sup.4C(O). In embodiments, L.sup.1 is NR.sup.4C(O)NH. In embodiments, L.sup.1 is NHC(O)NR.sup.4. In embodiments, L.sup.1 is C(O)O. In embodiments, L.sup.1 is OC(O). In embodiments, L.sup.1 is NH. In embodiments, L.sup.1 is C(O)NH. In embodiments, L.sup.1 is NHC(O). In embodiments, L.sup.1 is NHC(O)NH. In embodiments, L.sup.1 is CH.sub.2. In embodiments, L.sup.1 is OCH.sub.2. In embodiments, L.sup.1 is CH.sub.2O. In embodiments, L.sup.1 is CH.sub.2CH.sub.2. In embodiments, L.sup.1 is NHCH.sub.2. In embodiments, L.sup.1 is CH.sub.2NH. In embodiments, L.sup.1 is a bond.
[0271] In embodiments, L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0272] In embodiments, L.sup.1 is independently substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.1 is independently substituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.1 is independently unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.1 is independently unsubstituted methylene. In embodiments, L.sup.1 is independently unsubstituted ethylene. In embodiments, L.sup.1 is independently unsubstituted propylene. In embodiments, L.sup.1 is independently unsubstituted isopropylene. In embodiments, L.sup.1 is independently unsubstituted tert-butylene. In embodiments, L.sup.1 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.1 is independently substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.1 is independently unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.1 is independently substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.1 is independently substituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.1 is independently unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.1 is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently substituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.1 is independently substituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.1 is independently unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.1 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0273] In embodiments, L.sup.1 is independently bond, S(O).sub.2, N(R.sup.4), O, S, C(O), C(O)N(R.sup.4), N(R.sup.4)C(O), N(R.sup.4)C(O)NH, NHC(O) N(R.sup.4), C(O)O, OC(O), R.sup.35-substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.35-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.35-substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.35-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.35-substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or R.sup.35-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently bond, S(O).sub.2, N(R.sup.4), O, S, C(O), C(O)N(R.sup.4), N(R.sup.4)C(O), N(R.sup.4)C(O)NH, NHC(O) N(R.sup.4), C(O)O, OC(O), unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.1 is independently unsubstituted methylene. In embodiments, L.sup.1 is independently unsubstituted ethylene. In embodiments, L.sup.1 is independently methyl-substituted methylene.
[0274] R.sup.35 is independently oxo,
halogen, CX.sup.35.sub.3, CHX.sup.35.sub.2, CH.sub.2X.sup.35, OCX.sup.35.sub.3, OCH.sub.2X.sup.35, OCHX.sup.35.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.36-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.36-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.36-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.36-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.36-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.36-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.35 is independently oxo,
halogen, CX.sup.35.sub.3, CHX.sup.35.sub.2, CH.sub.2X.sup.35, OCX.sup.35.sub.3, OCH.sub.2X.sup.35, OCHX.sup.35.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.35 is independently F, Cl, Br, or I. In embodiments, R.sup.35 is independently unsubstituted methyl. In embodiments, R.sup.35 is independently unsubstituted ethyl.
[0275] R.sup.36 is independently oxo,
halogen, CX.sup.36.sub.3, CHX.sup.36.sub.2, CH.sub.2X.sup.36, OCX.sup.36.sub.3, OCH.sub.2X.sup.36, OCHX.sup.36.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.37-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.37-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.37-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.37-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.37-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.37-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.36 is independently oxo,
halogen, CX.sup.36.sub.3, CHX.sup.36.sub.2, CH.sub.2X.sup.36, OCX.sup.36.sub.3, OCH.sub.2X.sup.36, OCHX.sup.36.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.36 is independently F, Cl, Br, or I. In embodiments, R.sup.36 is independently unsubstituted methyl. In embodiments, R.sup.36 is independently unsubstituted ethyl.
[0276] R.sup.37 is independently oxo,
halogen, CX.sup.37.sub.3, CHX.sup.37.sub.2, CH.sub.2X.sup.37, OCX.sup.37.sub.3, OCH.sub.2X.sup.37, OCHX.sup.37.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.37 is independently F, Cl, Br, or I. In embodiments, R.sup.37 is independently unsubstituted methyl. In embodiments, R.sup.37 is independently unsubstituted ethyl.
[0277] In embodiments, R.sup.4 is independently hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4BOR.sup.4A, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0278] In embodiments, R.sup.4 is independently hydrogen. In embodiments, R.sup.4 is independently CX.sup.4.sub.3. In embodiments, R.sup.4 is independently CHX.sup.4.sub.2. In embodiments, R.sup.4 is independently CH.sub.2X.sup.4. In embodiments, R.sup.4 is independently CN. In embodiments, R.sup.4 is independently C(O)R.sup.4A. In embodiments, R.sup.4 is independently C(O)OR.sup.4A. In embodiments, R.sup.4 is independently C(O)NR.sup.4AR.sup.4B. In embodiments, R.sup.4 is independently COOH. In embodiments, R.sup.4 is independently CONH.sub.2. In embodiments, R.sup.4 is independently CF.sub.3. In embodiments, R.sup.4 is independently CHF.sub.2. In embodiments, R.sup.4 is independently CH.sub.2F. In embodiments, R.sup.4 is independently CH.sub.3. In embodiments, R.sup.4 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.4 is independently C(CH.sub.3).sub.3.
[0279] In embodiments, R.sup.4 is independently unsubstituted methyl. In embodiments, R.sup.4 is independently unsubstituted ethyl. In embodiments, R.sup.4 is independently unsubstituted propyl. In embodiments, R.sup.4 is independently unsubstituted isopropyl. In embodiments, R.sup.4 is independently unsubstituted n-propyl. In embodiments, R.sup.4 is independently unsubstituted butyl. In embodiments, R.sup.4 is independently unsubstituted n-butyl. In embodiments, R.sup.4 is independently unsubstituted t-butyl. In embodiments, R.sup.4 is independently unsubstituted pentyl. In embodiments, R.sup.4 is independently unsubstituted n-pentyl. In embodiments, R.sup.4 is independently unsubstituted hexyl. In embodiments, R.sup.4 is independently unsubstituted n-hexyl. In embodiments, R.sup.4 is independently unsubstituted heptyl. In embodiments, R.sup.4 is independently unsubstituted n-heptyl. In embodiments, R.sup.4 is independently unsubstituted octyl. In embodiments, R.sup.4 is independently unsubstituted n-octyl. In embodiments, R.sup.4 is independently unsubstituted benzyl. In embodiments, R.sup.4 is independently unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.4 is independently halo-substituted methyl. In embodiments, R.sup.4 is independently halo-substituted ethyl. In embodiments, R.sup.4 is independently halo-substituted isopropyl. In embodiments, R.sup.4 is independently halo-substituted n-propyl. In embodiments, R.sup.4 is independently halo-substituted n-butyl. In embodiments, R.sup.4 is independently halo-substituted t-butyl. In embodiments, R.sup.1 is independently halo-substituted n-pentyl. In embodiments, R.sup.4 is independently halo-substituted benzyl. In embodiments, R.sup.4 is independently halo-substituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 7 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted 7 to 9 membered heteroalkyl.
[0280] In embodiments, R.sup.4 is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4 is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4 is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4 is independently unsubstituted methyl. In embodiments, R.sup.4 is independently unsubstituted ethyl. In embodiments, R.sup.4 is independently unsubstituted propyl. In embodiments, R.sup.4 is independently unsubstituted isopropyl. In embodiments, R.sup.4 is independently unsubstituted tert-butyl. In embodiments, R.sup.4 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4 is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4 is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4 is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4 is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4 is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0281] In embodiments, R.sup.4A is independently hydrogen. In embodiments, R.sup.4A is independently CX.sup.4A.sub.3. In embodiments, R.sup.4A is independently CHX.sup.4A.sub.2. In embodiments, R.sup.4A is independently CH.sub.2X.sup.4A. In embodiments, R.sup.4A is independently CN. In embodiments, R.sup.4A is independently COOH. In embodiments, R.sup.4A is independently CONH.sub.2. In embodiments, X.sup.4A is independently F, Cl, Br, or I.
[0282] In embodiments, R.sup.4A is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4A is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4A is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4A is independently unsubstituted methyl. In embodiments, R.sup.4A is independently unsubstituted ethyl. In embodiments, R.sup.4A is independently unsubstituted propyl. In embodiments, R.sup.4A is independently unsubstituted isopropyl. In embodiments, R.sup.4A is independently unsubstituted tert-butyl. In embodiments, R.sup.4A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4A is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4A is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4A is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4A is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4A is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0283] In embodiments, R.sup.4B is independently hydrogen. In embodiments, R.sup.4B is independently CX.sup.4B.sub.3. In embodiments, R.sup.4B is independently CHX.sup.4B.sub.2. In embodiments, R.sup.4B is independently CH.sub.2X.sup.4B. In embodiments, R.sup.4B is independently CN. In embodiments, R.sup.4B is independently COOH. In embodiments, R.sup.4B is independently CONH.sub.2. In embodiments, X.sup.4B is independently F, Cl, Br, or I.
[0284] In embodiments, R.sup.4B is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4B is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4B is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.4B is independently unsubstituted methyl. In embodiments, R.sup.4B is independently unsubstituted ethyl. In embodiments, R.sup.4B is independently unsubstituted propyl. In embodiments, R.sup.4B is independently unsubstituted isopropyl. In embodiments, R.sup.4B is independently unsubstituted tert-butyl. In embodiments, R.sup.4B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.4B is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4B is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4B is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.4B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4B is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4B is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.4B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0285] In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0286] In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0287] In embodiments, R.sup.4 is independently hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, CN, COOH, CONH.sub.2, R.sup.29-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.29-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.29-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.29-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.29-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.29-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4 is independently hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.4 is independently F, Cl, Br, or I. In embodiments, R.sup.4 is independently hydrogen. In embodiments, R.sup.4 is independently unsubstituted methyl. In embodiments, R.sup.4 is independently unsubstituted ethyl.
[0288] R.sup.29 is independently oxo,
halogen, CX.sup.29.sub.3, CHX.sup.29.sub.2, CH.sub.2X.sup.29, OCX.sup.29.sub.3, OCH.sub.2X.sup.29, OCHX.sup.29.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, 03H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.30-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.30-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.30-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.30-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.30-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.30-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.29 is independently oxo,
halogen, CX.sup.29.sub.3, CHX.sup.29.sub.2, CH.sub.2X.sup.29, OCX.sup.29.sub.3, OCH.sub.2X.sup.29, OCHX.sup.29.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.29 is independently F, Cl, Br, or I. In embodiments, R.sup.29 is independently unsubstituted methyl. In embodiments, R.sup.29 is independently unsubstituted ethyl.
[0289] R.sup.30 is independently oxo,
halogen, CX.sup.30.sub.3, CHX.sup.30.sub.2, CH.sub.2X.sup.30, OCX.sup.30.sub.3, OCH.sub.2X.sup.30, OCHX.sup.30.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.31-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.31-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.31-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.31-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.31-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.31-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.30 is independently oxo,
halogen, CX.sup.30.sub.3, CHX.sup.30.sub.2, CH.sub.2X.sup.30, OCX.sup.30.sub.3, OCH.sub.2X.sup.30, OCHX.sup.30.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.30 is independently F, Cl, Br, or I. In embodiments, R.sup.30 is independently unsubstituted methyl. In embodiments, R.sup.30 is independently unsubstituted ethyl.
[0290] R.sup.31 is independently oxo,
halogen, CX.sup.31.sub.3, CHX.sup.31.sub.2, CH.sub.2X.sup.31, OCX.sup.31.sub.3, OCH.sub.2X.sup.31, OCHX.sup.31.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.31 is independently F, Cl, Br, or I. In embodiments, R.sup.31 is independently unsubstituted methyl. In embodiments, R.sup.31 is independently unsubstituted ethyl.
[0291] In embodiments, R.sup.4A is independently hydrogen, CX.sup.4A.sub.3, CHX.sup.4A.sub.2, CH.sub.2X.sup.4A, CN, COOH, CONH.sub.2, R.sup.29A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.29A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.29A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.29A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.29A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.29A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A is independently hydrogen, CX.sup.4A.sub.3, CHX.sup.4A.sub.2, CH.sub.2X.sup.4A, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.4A is independently F, Cl, Br, or I. In embodiments, R.sup.4A is independently hydrogen. In embodiments, R.sup.4A is independently unsubstituted methyl. In embodiments, R.sup.4A is independently unsubstituted ethyl.
[0292] In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.29A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.29A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.29A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0293] R.sup.29A is independently oxo,
halogen, CX.sup.29A.sub.3, CHX.sup.29A.sub.2, CH.sub.2X.sup.29A, OCX.sup.29A.sub.3, OCH.sub.2X.sup.29A, OCHX.sup.29A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.30A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.30A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.30A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.30A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.30A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.30A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.29A is independently oxo,
halogen, CX.sup.29A.sub.3, CHX.sup.29A.sub.2, CH.sub.2X.sup.29A, OCX.sup.29A.sub.3, OCH.sub.2X.sup.29A, OCHX.sup.29A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.29A is independently F, Cl, Br, or I. In embodiments, R.sup.29A is independently unsubstituted methyl. In embodiments, R.sup.29A is independently unsubstituted ethyl.
[0294] R.sup.30A is independently oxo,
halogen, CX.sup.30A.sub.3, CHX.sup.30A.sub.2, CH.sub.2X.sup.30A, OCX.sup.30A.sub.3, OCH.sub.2X.sup.30A, OCHX.sup.30A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.31A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.31A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.31A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.31A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.31A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.31A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.30A is independently oxo,
halogen, CX.sup.30A.sub.3, CHX.sup.30A.sub.2, CH.sub.2X.sup.30A, OCX.sup.30A.sub.3, OCH.sub.2X.sup.30A, OCHX.sup.30A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.30A is independently F, Cl, Br, or I. In embodiments, R.sup.30A is independently unsubstituted methyl. In embodiments, R.sup.30A is independently unsubstituted ethyl.
[0295] R.sup.31A is independently oxo,
halogen, CX.sup.31A.sub.3, CHX.sup.31A.sub.2, CH.sub.2X.sup.31A, OCX.sup.31A.sub.3, OCH.sub.2X.sup.31A, OCHX.sup.31A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.31A is independently F, Cl, Br, or I. In embodiments, R.sup.31A is independently unsubstituted methyl. In embodiments, R.sup.31A is independently unsubstituted ethyl.
[0296] In embodiments, R.sup.4B is independently hydrogen, CX.sup.4B.sub.3, CHX.sup.4B.sub.2, CH.sub.2X.sup.4B, CN, COOH, CONH.sub.2, R.sup.29B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.29B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.29B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.29B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.29B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.29B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4B is independently hydrogen, CX.sup.4B.sub.3, CHX.sup.4B.sub.2, CH.sub.2X.sup.4B, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.4B is independently F, Cl, Br, or I. In embodiments, R.sup.4B is independently hydrogen. In embodiments, R.sup.4B is independently unsubstituted methyl. In embodiments, R.sup.4B is independently unsubstituted ethyl.
[0297] In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.29B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.29B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.29B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0298] R.sup.29B is independently oxo,
halogen, CX.sup.29B.sub.3, CHX.sup.29B.sub.2, CH.sub.2X.sup.29B, OCX.sup.29B.sub.3, OCH.sub.2X.sup.29B, OCHX.sup.29B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.30B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.30B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.30B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.30B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.30B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.30B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.29B is independently oxo,
halogen, CX.sup.29B.sub.3, CHX.sup.29B.sub.2, CH.sub.2X.sup.29B, OCX.sup.29B.sub.3, OCH.sub.2X.sup.29B, OCHX.sup.29B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.29B is independently F, Cl, Br, or I. In embodiments, R.sup.29B is independently unsubstituted methyl. In embodiments, R.sup.29B is independently unsubstituted ethyl.
[0299] R.sup.30B is independently oxo,
halogen, CX.sup.30B.sub.3, CHX.sup.30B.sub.2, CH.sub.2X.sup.30B, OCX.sup.30B.sub.3, OCH.sub.2X.sup.30B, OCHX.sup.30B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.31B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.31B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.31B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.31B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.31B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.31B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.30B is independently oxo,
halogen, CX.sup.30B.sub.3, CHX.sup.30B.sub.2, CH.sub.2X.sup.30B, OCX.sup.30B.sub.3, OCH.sub.2X.sup.30B, OCHX.sup.30B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.30B is independently F, Cl, Br, or I. In embodiments, R.sup.30B is independently unsubstituted methyl. In embodiments, R.sup.30B is independently unsubstituted ethyl.
[0300] R.sup.31B is independently oxo,
halogen, CX.sup.31B.sub.3, CHX.sup.31B.sub.2, CH.sub.2X.sup.31B, OCX.sup.31B.sub.3, OCH.sub.2X.sup.31B, OCHX.sup.31B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.31B is independently F, Cl, Br, or I. In embodiments, R.sup.31B is independently unsubstituted methyl. In embodiments, R.sup.31B is independently unsubstituted ethyl.
[0301] In embodiments, L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene including a ring nitrogen bonded directly to E. In embodiments, L.sup.2 is NR.sup.5.
[0302] In embodiments, L.sup.2 is a bond. In embodiments, L.sup.2 is S(O).sub.2. In embodiments, L.sup.2 is NR.sup.5. In embodiments, L.sup.2 is O. In embodiments, L.sup.2 is S. In embodiments, L.sup.2 is C(O). In embodiments, L.sup.2 is C(O)NR.sup.5. In embodiments, L.sup.2 is NR.sup.5C(O). In embodiments, L.sup.2 is NR.sup.5C(O)NH. In embodiments, L.sup.2 is NHC(O)NR.sup.5. In embodiments, L.sup.2 is C(O)O. In embodiments, L.sup.2 is OC(O). In embodiments, L.sup.2 is NH. In embodiments, L.sup.2 is C(O)NH. In embodiments, L.sup.2 is NHC(O). In embodiments, L.sup.2 is NHC(O)NH. In embodiments, L.sup.2 is CH.sub.2. In embodiments, L.sup.2 is OCH.sub.2. In embodiments, L.sup.2 is CH.sub.2O. In embodiments, L.sup.2 is NHCH.sub.2. In embodiments, L.sup.2 is CH.sub.2NH.
[0303] In embodiments, L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.4C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0304] In embodiments, L.sup.2 is independently substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.2 is independently substituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.2 is independently unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, L.sup.2 is independently unsubstituted methylene. In embodiments, L.sup.2 is independently unsubstituted ethylene. In embodiments, L.sup.2 is independently unsubstituted propylene. In embodiments, L.sup.2 is independently unsubstituted isopropylene. In embodiments, L.sup.2 is independently unsubstituted tert-butylene. In embodiments, L.sup.2 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.2 is independently substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.2 is independently unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L.sup.2 is independently substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.2 is independently substituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.2 is independently unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, L.sup.2 is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently substituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.2 is independently substituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.2 is independently unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene). In embodiments, L.sup.2 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently substituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0305] In embodiments, L.sup.2 is independently bond, S(O).sub.2, N(R.sup.5), O, S, C(O), C(O)N(R.sup.5), N(R.sup.5)C(O), N(R.sup.5)C(O)NH, NHC(O) N(R.sup.5), C(O)O, OC(O), R.sup.38-substituted or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.38-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.38-substituted or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.38-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.38-substituted or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or R.sup.38-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently bond, S(O).sub.2, N(R.sup.5), O, S, C(O), C(O)N(R.sup.5), N(R.sup.5)C(O), N(R.sup.5)C(O)NH, NHC(O) N(R.sup.5), C(O)O, OC(O), unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenylene), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L.sup.2 is independently unsubstituted methylene. In embodiments, L.sup.2 is independently unsubstituted ethylene. In embodiments, L.sup.2 is independently methyl-substituted methylene.
[0306] R.sup.38 is independently oxo,
halogen, CX.sup.38.sub.3, CHX.sup.38.sub.2, CH.sub.2X.sup.38, OCX.sup.38.sub.3, OCH.sub.2X.sup.38, OCHX.sup.38.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.39-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.39-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.39-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.39-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.39-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.39-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.38 is independently oxo,
halogen, CX.sup.38.sub.3, CHX.sup.38.sub.2, CH.sub.2X.sup.38, OCX.sup.38.sub.3, OCH.sub.2X.sup.38, OCHX.sup.38.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.38 is independently F, Cl, Br, or I. In embodiments, R.sup.38 is independently unsubstituted methyl. In embodiments, R.sup.38 is independently unsubstituted ethyl.
[0307] R.sup.39 is independently oxo,
halogen, CX.sup.39.sub.3, CHX.sup.39.sub.2, CH.sub.2X.sup.39, OCX.sup.39.sub.3, OCH.sub.2X.sup.39, OCHX.sup.39.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.40-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.40-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.40-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.40-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.40-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.40-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.39 is independently oxo,
halogen, CX.sup.39.sub.3, CHX.sup.39.sub.2, CH.sub.2X.sup.39, OCX.sup.39.sub.3, OCH.sub.2X.sup.39, OCHX.sup.39.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.39 is independently F, Cl, Br, or I. In embodiments, R.sup.39 is independently unsubstituted methyl. In embodiments, R.sup.39 is independently unsubstituted ethyl.
[0308] R.sup.40 is independently oxo,
halogen, CX.sup.40.sub.3, CHX.sup.40.sub.2, CH.sub.2X.sup.40, OCX.sup.40.sub.3, OCH.sub.2X.sup.40, OCHX.sup.40.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.40 is independently F, Cl, Br, or I. In embodiments, R.sup.40 is independently unsubstituted methyl. In embodiments, R.sup.40 is independently unsubstituted ethyl.
[0309] In embodiments, R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R.sup.5 is hydrogen or unsubstituted C.sub.1-C.sub.3 alkyl. In embodiments, R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl. In embodiments, R.sup.5 is hydrogen.
[0310] In embodiments, R.sup.5 is independently unsubstituted methyl. In embodiments, R.sup.5 is independently unsubstituted ethyl. In embodiments, R.sup.5 is independently unsubstituted propyl. In embodiments, R.sup.5 is independently unsubstituted isopropyl. In embodiments, R.sup.5 is independently unsubstituted n-propyl. In embodiments, R.sup.5 is independently unsubstituted butyl. In embodiments, R.sup.5 is independently unsubstituted n-butyl. In embodiments, R.sup.5 is independently unsubstituted t-butyl. In embodiments, R.sup.5 is independently unsubstituted pentyl. In embodiments, R.sup.5 is independently unsubstituted n-pentyl. In embodiments, R.sup.5 is independently unsubstituted hexyl. In embodiments, R.sup.5 is independently unsubstituted n-hexyl. In embodiments, R.sup.5 is independently unsubstituted heptyl. In embodiments, R.sup.5 is independently unsubstituted n-heptyl. In embodiments, R.sup.5 is independently unsubstituted octyl. In embodiments, R.sup.5 is independently unsubstituted n-octyl. In embodiments, R.sup.5 is independently unsubstituted benzyl. In embodiments, R.sup.5 is independently unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.5 is independently halo-substituted methyl. In embodiments, R.sup.5 is independently halo-substituted ethyl. In embodiments, R.sup.5 is independently halo-substituted isopropyl. In embodiments, R.sup.5 is independently halo-substituted n-propyl. In embodiments, R.sup.5 is independently halo-substituted n-butyl. In embodiments, R.sup.5 is independently halo-substituted t-butyl. In embodiments, R.sup.1 is independently halo-substituted n-pentyl. In embodiments, R.sup.5 is independently halo-substituted benzyl. In embodiments, R.sup.5 is independently halo-substituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.5 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 2 to 7 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R.sup.5 is independently unsubstituted 7 to 9 membered heteroalkyl.
[0311] In embodiments, R.sup.5 is independently hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0312] In embodiments, R.sup.5 is independently hydrogen. In embodiments, R.sup.5 is independently CX.sup.5.sub.3. In embodiments, R.sup.5 is independently CHX.sup.5.sub.2. In embodiments, R.sup.5 is independently CH.sub.2X.sup.5. In embodiments, R.sup.5 is independently CN. In embodiments, R.sup.5 is independently C(O)R.sup.5A. In embodiments, R.sup.5 is independently C(O)OR.sup.5A. In embodiments, R.sup.5 is independently C(O)NR.sup.5AR.sup.5B. In embodiments, R.sup.5 is independently COOH. In embodiments, R.sup.5 is independently CONH.sub.2. In embodiments, R.sup.5 is independently CF.sub.3. In embodiments, R.sup.5 is independently CHF.sub.2. In embodiments, R.sup.5 is independently CH.sub.2F. In embodiments, R.sup.5 is independently CH.sub.3. In embodiments, R.sup.5 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.5 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.5 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.5 is independently C(CH.sub.3).sub.3.
[0313] In embodiments, R.sup.5 is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5 is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5 is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5 is independently unsubstituted methyl. In embodiments, R.sup.5 is independently unsubstituted ethyl. In embodiments, R.sup.5 is independently unsubstituted propyl. In embodiments, R.sup.5 is independently unsubstituted isopropyl. In embodiments, R.sup.5 is independently unsubstituted tert-butyl. In embodiments, R.sup.5 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5 is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5 is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5 is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5 is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5 is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0314] In embodiments, R.sup.5A is independently hydrogen. In embodiments, R.sup.5A is independently CX.sup.5A.sub.3. In embodiments, R.sup.5A is independently CHX.sup.5A.sub.2. In embodiments, R.sup.5A is independently CH.sub.2X.sup.5A. In embodiments, R.sup.5A is independently CN. In embodiments, R.sup.5A is independently COOH. In embodiments, R.sup.5A is independently CONH.sub.2. In embodiments, X.sup.5A is independently F, Cl, Br, or I.
[0315] In embodiments, R.sup.5A is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5A is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5A is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5A is independently unsubstituted methyl. In embodiments, R.sup.5A is independently unsubstituted ethyl. In embodiments, R.sup.5A is independently unsubstituted propyl. In embodiments, R.sup.5A is independently unsubstituted isopropyl. In embodiments, R.sup.5A is independently unsubstituted tert-butyl. In embodiments, R.sup.5A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5A is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5A is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5A is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5A is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5A is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0316] In embodiments, R.sup.5B is independently hydrogen. In embodiments, R.sup.5B is independently CX.sup.5B.sub.3. In embodiments, R.sup.5B is independently CHX.sup.5B.sub.2. In embodiments, R.sup.5B is independently CH.sub.2X.sup.5B. In embodiments, R.sup.5B is independently CN. In embodiments, R.sup.5B is independently COOH. In embodiments, R.sup.5B is independently CONH.sub.2. In embodiments, X.sup.5B is independently F, Cl, Br, or I.
[0317] In embodiments, R.sup.5B is independently substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5B is independently substituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5B is independently unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2). In embodiments, R.sup.5B is independently unsubstituted methyl. In embodiments, R.sup.5B is independently unsubstituted ethyl. In embodiments, R.sup.5B is independently unsubstituted propyl. In embodiments, R.sup.5B is independently unsubstituted isopropyl. In embodiments, R.sup.5B is independently unsubstituted tert-butyl. In embodiments, R.sup.5B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R.sup.5B is independently substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5B is independently substituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5B is independently unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6). In embodiments, R.sup.5B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5B is independently substituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5B is independently unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl). In embodiments, R.sup.5B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0318] In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0319] In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form a substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0320] In embodiments, R.sup.5 is independently hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, CN, COOH, CONH.sub.2, R.sup.32-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.32-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.32-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.32-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.32-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.32-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5 is independently hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.5 is independently F, Cl, Br, or I. In embodiments, R.sup.5 is independently hydrogen. In embodiments, R.sup.5 is independently unsubstituted methyl. In embodiments, R.sup.5 is independently unsubstituted ethyl.
[0321] R.sup.32 is independently oxo,
halogen, CX.sup.32.sub.3, CHX.sup.32.sub.2, CH.sub.2X.sup.32, OCX.sup.32.sub.3, OCH.sub.2X.sup.32, OCHX.sup.32.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.33-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.33-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.33-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.33-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.33-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.33-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.32 is independently oxo,
halogen, CX.sup.32.sub.3, CHX.sup.32.sub.2, CH.sub.2X.sup.32, OCX.sup.32.sub.3, OCH.sub.2X.sup.32, OCHX.sup.32.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.32 is independently F, Cl, Br, or I. In embodiments, R.sup.32 is independently unsubstituted methyl. In embodiments, R.sup.32 is independently unsubstituted ethyl.
[0322] R.sup.33 is independently oxo,
halogen, CX.sup.33.sub.3, CHX.sup.33.sub.2, CH.sub.2X.sup.33, OCX.sup.33.sub.3, OCH.sub.2X.sup.33, OCHX.sup.33.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.34-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.34-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.34-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.34-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.34-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.34-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.33 is independently oxo,
halogen, CX.sup.33.sub.3, CHX.sup.33.sub.2, CH.sub.2X.sup.33, OCX.sup.33.sub.3, OCH.sub.2X.sup.33, OCHX.sup.33.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.33 is independently F, Cl, Br, or I. In embodiments, R.sup.33 is independently unsubstituted methyl. In embodiments, R.sup.33 is independently unsubstituted ethyl.
[0323] R.sup.34 is independently oxo,
halogen, CX.sup.34.sub.3, CHX.sup.34.sub.2, CH.sub.2X.sup.34, OCX.sup.34.sub.3, OCH.sub.2X.sup.34, OCHX.sup.34.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.34 is independently F, Cl, Br, or I. In embodiments, R.sup.34 is independently unsubstituted methyl. In embodiments, R.sup.34 is independently unsubstituted ethyl.
[0324] In embodiments, R.sup.5A is independently hydrogen, CX.sup.5A.sub.3, CHX.sup.5A.sub.2, CH.sub.2X.sup.5A, CN, COOH, CONH.sub.2, R.sup.32A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.32A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.32A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.32A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.32A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.32A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A is independently hydrogen, CX.sup.5A.sub.3, CHX.sup.5A.sub.2, CH.sub.2X.sup.5A, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.5A is independently F, Cl, Br, or I. In embodiments, R.sup.5A is independently hydrogen. In embodiments, R.sup.5A is independently unsubstituted methyl. In embodiments, R.sup.5A is independently unsubstituted ethyl.
[0325] In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.32A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.32A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.32A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0326] R.sup.32A is independently oxo,
halogen, CX.sup.32A.sub.3, CHX.sup.32A.sub.2, CH.sub.2X.sup.32A, OCX.sup.32A.sub.3, OCH.sub.2X.sup.32A, OCHX.sup.32A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.33A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.33A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.33A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.33A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.33A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.33A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.32A is independently oxo,
halogen, CX.sup.32A.sub.3, CHX.sup.32A.sub.2, CH.sub.2X.sup.32A, OCX.sup.32A.sub.3, OCH.sub.2X.sup.32A, OCHX.sup.32A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.32A is independently F, Cl, Br, or I. In embodiments, R.sup.32A is independently unsubstituted methyl. In embodiments, R.sup.32A is independently unsubstituted ethyl.
[0327] R.sup.33A is independently oxo,
halogen, CX.sup.33A.sub.3, CHX.sup.33A.sub.2, CH.sub.2X.sup.33A, OCX.sup.33A.sub.3, OCH.sub.2X.sup.33A, OCHX.sup.33A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.34A-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.34A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.34A-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.34A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.34A-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.34A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.33A is independently oxo,
halogen, CX.sup.33A.sub.3, CHX.sup.33A.sub.2, CH.sub.2X.sup.33A, OCX.sup.33A.sub.3, OCH.sub.2X.sup.33A, OCHX.sup.33A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.33A is independently F, Cl, Br, or I. In embodiments, R.sup.33A is independently unsubstituted methyl. In embodiments, R.sup.33A is independently unsubstituted ethyl.
[0328] R.sup.34A is independently oxo,
halogen, CX.sup.34A.sub.3, CHX.sup.34A.sub.2, CH.sub.2X.sup.34A, OCX.sup.34A.sub.3, OCH.sub.2X.sup.34A, OCHX.sup.34A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.34A is independently F, Cl, Br, or I. In embodiments, R.sup.34A is independently unsubstituted methyl. In embodiments, R.sup.34A is independently unsubstituted ethyl.
[0329] In embodiments, R.sup.5B is independently hydrogen, CX.sup.5B.sub.3, CHX.sup.5B.sub.2, CH.sub.2X.sup.5B, CN, COOH, CONH.sub.2, R.sup.32B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.32B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.32B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.32B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.32B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5B is independently hydrogen, CX.sup.5B.sub.3, CHX.sup.5B.sub.2, CH.sub.2X.sup.5B, CN, COOH, CONH.sub.2, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.5B is independently F, Cl, Br, or I. In embodiments, R.sup.5B is independently hydrogen. In embodiments, R.sup.5B is independently unsubstituted methyl. In embodiments, R.sup.5B is independently unsubstituted ethyl.
[0330] In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.32B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or R.sup.32B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a R.sup.32B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
[0331] R.sup.32B is independently oxo,
halogen, CX.sup.32B.sub.3, CHX.sup.32B.sub.2, CH.sub.2X.sup.32B, OCX.sup.32B.sub.3, OCH.sub.2X.sup.32B, OCHX.sup.32B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.33B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.33B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.33B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.33B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.33B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.33B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.32B is independently oxo,
halogen, CX.sup.32B.sub.3, CHX.sup.32B.sub.2, CH.sub.2X.sup.32B, OCX.sup.32B.sub.3, OCH.sub.2X.sup.32B, OCHX.sup.32B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.32B is independently F, Cl, Br, or I. In embodiments, R.sup.32B is independently unsubstituted methyl. In embodiments, R.sup.32B is independently unsubstituted ethyl.
[0332] R.sup.33B is independently oxo,
halogen, CX.sup.33B.sub.3, CHX.sup.33B.sub.2, CH.sub.2X.sup.33B, OCX.sup.33B.sub.3, OCH.sub.2X.sup.33B, OCHX.sup.33B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, R.sup.34B-substituted or unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), R.sup.34B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R.sup.34B-substituted or unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), R.sup.34B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R.sup.34B-substituted or unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or R.sup.34B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R.sup.33B is independently oxo,
halogen, CX.sup.33B.sub.3, CHX.sup.33B.sub.2, CH.sub.2X.sup.33B, OCX.sup.33B.sub.3, OCH.sub.2X.sup.33B, OCHX.sup.33B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.33B is independently F, Cl, Br, or I. In embodiments, R.sup.33B is independently unsubstituted methyl. In embodiments, R.sup.33B is independently unsubstituted ethyl.
[0333] R.sup.34B is independently oxo,
halogen, CX.sup.34B.sub.3, CHX.sup.34B.sub.2, CH.sub.2X.sup.34B, OCX.sup.34B.sub.3, OCH.sub.2X.sup.34B, OCHX.sup.34B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, unsubstituted alkyl (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C.sub.6-C.sub.10 or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X.sup.34B is independently F, Cl, Br, or I. In embodiments, R.sup.34B is independently unsubstituted methyl. In embodiments, R.sup.34B is independently unsubstituted ethyl.
[0334] In embodiments, X is F. In embodiments, X is Cl. In embodiments, X is Br. In embodiments, X is I. In embodiments, X.sup.1 is F. In embodiments, X.sup.1 is Cl. In embodiments, X.sup.1 is Br. In embodiments, X.sup.1 is I. In embodiments, X.sup.2 is F. In embodiments, X.sup.2 is Cl. In embodiments, X.sup.2 is Br. In embodiments, X.sup.2 is I. In embodiments, X.sup.4 is F. In embodiments, X.sup.4 is Cl. In embodiments, X.sup.4 is Br. In embodiments, X.sup.4 is I. In embodiments, X.sup.5 is F. In embodiments, X.sup.5 is Cl. In embodiments, X.sup.5 is Br. In embodiments, X.sup.5 is I.
[0335] In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments, n4 is 0. In embodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4.
[0336] In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, m4 is 1. In embodiments, m4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2.
[0337] In embodiments, v1 is 1. In embodiments, v1 is 2. In embodiments, v2 is 1. In embodiments, v2 is 2. In embodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments, v5 is 2.
[0338] In embodiments, E is a covalent cysteine modifier moiety.
[0339] In embodiments, E is:
##STR00019##
[0340] R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B, NHC(O)NHNR.sup.15AR.sup.15B, NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2, CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, ONR.sup.16AR.sup.16B, NHC(O)NHNR.sup.16AR.sup.16B, NHC(O)NR.sup.16AR.sup.16B, N(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B, NHC(O)NHNR.sup.17AR.sup.17B, NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
[0341] Each R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I. The symbols n15, n16, n17, v15, v16, and v17, are independently and integer from 0 to 4. The symbols m15, m16, and m17 are independently and integer between 1 and 2.
[0342] In embodiments, E is:
##STR00020##
and X.sup.17 is Cl. In embodiments, E is:
##STR00021##
In embodiments, X.sup.17 is Cl.
[0343] In embodiments, E is:
##STR00022##
and R.sup.15, R.sup.16, and R.sup.17 are independently hydrogen. In embodiments, E is:
##STR00023##
In embodiments, R.sup.15, R.sup.16, and R.sup.17 are independently hydrogen.
[0344] In embodiments, E is:
##STR00024##
R.sup.15 is independently hydrogen; R.sup.16 is independently hydrogen or CH.sub.2NR.sup.16AR.sup.16B; R.sup.17 is independently hydrogen; and R.sup.16A and R.sup.16B are independently hydrogen or unsubstituted alkyl. In embodiments, E is:
##STR00025##
In embodiments, R.sup.15 is independently hydrogen. In embodiments, R.sup.16 is independently hydrogen or CH.sub.2NR.sup.16AR.sup.16B. In embodiments, R.sup.17 is independently hydrogen. In embodiments, R.sup.16A and R.sup.16 are independently hydrogen or unsubstituted alkyl. In embodiments, R.sup.16A and R.sup.16B are independently unsubstituted methyl.
[0345] In embodiments, E is:
##STR00026##
In embodiments, E is:
##STR00027##
In embodiments, E is:
##STR00028##
In embodiments, E is:
##STR00029##
In embodiments, E is:
##STR00030##
In embodiments, E is:
##STR00031##
In embodiments, E is:
##STR00032##
In embodiments, E is:
##STR00033##
In embodiments, E is:
##STR00034##
In embodiments, E is:
##STR00035##
[0346] X may independently be F. X may independently be Cl. X may independently be Br. X may independently be I. X.sup.15 may independently be F. X.sup.15 may independently be Cl. X.sup.15 may independently be Br. X.sup.15 may independently be I. X.sup.16 may independently be F. X.sup.16 may independently be Cl. X.sup.16 may independently be Br. X.sup.16 may independently be I. X.sup.17 may independently be F. X.sup.17 may independently be Cl. X.sup.17 may independently be Br. X.sup.17 may independently be I. X.sup.18 may independently be F. X.sup.18 may independently be Cl. X.sup.18 may independently be Br. X.sup.18 may independently be I. n15 may independently be 0. n15 may independently be 1. n15 may independently be 2. n15 may independently be 3. n15 may independently be 4. n16 may independently be 0. n16 may independently be 1. n16 may independently be 2. n16 may independently be 3. n16 may independently be 4. n17 may independently be 0. n17 may independently be 1. n17 may independently be 2. n17 may independently be 3. n17 may independently be 4. v15 may independently be 0. v15 may independently be 1. v15 may independently be 2. v15 may independently be 3. v15 may independently be 4. v16 may independently be 0. v16 may independently be 1. v16 may independently be 2. v16 may independently be 3. v16 may independently be 4. v17 may independently be 0. v17 may independently be 1. v17 may independently be 2. v17 may independently be 3. v17 may independently be 4. m15 may independently be 1. m15 may independently be 2. m16 may independently be 1. m16 may independently be 2. m17 may independently be 1. m17 may independently be 2.
[0347] In embodiments, R.sup.15 is hydrogen. In embodiments, R.sup.15 is halogen. In embodiments, R.sup.15 is CX.sup.15.sub.3. In embodiments, R.sup.15 is CHX.sup.15.sub.2. In embodiments, R.sup.15 is CH.sub.2X.sup.15. In embodiments, R.sup.15 is CN. In embodiments, R.sup.15 is SO.sub.n15R.sup.15D. In embodiments, R.sup.15 is SO.sub.v15NR.sup.15AR.sup.15B. In embodiments, R.sup.15 is NHNR.sup.15AR.sup.15B. In embodiments, R.sup.15 is ONR.sup.15AR.sup.15B. In embodiments, R.sup.15 is NHC(O)NHNR.sup.15AR.sup.15B. In embodiments, R.sup.15 is NHC(O)NR.sup.15AR.sup.15B. In embodiments, R.sup.15 is N(O).sub.m15. In embodiments, R.sup.15 is NR.sup.15AR.sup.15B. In embodiments, R.sup.15 is C(O)R.sup.15C. In embodiments, R.sup.15 is C(O)OR.sup.15C. In embodiments, R.sup.15 is C(O)NR.sup.15AR.sup.15B. In embodiments, R.sup.15 is OR.sup.15D. In embodiments, R.sup.15 is NR.sup.15ASO.sub.2R.sup.15D. In embodiments, R.sup.15 is NR.sup.15AC(O)R.sup.15C. In embodiments, R.sup.15 is NR.sup.15AC(O)OR.sup.15C. In embodiments, R.sup.15 is NR.sup.15AOR.sup.15C. In embodiments, R.sup.15 is OCX.sup.15.sub.3. In embodiments, R.sup.15 is OCHX.sup.15.sub.2. In embodiments, R.sup.15 is substituted or unsubstituted alkyl. In embodiments, R.sup.15 is substituted or unsubstituted heteroalkyl. In embodiments, R.sup.15 is substituted or unsubstituted cycloalkyl. In embodiments, R.sup.15 is substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.15 is substituted or unsubstituted aryl. In embodiments, R.sup.15 is substituted or unsubstituted heteroaryl. In embodiments, R.sup.15 is substituted alkyl. In embodiments, R.sup.15 is substituted heteroalkyl. In embodiments, R.sup.15 is substituted cycloalkyl. In embodiments, R.sup.15 is substituted heterocycloalkyl. In embodiments, R.sup.15 is substituted aryl. In embodiments, R.sup.15 is substituted heteroaryl. In embodiments, R.sup.15 is unsubstituted alkyl. In embodiments, R.sup.15 is unsubstituted heteroalkyl. In embodiments, R.sup.15 is unsubstituted cycloalkyl. In embodiments, R.sup.15 is unsubstituted heterocycloalkyl. In embodiments, R.sup.15 is unsubstituted aryl. In embodiments, R.sup.15 is unsubstituted heteroaryl. In embodiments, R.sup.15 is unsubstituted methyl. In embodiments, R.sup.15 is unsubstituted ethyl. In embodiments, R.sup.15 is unsubstituted propyl. In embodiments, R.sup.15 is unsubstituted isopropyl. In embodiments, R.sup.15 is unsubstituted butyl. In embodiments, R.sup.15 is unsubstituted tert-butyl.
[0348] In embodiments, R.sup.15A is hydrogen. In embodiments, R.sup.15A is CX.sub.3. In embodiments, R.sup.15A is CN. In embodiments, R.sup.15A is COOH. In embodiments, R.sup.15A is CONH.sub.2. In embodiments, R.sup.15A is CHX.sub.2. In embodiments, R.sup.15A is CH.sub.2X. In embodiments, R.sup.15A is unsubstituted methyl. In embodiments, R.sup.15A is unsubstituted ethyl. In embodiments, R.sup.15A is unsubstituted propyl. In embodiments, R.sup.15A is unsubstituted isopropyl. In embodiments, R.sup.15A is unsubstituted butyl. In embodiments, R.sup.15A is unsubstituted tert-butyl.
[0349] In embodiments, R.sup.15B is hydrogen. In embodiments, R.sup.15B is CX.sub.3. In embodiments, R.sup.15B is CN. In embodiments, R.sup.15B is COOH. In embodiments, R.sup.15B is CONH.sub.2. In embodiments, R.sup.15B is CHX.sub.2. In embodiments, R.sup.15B is CH.sub.2X. In embodiments, R.sup.15B is unsubstituted methyl. In embodiments, R.sup.15B is unsubstituted ethyl. In embodiments, R.sup.15B is unsubstituted propyl. In embodiments, R.sup.15B is unsubstituted isopropyl. In embodiments, R.sup.15B is unsubstituted butyl. In embodiments, R.sup.15B is unsubstituted tert-butyl.
[0350] In embodiments, R.sup.15C is hydrogen. In embodiments, R.sup.15C is CX.sub.3. In embodiments, R.sup.15C is CN. In embodiments, R.sup.15C is COOH. In embodiments, R.sup.15C is CONH.sub.2. In embodiments, R.sup.15C is CHX.sub.2. In embodiments, R.sup.15C is CH.sub.2X. In embodiments, R.sup.15C is unsubstituted methyl. In embodiments, R.sup.15C is unsubstituted ethyl. In embodiments, R.sup.15C is unsubstituted propyl. In embodiments, R.sup.15C is unsubstituted isopropyl. In embodiments, R.sup.15C is unsubstituted butyl. In embodiments, R.sup.15C is unsubstituted tert-butyl.
[0351] In embodiments, R.sup.15D is hydrogen. In embodiments, R.sup.15D is CX.sub.3. In embodiments, R.sup.15D is CN. In embodiments, R.sup.15D is COOH. In embodiments, R.sup.15D is CONH.sub.2. In embodiments, R.sup.15D is CHX.sub.2. In embodiments, R.sup.15D is CH.sub.2X. In embodiments, R.sup.15D is unsubstituted methyl. In embodiments, R.sup.15D is unsubstituted ethyl. In embodiments, R.sup.15D is unsubstituted propyl. In embodiments, R.sup.15D is unsubstituted isopropyl. In embodiments, R.sup.15D is unsubstituted butyl. In embodiments, R.sup.15D is unsubstituted tert-butyl.
[0352] In embodiments, R.sup.15 is independently hydrogen, oxo,
halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, OCH.sub.2X.sup.15, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, R.sup.72-substituted or unsubstituted alkyl, R.sup.72-substituted or unsubstituted heteroalkyl, R.sup.72-substituted or unsubstituted cycloalkyl, R.sup.72-substituted or unsubstituted heterocycloalkyl, R.sup.72-substituted or unsubstituted aryl, or R.sup.72-substituted or unsubstituted heteroaryl. X.sup.15 is halogen. In embodiments, X.sup.15 is F.
[0353] R.sup.72 is independently oxo,
halogen, CX.sup.72.sub.3, CHX.sup.72.sub.2, OCH.sub.2X.sup.72, OCHX.sup.72.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, S H, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.72.sub.3, OCHX.sup.72.sub.2, R.sup.73-substituted or unsubstituted alkyl, R.sup.73-substituted or unsubstituted heteroalkyl, R.sup.73-substituted or unsubstituted cycloalkyl, R.sup.73-substituted or unsubstituted heterocycloalkyl, R.sup.73-substituted or unsubstituted aryl, or R.sup.73-substituted or unsubstituted heteroaryl. X.sup.72 is halogen. In embodiments, X.sup.72 is F.
[0354] R.sup.73 is independently oxo,
halogen, CX.sup.73.sub.3, CHX.sup.73.sub.2, OCH.sub.2X.sup.73, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.73.sub.3, OCHX.sup.73.sub.2, R.sup.74-substituted or unsubstituted alkyl, R.sup.74-substituted or unsubstituted heteroalkyl, R.sup.74-substituted or unsubstituted cycloalkyl, R.sup.74-substituted or unsubstituted heterocycloalkyl, R.sup.74-substituted or unsubstituted aryl, or R.sup.74-substituted or unsubstituted heteroaryl. X.sup.73 is halogen. In embodiments, X.sup.73 is F.
[0355] In embodiments, R.sup.15A is independently hydrogen, oxo,
halogen, CX.sup.15A.sub.3, CHX.sup.15A.sub.2, OCH.sub.2X.sup.15A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.15A.sub.3, OCHX.sup.15A.sub.2, R.sup.72A-substituted or unsubstituted alkyl, R.sup.72A-substituted or unsubstituted heteroalkyl, R.sup.72A-substituted or unsubstituted cycloalkyl, R.sup.72A-substituted or unsubstituted heterocycloalkyl, R.sup.72A-substituted or unsubstituted aryl, or R.sup.72A-substituted or unsubstituted heteroaryl. X.sup.15A is halogen. In embodiments, X.sup.15A is F.
[0356] R.sup.72A is independently oxo,
halogen, CX.sup.72A.sub.3, CHX.sup.72A.sub.2, OCH.sub.2X.sup.72A, OCHX.sup.72A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.72A.sub.3, OCHX.sup.72A.sub.2, R.sup.73A-substituted or unsubstituted alkyl, R.sup.73A-substituted or unsubstituted heteroalkyl, R.sup.73A-substituted or unsubstituted cycloalkyl, R.sup.73A-substituted or unsubstituted heterocycloalkyl, R.sup.73A-substituted or unsubstituted aryl, or R.sup.73A-substituted or unsubstituted heteroaryl. X.sup.72A is halogen. In embodiments, X.sup.72A is F.
[0357] R.sup.73A is independently oxo,
halogen, CX.sup.73A.sub.3, CHX.sup.73A.sub.2, OCH.sub.2X.sup.73A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.73A.sub.3, OCHX.sup.73A.sub.2, R.sup.74A-substituted or unsubstituted alkyl, R.sup.74A-substituted or unsubstituted heteroalkyl, R.sup.74A-substituted or unsubstituted cycloalkyl, R.sup.74A-substituted or unsubstituted heterocycloalkyl, R.sup.74A-substituted or unsubstituted aryl, or R.sup.74A-substituted or unsubstituted heteroaryl. X.sup.73A is halogen. In embodiments, X.sup.73A is F.
[0358] In embodiments, R.sup.15B is independently hydrogen, oxo,
halogen, CX.sup.15B.sub.3, CHX.sup.15B.sub.2, OCH.sub.2X.sup.15B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.15B.sub.3, OCHX.sup.15B.sub.2, R.sup.72B-substituted or unsubstituted alkyl, R.sup.72B-substituted or unsubstituted heteroalkyl, R.sup.72B-substituted or unsubstituted cycloalkyl, R.sup.72B-substituted or unsubstituted heterocycloalkyl, R.sup.72B-substituted or unsubstituted aryl, or R.sup.72B-substituted or unsubstituted heteroaryl. X.sup.15B is halogen. In embodiments, X.sup.15B is F.
[0359] R.sup.72B is independently oxo,
halogen, CX.sup.72B.sub.3, CHX.sup.72B.sub.2, OCH.sub.2X.sup.72B, OCHX.sup.72B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.72B.sub.3, OCHX.sup.72B.sub.2, R.sup.73B-substituted or unsubstituted alkyl, R.sup.73B-substituted or unsubstituted heteroalkyl, R.sup.73B-substituted or unsubstituted cycloalkyl, R.sup.73B-substituted or unsubstituted heterocycloalkyl, R.sup.73B-substituted or unsubstituted aryl, or R.sup.73B-substituted or unsubstituted heteroaryl. X.sup.72B is halogen. In embodiments, X.sup.72B is F.
[0360] R.sup.73B is independently oxo,
halogen, CX.sup.73B.sub.3, CHX.sup.73B.sub.2, OCH.sub.2X.sup.73B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.73B.sub.3, OCHX.sup.73B.sub.2, R.sup.74B-substituted or unsubstituted alkyl, R.sup.74B-substituted or unsubstituted heteroalkyl, R.sup.74B-substituted or unsubstituted cycloalkyl, R.sup.74B-substituted or unsubstituted heterocycloalkyl, R.sup.74B-substituted or unsubstituted aryl, or R.sup.74B-substituted or unsubstituted heteroaryl. X.sup.73B is halogen. In embodiments, X.sup.73B is F.
[0361] In embodiments, R.sup.15C is independently hydrogen, oxo,
halogen, CX.sup.15C.sub.3, CHX.sup.15C.sub.2, OCH.sub.2X.sup.15C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.15C.sub.3, OCHX.sup.15C.sub.2, R.sup.72C-substituted or unsubstituted alkyl, R.sup.72C-substituted or unsubstituted heteroalkyl, R.sup.72C-substituted or unsubstituted cycloalkyl, R.sup.72C-substituted or unsubstituted heterocycloalkyl, R.sup.72C-substituted or unsubstituted aryl, or R.sup.72C-substituted or unsubstituted heteroaryl. X.sup.15C is halogen. In embodiments, X.sup.15C is F.
[0362] R.sup.72C is independently oxo,
halogen, CX.sup.72C.sub.3, CHX.sup.72C.sub.2, OCH.sub.2X.sup.72C, OCHX.sup.72C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.72C.sub.3, OCHX.sup.72C.sub.2, R.sup.73C-substituted or unsubstituted alkyl, R.sup.73C-substituted or unsubstituted heteroalkyl, R.sup.73C-substituted or unsubstituted cycloalkyl, R.sup.73C-substituted or unsubstituted heterocycloalkyl, R.sup.73C-substituted or unsubstituted aryl, or R.sup.73C-substituted or unsubstituted heteroaryl. X.sup.72C is halogen. In embodiments, X.sup.72C is F.
[0363] R.sup.73C is independently oxo,
halogen, CX.sup.73C.sub.3, CHX.sup.73C.sub.2, OCH.sub.2X.sup.73C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.73C.sub.3, OCHX.sup.73C.sub.2, R.sup.74C-substituted or unsubstituted alkyl, R.sup.74C-substituted or unsubstituted heteroalkyl, R.sup.74C-substituted or unsubstituted cycloalkyl, R.sup.74C-substituted or unsubstituted heterocycloalkyl, R.sup.74C-substituted or unsubstituted aryl, or R.sup.74C-substituted or unsubstituted heteroaryl. X.sup.73C is halogen. In embodiments, X.sup.73C is F.
[0364] In embodiments, R.sup.15D is independently hydrogen, oxo,
halogen, CX.sup.15D.sub.3, CHX.sup.15D.sub.2, OCH.sub.2X.sup.15D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.15D.sub.3, OCHX.sup.15D.sub.2, R.sup.72D-substituted or unsubstituted alkyl, R.sup.72D-substituted or unsubstituted heteroalkyl, R.sup.72D-substituted or unsubstituted cycloalkyl, R.sup.72D-substituted or unsubstituted heterocycloalkyl, R.sup.72D-substituted or unsubstituted aryl, or R.sup.72D-substituted or unsubstituted heteroaryl. X.sup.15D is halogen. In embodiments, X.sup.15D is F.
[0365] R.sup.72D is independently oxo,
halogen, CX.sup.72D.sub.3, CHX.sup.72D.sub.2, OCH.sub.2X.sup.72D, OCHX.sup.72D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.72D.sub.3, OCHX.sup.72D.sub.2, R.sup.73D-substituted or unsubstituted alkyl, R.sup.73D-substituted or unsubstituted heteroalkyl, R.sup.73D-substituted or unsubstituted cycloalkyl, R.sup.73D-substituted or unsubstituted heterocycloalkyl, R.sup.73D-substituted or unsubstituted aryl, or R.sup.73D-substituted or unsubstituted heteroaryl. X.sup.72D is halogen. In embodiments, X.sup.72D is F.
[0366] R.sup.73D is independently oxo,
halogen, CX.sup.73D.sub.3, CHX.sup.73D.sub.2, OCH.sub.2X.sup.73D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.73D.sub.3, OCHX.sup.73D.sub.2, R.sup.74D-substituted or unsubstituted alkyl, R.sup.74D-substituted or unsubstituted heteroalkyl, R.sup.74D-substituted or unsubstituted cycloalkyl, R.sup.74D-substituted or unsubstituted heterocycloalkyl, R.sup.74D-substituted or unsubstituted aryl, or R.sup.74D-substituted or unsubstituted heteroaryl. X.sup.73D is halogen. In embodiments, X.sup.73D is F.
[0367] In embodiments, R.sup.16 is hydrogen. In embodiments, R.sup.16 is halogen. In embodiments, R.sup.16 is CX.sup.16.sub.3. In embodiments, R.sup.16 is CHX.sup.16.sub.2. In embodiments, R.sup.16 is CH.sub.2X.sup.16. In embodiments, R.sup.16 is CN. In embodiments, R.sup.16 is SO.sub.n16R.sup.16D. In embodiments, R.sup.16 is SO.sub.v16NR.sup.16AR.sup.16B. In embodiments, R.sup.16 is NHNR.sup.16AR.sup.16B. In embodiments, R.sup.16 is ONR.sup.16AR.sup.16B. In embodiments, R.sup.16 is NHC(O)NHNR.sup.16AR.sup.16B. In embodiments, R.sup.16 is NHC(O)NR.sup.16AR.sup.16B. In embodiments, R.sup.16 is N(O).sub.m16. In embodiments, R.sup.16 is NR.sup.16AR.sup.16B. In embodiments, R.sup.16 is C(O)R.sup.16C. In embodiments, R.sup.16 is C(O)OR.sup.16C. In embodiments, R.sup.16 is C(O)NR.sup.16AR.sup.16B. In embodiments, R.sup.16 is OR.sup.16D. In embodiments, R.sup.16 is NR.sup.16ASO.sub.2R.sup.16D. In embodiments, R.sup.16 is NR.sup.16AC(O)R.sup.16C. In embodiments, R.sup.16 is NR.sup.16AC(O)OR.sup.16C. In embodiments, R.sup.16 is NR.sup.16AOR.sup.16C. In embodiments, R.sup.16 is OCX.sup.16.sub.3. In embodiments, R.sup.16 is OCHX.sup.16.sub.2. In embodiments, R.sup.16 is substituted or unsubstituted alkyl. In embodiments, R.sup.16 is substituted or unsubstituted heteroalkyl. In embodiments, R.sup.16 is substituted or unsubstituted cycloalkyl. In embodiments, R.sup.16 is substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.16 is substituted or unsubstituted aryl. In embodiments, R.sup.16 is substituted or unsubstituted heteroaryl. In embodiments, R.sup.16 is substituted alkyl. In embodiments, R.sup.16 is substituted heteroalkyl. In embodiments, R.sup.16 is substituted cycloalkyl. In embodiments, R.sup.16 is substituted heterocycloalkyl. In embodiments, R.sup.16 is substituted aryl. In embodiments, R.sup.16 is substituted heteroaryl. In embodiments, R.sup.16 is unsubstituted alkyl. In embodiments, R.sup.16 is unsubstituted heteroalkyl. In embodiments, R.sup.16 is unsubstituted cycloalkyl. In embodiments, R.sup.16 is unsubstituted heterocycloalkyl. In embodiments, R.sup.16 is unsubstituted aryl. In embodiments, R.sup.16 is unsubstituted heteroaryl. In embodiments, R.sup.16 is unsubstituted methyl. In embodiments, R.sup.16 is unsubstituted ethyl. In embodiments, R.sup.16 is unsubstituted propyl. In embodiments, R.sup.16 is unsubstituted isopropyl. In embodiments, R.sup.16 is unsubstituted butyl. In embodiments, R.sup.16 is unsubstituted tert-butyl.
[0368] In embodiments, R.sup.16A is hydrogen. In embodiments, R.sup.16A is CX.sub.3. In embodiments, R.sup.16A is CN. In embodiments, R.sup.16A is COOH. In embodiments, R.sup.16A is CONH.sub.2. In embodiments, R.sup.16A is CHX.sub.2. In embodiments, R.sup.16A is CH.sub.2X. In embodiments, R.sup.16A is unsubstituted methyl. In embodiments, R.sup.16A is unsubstituted ethyl. In embodiments, R.sup.16A is unsubstituted propyl. In embodiments, R.sup.16A is unsubstituted isopropyl. In embodiments, R.sup.16A is unsubstituted butyl. In embodiments, R.sup.16A is unsubstituted tert-butyl.
[0369] In embodiments, R.sup.16B is hydrogen. In embodiments, R.sup.16B is CX.sub.3. In embodiments, R.sup.16B is CN. In embodiments, R.sup.16B is COOH. In embodiments, R.sup.16B is CONH.sub.2. In embodiments, R.sup.16B is CHX.sub.2. In embodiments, R.sup.16B is CH.sub.2X. In embodiments, R.sup.16B is unsubstituted methyl. In embodiments, R.sup.16B is unsubstituted ethyl. In embodiments, R.sup.16B is unsubstituted propyl. In embodiments, R.sup.16B is unsubstituted isopropyl. In embodiments, R.sup.16B is unsubstituted butyl. In embodiments, R.sup.16B is unsubstituted tert-butyl.
[0370] In embodiments, R.sup.16C is hydrogen. In embodiments, R.sup.16C is CX.sub.3. In embodiments, R.sup.16C is CN. In embodiments, R.sup.16C is COOH. In embodiments, R.sup.16C is CONH.sub.2. In embodiments, R.sup.16C is CHX.sub.2. In embodiments, R.sup.16C is CH.sub.2X. In embodiments, R.sup.16C is unsubstituted methyl. In embodiments, R.sup.16C is unsubstituted ethyl. In embodiments, R.sup.16C is unsubstituted propyl. In embodiments, R.sup.16C is unsubstituted isopropyl. In embodiments, R.sup.16C is unsubstituted butyl. In embodiments, R.sup.16C is unsubstituted tert-butyl.
[0371] In embodiments, R.sup.16D is hydrogen. In embodiments, R.sup.16D is CX.sub.3. In embodiments, R.sup.16D is CN. In embodiments, R.sup.16D is COOH. In embodiments, R.sup.16D is CONH.sub.2. In embodiments, R.sup.16D is CHX.sub.2. In embodiments, R.sup.16D is CH.sub.2X. In embodiments, R.sup.16D is unsubstituted methyl. In embodiments, R.sup.16D is unsubstituted ethyl. In embodiments, R.sup.16D is unsubstituted propyl. In embodiments, R.sup.16D is unsubstituted isopropyl. In embodiments, R.sup.16D is unsubstituted butyl. In embodiments, R.sup.16D is unsubstituted tert-butyl.
[0372] In embodiments, R.sup.16 is independently hydrogen, oxo,
halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2, OCH.sub.2X.sup.16, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, R.sup.75-substituted or unsubstituted alkyl, R.sup.75-substituted or unsubstituted heteroalkyl, R.sup.75-substituted or unsubstituted cycloalkyl, R.sup.75-substituted or unsubstituted heterocycloalkyl, R.sup.75-substituted or unsubstituted aryl, or R.sup.75-substituted or unsubstituted heteroaryl. X.sup.16 is halogen. In embodiments, X.sup.16 is F.
[0373] R.sup.75 is independently oxo,
halogen, CX.sup.75.sub.3, CHX.sup.75.sub.2, OCH.sub.2X.sup.75, OCHX.sup.75.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, S H, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.75.sub.3, OCHX.sup.75.sub.2, R.sup.76-substituted or unsubstituted alkyl, R.sup.76-substituted or unsubstituted heteroalkyl, R.sup.76-substituted or unsubstituted cycloalkyl, R.sup.76-substituted or unsubstituted heterocycloalkyl, R.sup.76-substituted or unsubstituted aryl, or R.sup.76-substituted or unsubstituted heteroaryl. X.sup.75 is halogen. In embodiments, X.sup.75 is F.
[0374] R.sup.76 is independently oxo,
halogen, CX.sup.76.sub.3, CHX.sup.76.sub.2, OCH.sub.2X.sup.76, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.76.sub.3, OCHX.sup.76.sub.2, R.sup.77-substituted or unsubstituted alkyl, R.sup.77-substituted or unsubstituted heteroalkyl, R.sup.77-substituted or unsubstituted cycloalkyl, R.sup.77-substituted or unsubstituted heterocycloalkyl, R.sup.77-substituted or unsubstituted aryl, or R.sup.77-substituted or unsubstituted heteroaryl. X.sup.76 is halogen. In embodiments, X.sup.76 is F.
[0375] In embodiments, R.sup.16A is independently hydrogen, oxo,
halogen, CX.sup.16A.sub.3, CHX.sup.16A.sub.2, OCH.sub.2X.sup.16A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.16A.sub.3, OCHX.sup.16A.sub.2, R.sup.75A-substituted or unsubstituted alkyl, R.sup.75A-substituted or unsubstituted heteroalkyl, R.sup.75A-substituted or unsubstituted cycloalkyl, R.sup.75A-substituted or unsubstituted heterocycloalkyl, R.sup.75A-substituted or unsubstituted aryl, or R.sup.75A-substituted or unsubstituted heteroaryl. X.sup.16A is halogen. In embodiments, X.sup.16A is F.
[0376] R.sup.75A is independently oxo,
halogen, CX.sup.75A.sub.3, CHX.sup.75A.sub.2, OCH.sub.2X.sup.75A, OCHX.sup.75A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.75A.sub.3, OCHX.sup.75A.sub.2, R.sup.76A-substituted or unsubstituted alkyl, R.sup.76A-substituted or unsubstituted heteroalkyl, R.sup.76A-substituted or unsubstituted cycloalkyl, R.sup.76A-substituted or unsubstituted heterocycloalkyl, R.sup.76A-substituted or unsubstituted aryl, or R.sup.76A-substituted or unsubstituted heteroaryl. X.sup.75A is halogen. In embodiments, X.sup.75A is F.
[0377] R.sup.76A is independently oxo,
halogen, CX.sup.76A.sub.3, CHX.sup.76A.sub.2, OCH.sub.2X.sup.76A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.76A.sub.3, OCHX.sup.76A.sub.2, R.sup.77A-substituted or unsubstituted alkyl, R.sup.77A-substituted or unsubstituted heteroalkyl, R.sup.77A-substituted or unsubstituted cycloalkyl, R.sup.77A-substituted or unsubstituted heterocycloalkyl, R.sup.77A-substituted or unsubstituted aryl, or R.sup.77A-substituted or unsubstituted heteroaryl. X.sup.76A is halogen. In embodiments, X.sup.76A is F.
[0378] In embodiments, R.sup.16B is independently hydrogen, oxo,
halogen, CX.sup.16B.sub.3, CHX.sup.16B.sub.2, OCH.sub.2X.sup.16B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.16B.sub.3, OCHX.sup.16B.sub.2, R.sup.75B-substituted or unsubstituted alkyl, R.sup.75B-substituted or unsubstituted heteroalkyl, R.sup.75B-substituted or unsubstituted cycloalkyl, R.sup.75B-substituted or unsubstituted heterocycloalkyl, R.sup.75B-substituted or unsubstituted aryl, or R.sup.75B-substituted or unsubstituted heteroaryl. X.sup.16B is halogen. In embodiments, X.sup.16B is F.
[0379] R.sup.75B is independently oxo,
halogen, CX.sup.75B.sub.3, CHX.sup.75B.sub.2, OCH.sub.2X.sup.75B, OCHX.sup.75B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.75B.sub.3, OCHX.sup.75B.sub.2, R.sup.76B-substituted or unsubstituted alkyl, R.sup.76B-substituted or unsubstituted heteroalkyl, R.sup.76B-substituted or unsubstituted cycloalkyl, R.sup.76B-substituted or unsubstituted heterocycloalkyl, R.sup.76B-substituted or unsubstituted aryl, or R.sup.76B-substituted or unsubstituted heteroaryl. X.sup.75B is halogen. In embodiments, X.sup.75B is F.
[0380] R.sup.76B is independently oxo,
halogen, CX.sup.76B.sub.3, CHX.sup.76B.sub.2, OCH.sub.2X.sup.76B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.76B.sub.3, OCHX.sup.76B.sub.2, R.sup.77B-substituted or unsubstituted alkyl, R.sup.77B-substituted or unsubstituted heteroalkyl, R.sup.77B-substituted or unsubstituted cycloalkyl, R.sup.77B-substituted or unsubstituted heterocycloalkyl, R.sup.77B-substituted or unsubstituted aryl, or R.sup.77B-substituted or unsubstituted heteroaryl. X.sup.76B is halogen. In embodiments, X.sup.76B is F.
[0381] In embodiments, R.sup.16C is independently hydrogen, oxo,
halogen, CX.sup.16C.sub.3, CHX.sup.16C.sub.2, OCH.sub.2X.sup.16C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.16C.sub.3, OCHX.sup.16C.sub.2, R.sup.75C-substituted or unsubstituted alkyl, R.sup.75C-substituted or unsubstituted heteroalkyl, R.sup.75C-substituted or unsubstituted cycloalkyl, R.sup.75C-substituted or unsubstituted heterocycloalkyl, R.sup.75C-substituted or unsubstituted aryl, or R.sup.75C-substituted or unsubstituted heteroaryl. X.sup.16C is halogen. In embodiments, X.sup.16C is F.
[0382] R.sup.75C is independently oxo,
halogen, CX.sup.75C.sub.3, CHX.sup.75C.sub.2, OCH.sub.2X.sup.75C, OCHX.sup.75C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.75C.sub.3, OCHX.sup.75C.sub.2, R.sup.76C-substituted or unsubstituted alkyl, R.sup.76C-substituted or unsubstituted heteroalkyl, R.sup.76C-substituted or unsubstituted cycloalkyl, R.sup.76C-substituted or unsubstituted heterocycloalkyl, R.sup.76C-substituted or unsubstituted aryl, or R.sup.76C-substituted or unsubstituted heteroaryl. X.sup.75C is halogen. In embodiments, X.sup.75C is F.
[0383] R.sup.76C is independently oxo,
halogen, CX.sup.76C.sub.3, CHX.sup.76C.sub.2, OCH.sub.2X.sup.76C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.76C.sub.3, OCHX.sup.76C.sub.2, R.sup.77C-substituted or unsubstituted alkyl, R.sup.77C-substituted or unsubstituted heteroalkyl, R.sup.77C-substituted or unsubstituted cycloalkyl, R.sup.77C-substituted or unsubstituted heterocycloalkyl, R.sup.77C-substituted or unsubstituted aryl, or R.sup.77C-substituted or unsubstituted heteroaryl. X.sup.76C is halogen. In embodiments, X.sup.76C is F.
[0384] In embodiments, R.sup.16D is independently hydrogen, oxo,
halogen, CX.sup.16D.sub.3, CHX.sup.16D.sub.2, OCH.sub.2X.sup.16D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.16D.sub.3, OCHX.sup.16D.sub.2, R.sup.75D-substituted or unsubstituted alkyl, R.sup.75D-substituted or unsubstituted heteroalkyl, R.sup.75D-substituted or unsubstituted cycloalkyl, R.sup.75D-substituted or unsubstituted heterocycloalkyl, R.sup.75D-substituted or unsubstituted aryl, or R.sup.75D-substituted or unsubstituted heteroaryl. X.sup.16D is halogen. In embodiments, X.sup.16D is F.
[0385] R.sup.75D is independently oxo,
halogen, CX.sup.75D.sub.3, CHX.sup.75D.sub.2, OCH.sub.2X.sup.75D, OCHX.sup.75D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.75D.sub.3, OCHX.sup.75D.sub.2, R.sup.76D-substituted or unsubstituted alkyl, R.sup.76D-substituted or unsubstituted heteroalkyl, R.sup.76D-substituted or unsubstituted cycloalkyl, R.sup.76D-substituted or unsubstituted heterocycloalkyl, R.sup.76D-substituted or unsubstituted aryl, or R.sup.76D-substituted or unsubstituted heteroaryl. X.sup.75D is halogen. In embodiments, X.sup.75D is F.
[0386] R.sup.76D is independently oxo,
halogen, CX.sup.76D.sub.3, CHX.sup.76D.sub.2, OCH.sub.2X.sup.76D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.76D.sub.3, OCHX.sup.76D.sub.2, R.sup.77D-substituted or unsubstituted alkyl, R.sup.77D-substituted or unsubstituted heteroalkyl, R.sup.77D-substituted or unsubstituted cycloalkyl, R.sup.77D-substituted or unsubstituted heterocycloalkyl, R.sup.77D-substituted or unsubstituted aryl, or R.sup.77D-substituted or unsubstituted heteroaryl. X.sup.76D is halogen. In embodiments, X.sup.76D is F.
[0387] In embodiments, R.sup.17 is hydrogen. In embodiments, R.sup.17 is halogen. In embodiments, R.sup.17 is CX.sup.17.sub.3. In embodiments, R.sup.17 is CHX.sup.17.sub.2. In embodiments, R.sup.17 is CH.sub.2X.sup.17. In embodiments, R.sup.17 is CN. In embodiments, R.sup.17 is SO.sub.n17R.sup.17D. In embodiments, R.sup.17 is SO.sub.v17NR.sup.17AR.sup.17B. In embodiments, R.sup.17 is NHNR.sup.17AR.sup.17B. In embodiments, R.sup.17 is ONR.sup.17AR.sup.17B. In embodiments, R.sup.17 is NHC(O)NHNR.sup.17AR.sup.17B. In embodiments, R.sup.17 is NHC(O)NR.sup.17AR.sup.17B. In embodiments, R.sup.17 is N(O).sub.m17. In embodiments, R.sup.17 is NR.sup.17AR.sup.17B. In embodiments, R.sup.17 is C(O)R.sup.17C. In embodiments, R.sup.17 is C(O)OR.sup.17C. In embodiments, R.sup.17 is C(O)NR.sup.17AR.sup.17B. In embodiments, R.sup.17 is OR.sup.17C. In embodiments, R.sup.17 is NR.sup.17ASO.sub.2R.sup.17D. In embodiments, R.sup.17 is NR.sup.17AC(O)R.sup.17C. In embodiments, R.sup.17 is NR.sup.17AC(O)OR.sup.17C. In embodiments, R.sup.17 is NR.sup.17AOR.sup.17C. In embodiments, R.sup.17 is OCX.sup.17.sub.3. In embodiments, R.sup.17 is OCHX.sup.172. In embodiments, R.sup.17 is substituted or unsubstituted alkyl. In embodiments, R.sup.17 is substituted or unsubstituted heteroalkyl. In embodiments, R.sup.17 is substituted or unsubstituted cycloalkyl. In embodiments, R.sup.17 is substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.17 is substituted or unsubstituted aryl. In embodiments, R.sup.17 is substituted or unsubstituted heteroaryl. In embodiments, R.sup.17 is substituted alkyl. In embodiments, R.sup.17 is substituted heteroalkyl. In embodiments, R.sup.17 is substituted cycloalkyl. In embodiments, R.sup.17 is substituted heterocycloalkyl. In embodiments, R.sup.17 is substituted aryl. In embodiments, R.sup.17 is substituted heteroaryl. In embodiments, R.sup.17 is unsubstituted alkyl. In embodiments, R.sup.17 is unsubstituted heteroalkyl. In embodiments, R.sup.17 is unsubstituted cycloalkyl. In embodiments, R.sup.17 is unsubstituted heterocycloalkyl. In embodiments, R.sup.17 is unsubstituted aryl. In embodiments, R.sup.17 is unsubstituted heteroaryl. In embodiments, R.sup.17 is unsubstituted methyl. In embodiments, R.sup.17 is unsubstituted ethyl. In embodiments, R.sup.17 is unsubstituted propyl. In embodiments, R.sup.17 is unsubstituted isopropyl. In embodiments, R.sup.17 is unsubstituted butyl. In embodiments, R.sup.17 is unsubstituted tert-butyl.
[0388] In embodiments, R.sup.17A is hydrogen. In embodiments, R.sup.17A is CX.sub.3. In embodiments, R.sup.17A is CN. In embodiments, R.sup.17A is COOH. In embodiments, R.sup.17A is CONH.sub.2. In embodiments, R.sup.17A is CHX.sub.2. In embodiments, R.sup.17A is CH.sub.2X. In embodiments, R.sup.17A is unsubstituted methyl. In embodiments, R.sup.17A is unsubstituted ethyl. In embodiments, R.sup.17A is unsubstituted propyl. In embodiments, R.sup.17A is unsubstituted isopropyl. In embodiments, R.sup.17A is unsubstituted butyl. In embodiments, R.sup.17A is unsubstituted tert-butyl.
[0389] In embodiments, R.sup.17B is hydrogen. In embodiments, R.sup.17B is CX.sub.3. In embodiments, R.sup.17B is CN. In embodiments, R.sup.17B is COOH. In embodiments, R.sup.17B is CONH.sub.2. In embodiments, R.sup.17B is CHX.sub.2. In embodiments, R.sup.17B is CH.sub.2X. In embodiments, R.sup.17B is unsubstituted methyl. In embodiments, R.sup.17B is unsubstituted ethyl. In embodiments, R.sup.17B is unsubstituted propyl. In embodiments, R.sup.17B is unsubstituted isopropyl. In embodiments, R.sup.17B is unsubstituted butyl. In embodiments, R.sup.17B is unsubstituted tert-butyl.
[0390] In embodiments, R.sup.17C is hydrogen. In embodiments, R.sup.17C is CX.sub.3. In embodiments, R.sup.17C is CN. In embodiments, R.sup.17C is COOH. In embodiments, R.sup.17C is CONH.sub.2. In embodiments, R.sup.17C is CHX.sub.2. In embodiments, R.sup.17C is CH.sub.2X. In embodiments, R.sup.17C is unsubstituted methyl. In embodiments, R.sup.17C is unsubstituted ethyl. In embodiments, R.sup.17C is unsubstituted propyl. In embodiments, R.sup.17C is unsubstituted isopropyl. In embodiments, R.sup.17C is unsubstituted butyl. In embodiments, R.sup.17C is unsubstituted tert-butyl.
[0391] In embodiments, R.sup.17D is hydrogen. In embodiments, R.sup.17D is CX.sub.3. In embodiments, R.sup.17D is CN. In embodiments, R.sup.17D is COOH. In embodiments, R.sup.17D is CONH.sub.2. In embodiments, R.sup.17D is CHX.sub.2. In embodiments, R.sup.17D is CH.sub.2X. In embodiments, R.sup.17D is unsubstituted methyl. In embodiments, R.sup.17D is unsubstituted ethyl. In embodiments, R.sup.17D is unsubstituted propyl. In embodiments, R.sup.17D is unsubstituted isopropyl. In embodiments, R.sup.17D is unsubstituted butyl. In embodiments, R.sup.17D is unsubstituted tert-butyl.
[0392] In embodiments, R.sup.17 is independently hydrogen, oxo,
halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, OCH.sub.2X.sup.17, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, R.sup.78-substituted or unsubstituted alkyl, R.sup.78-substituted or unsubstituted heteroalkyl, R.sup.78-substituted or unsubstituted cycloalkyl, R.sup.78-substituted or unsubstituted heterocycloalkyl, R.sup.78-substituted or unsubstituted aryl, or R.sup.78-substituted or unsubstituted heteroaryl. X.sup.17 is halogen. In embodiments, X.sup.17 is F.
[0393] R.sup.78 is independently oxo,
halogen, CX.sup.78.sub.3, CHX.sup.78.sub.2, OCH.sub.2X.sup.78, OCHX.sup.78.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, S H, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.78.sub.3, OCHX.sup.78.sub.2, R.sup.79-substituted or unsubstituted alkyl, R.sup.79-substituted or unsubstituted heteroalkyl, R.sup.79-substituted or unsubstituted cycloalkyl, R.sup.79-substituted or unsubstituted heterocycloalkyl, R.sup.79-substituted or unsubstituted aryl, or R.sup.79-substituted or unsubstituted heteroaryl. X.sup.78 is halogen. In embodiments, X.sup.78 is F.
[0394] R.sup.79 is independently oxo,
halogen, CX.sup.79.sub.3, CHX.sup.79.sub.2, OCH.sub.2X.sup.79, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.79.sub.3, OCHX.sup.79.sub.2, R.sup.80-substituted or unsubstituted alkyl, R.sup.80-substituted or unsubstituted heteroalkyl, R.sup.80-substituted or unsubstituted cycloalkyl, R.sup.80-substituted or unsubstituted heterocycloalkyl, R.sup.80-substituted or unsubstituted aryl, or R.sup.80-substituted or unsubstituted heteroaryl. X.sup.79 is halogen. In embodiments, X.sup.79 is F.
[0395] In embodiments, R.sup.17A is independently hydrogen, oxo,
halogen, CX.sup.17A.sub.3, CHX.sup.17A.sub.2, OCH.sub.2X.sup.17A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.17A.sub.3, OCHX.sup.17A.sub.2, R.sup.78A-substituted or unsubstituted alkyl, R.sup.78A-substituted or unsubstituted heteroalkyl, R.sup.78A-substituted or unsubstituted cycloalkyl, R.sup.78A-substituted or unsubstituted heterocycloalkyl, R.sup.78A-substituted or unsubstituted aryl, or R.sup.78A-substituted or unsubstituted heteroaryl. X.sup.17A is halogen. In embodiments, X.sup.17A is F.
[0396] R.sup.78A is independently oxo,
halogen, CX.sup.78A.sub.3, CHX.sup.78A.sub.2, OCH.sub.2X.sup.78A, OCHX.sup.78A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.78A.sub.3, OCHX.sup.78A.sub.2, R.sup.79A-substituted or unsubstituted alkyl, R.sup.79A-substituted or unsubstituted heteroalkyl, R.sup.79A-substituted or unsubstituted cycloalkyl, R.sup.79A-substituted or unsubstituted heterocycloalkyl, R.sup.79A-substituted or unsubstituted aryl, or R.sup.79A-substituted or unsubstituted heteroaryl. X.sup.78A is halogen. In embodiments, X.sup.78A is F.
[0397] R.sup.79A is independently oxo,
halogen, CX.sup.79A.sub.3, CHX.sup.79A.sub.2, OCH.sub.2X.sup.79A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.79A.sub.3, OCHX.sup.79A.sub.2, R.sup.80A-substituted or unsubstituted alkyl, R.sup.80A-substituted or unsubstituted heteroalkyl, R.sup.80A-substituted or unsubstituted cycloalkyl, R.sup.80A-substituted or unsubstituted heterocycloalkyl, R.sup.80A-substituted or unsubstituted aryl, or R.sup.80A-substituted or unsubstituted heteroaryl. X.sup.79A is halogen. In embodiments, X.sup.79A is F.
[0398] In embodiments, R.sup.17B is independently hydrogen, oxo,
halogen, CX.sup.17B.sub.3, CHX.sup.17B.sub.2, OCH.sub.2X.sup.17B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.17B.sub.3, OCHX.sup.17B.sub.2, R.sup.78B-substituted or unsubstituted alkyl, R.sup.78B-substituted or unsubstituted heteroalkyl, R.sup.78B-substituted or unsubstituted cycloalkyl, R.sup.78B-substituted or unsubstituted heterocycloalkyl, R.sup.78B-substituted or unsubstituted aryl, or R.sup.78B-substituted or unsubstituted heteroaryl. X.sup.17B is halogen. In embodiments, X.sup.17B is F.
[0399] R.sup.78B is independently oxo,
halogen, CX.sup.78B.sub.3, CHX.sup.78B.sub.2, OCH.sub.2X.sup.78B, OCHX.sup.78B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.78B.sub.3, OCHX.sup.78B.sub.2, R.sup.79B-substituted or unsubstituted alkyl, R.sup.79B-substituted or unsubstituted heteroalkyl, R.sup.79B-substituted or unsubstituted cycloalkyl, R.sup.79B-substituted or unsubstituted heterocycloalkyl, R.sup.79B-substituted or unsubstituted aryl, or R.sup.79B-substituted or unsubstituted heteroaryl. X.sup.78B is halogen. In embodiments, X.sup.78B is F.
[0400] R.sup.79B is independently oxo,
halogen, CX.sup.79B.sub.3, CHX.sup.79B.sub.2, OCH.sub.2X.sup.79B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.79B.sub.3, OCHX.sup.79B.sub.2, R.sup.80B-substituted or unsubstituted alkyl, R.sup.80B-substituted or unsubstituted heteroalkyl, R.sup.80B-substituted or unsubstituted cycloalkyl, R.sup.80B-substituted or unsubstituted heterocycloalkyl, R.sup.B-substituted or unsubstituted aryl, or R.sup.80B-substituted or unsubstituted heteroaryl. X.sup.79B is halogen. In embodiments, X.sup.79B is F.
[0401] In embodiments, R.sup.17C is independently hydrogen, oxo,
halogen, CX.sup.17C.sub.3, CHX.sup.17C.sub.2, OCH.sub.2X.sup.17C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.17C.sub.3, OCHX.sup.17C.sub.2, R.sup.78C-substituted or unsubstituted alkyl, R.sup.78C-substituted or unsubstituted heteroalkyl, R.sup.78C-substituted or unsubstituted cycloalkyl, R.sup.78C-substituted or unsubstituted heterocycloalkyl, R.sup.78C-substituted or unsubstituted aryl, or R.sup.78C-substituted or unsubstituted heteroaryl. X.sup.17C is halogen. In embodiments, X.sup.17C is F.
[0402] R.sup.78C is independently oxo,
halogen, CX.sup.78C.sub.3, CHX.sup.78C.sub.2, OCH.sub.2X.sup.78C, OCHX.sup.78C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.78C.sub.3, OCHX.sup.78C.sub.2, R.sup.79C-substituted or unsubstituted alkyl, R.sup.79C-substituted or unsubstituted heteroalkyl, R.sup.79C-substituted or unsubstituted cycloalkyl, R.sup.79C-substituted or unsubstituted heterocycloalkyl, R.sup.79C-substituted or unsubstituted aryl, or R.sup.79C-substituted or unsubstituted heteroaryl. X.sup.78C is halogen. In embodiments, X.sup.78C is F.
[0403] R.sup.79C is independently oxo,
halogen, CX.sup.79C.sub.3, CHX.sup.79C.sub.2, OCH.sub.2X.sup.79C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.79C.sub.3, OCHX.sup.79C.sub.2, R.sup.80C-substituted or unsubstituted alkyl, R.sup.80C-substituted or unsubstituted heteroalkyl, R.sup.80C-substituted or unsubstituted cycloalkyl, R.sup.80C-substituted or unsubstituted heterocycloalkyl, R.sup.80C-substituted or unsubstituted aryl, or R.sup.80C-substituted or unsubstituted heteroaryl. X.sup.79C is halogen. In embodiments, X.sup.79C is F.
[0404] In embodiments, R.sup.17D is independently hydrogen, oxo,
halogen, CX.sup.17D.sub.3, CHX.sup.17D.sub.2, OCH.sub.2X.sup.17D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.17D.sub.3, OCHX.sup.17D.sub.2, R.sup.78D-substituted or unsubstituted alkyl, R.sup.78D-substituted or unsubstituted heteroalkyl, R.sup.78D-substituted or unsubstituted cycloalkyl, R.sup.78D-substituted or unsubstituted heterocycloalkyl, R.sup.78D-substituted or unsubstituted aryl, or R.sup.78D-substituted or unsubstituted heteroaryl. X.sup.17D is halogen. In embodiments, X.sup.17D is F.
[0405] R.sup.78D is independently oxo,
halogen, CX.sup.78D.sub.3, CHX.sup.78D.sub.2, OCH.sub.2X.sup.78D, OCHX.sup.78D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.78D.sub.3, OCHX.sup.78D.sub.2, R.sup.79D-substituted or unsubstituted alkyl, R.sup.79D-substituted or unsubstituted heteroalkyl, R.sup.79D-substituted or unsubstituted cycloalkyl, R.sup.79D-substituted or unsubstituted heterocycloalkyl, R.sup.79D-substituted or unsubstituted aryl, or R.sup.79D-substituted or unsubstituted heteroaryl. X.sup.78D is halogen. In embodiments, X.sup.78D is F.
[0406] R.sup.79D is independently oxo,
halogen, CX.sup.79D.sub.3, CHX.sup.79D.sub.2, OCH.sub.2X.sup.79D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.79D.sub.3, OCHX.sup.79D.sub.2, R.sup.80D-substituted or unsubstituted alkyl, R.sup.80D-substituted or unsubstituted heteroalkyl, R.sup.80D-substituted or unsubstituted cycloalkyl, R.sup.80D-substituted or unsubstituted heterocycloalkyl, R.sup.80D-substituted or unsubstituted aryl, or R.sup.80D-substituted or unsubstituted heteroaryl. X.sup.79D is halogen. In embodiments, X.sup.79D is F.
[0407] In embodiments, R.sup.18 is hydrogen. In embodiments, R.sup.18 is halogen. In embodiments, R.sup.18 is CX.sup.18.sub.3. In embodiments, R.sup.18 is CHX.sup.18.sub.2. In embodiments, R.sup.18 is CH.sub.2X.sup.18. In embodiments, R.sup.18 is CN. In embodiments, R.sup.18 is SO.sub.n18R.sup.18D. In embodiments, R.sup.18 is SO.sub.v18NR.sup.18AR.sup.18B. In embodiments, R.sup.18 is NHNR.sup.18AR.sup.18B. In embodiments, R.sup.18 is ONR.sup.18AR.sup.18B. In embodiments, R.sup.18 is NHC(O)NHNR.sup.18AR.sup.18B. In embodiments, R.sup.18 is NHC(O)NR.sup.18AR.sup.18B. In embodiments, R.sup.18 is N(O).sub.m18. In embodiments, R.sup.18 is NR.sup.18AR.sup.18B. In embodiments, R.sup.18 is C(O)R.sup.18C. In embodiments, R.sup.18 is C(O)OR.sup.18C. In embodiments, R.sup.18 is C(O)NR.sup.18AR.sup.18B. In embodiments, R.sup.18 is OR.sup.18D. In embodiments, R.sup.18 is NR.sup.18ASO.sub.2R.sup.18D. In embodiments, R.sup.18 is NR.sup.18AC(O)R.sup.18C. In embodiments, R.sup.18 is NR.sup.18AC(O)OR.sup.18C. In embodiments, R.sup.18 is NR.sup.18AOR.sup.18C. In embodiments, R.sup.18 is OCX.sup.18.sub.3. In embodiments, R.sup.18 is OCHX.sup.18.sub.2. In embodiments, R.sup.18 is substituted or unsubstituted alkyl. In embodiments, R.sup.18 is substituted or unsubstituted heteroalkyl. In embodiments, R.sup.18 is substituted or unsubstituted cycloalkyl. In embodiments, R.sup.18 is substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.18 is substituted or unsubstituted aryl. In embodiments, R.sup.18 is substituted or unsubstituted heteroaryl. In embodiments, R.sup.18 is substituted alkyl. In embodiments, R.sup.18 is substituted heteroalkyl. In embodiments, R.sup.18 is substituted cycloalkyl. In embodiments, R.sup.18 is substituted heterocycloalkyl. In embodiments, R.sup.18 is substituted aryl. In embodiments, R.sup.18 is substituted heteroaryl. In embodiments, R.sup.18 is unsubstituted alkyl. In embodiments, R.sup.18 is unsubstituted heteroalkyl. In embodiments, R.sup.18 is unsubstituted cycloalkyl. In embodiments, R.sup.18 is unsubstituted heterocycloalkyl. In embodiments, R.sup.18 is unsubstituted aryl. In embodiments, R.sup.18 is unsubstituted heteroaryl. In embodiments, R.sup.18 is unsubstituted methyl. In embodiments, R.sup.18 is unsubstituted ethyl. In embodiments, R.sup.18 is unsubstituted propyl. In embodiments, R.sup.18 is unsubstituted isopropyl. In embodiments, R.sup.18 is unsubstituted butyl. In embodiments, R.sup.18 is unsubstituted tert-butyl.
[0408] In embodiments, R.sup.18A is hydrogen. In embodiments, R.sup.18A is CX.sub.3. In embodiments, R.sup.18A is CN. In embodiments, R.sup.18A is COOH. In embodiments, R.sup.18A is CONH.sub.2. In embodiments, R.sup.18A is CHX.sub.2. In embodiments, R.sup.18A is CH.sub.2X. In embodiments, R.sup.18A is unsubstituted methyl. In embodiments, R.sup.18A is unsubstituted ethyl. In embodiments, R.sup.18A is unsubstituted propyl. In embodiments, R.sup.18A is unsubstituted isopropyl. In embodiments, R.sup.18A is unsubstituted butyl. In embodiments, R.sup.18A is unsubstituted tert-butyl.
[0409] In embodiments, R.sup.18B is hydrogen. In embodiments, R.sup.18B is CX.sub.3. In embodiments, R.sup.18B is CN. In embodiments, R.sup.18B is COOH. In embodiments, R.sup.18B is CONH.sub.2. In embodiments, R.sup.18B is CHX.sub.2. In embodiments, R.sup.18B is CH.sub.2X. In embodiments, R.sup.18B is unsubstituted methyl. In embodiments, R.sup.18B is unsubstituted ethyl. In embodiments, R.sup.18B is unsubstituted propyl. In embodiments, R.sup.18B is unsubstituted isopropyl. In embodiments, R.sup.18B is unsubstituted butyl. In embodiments, R.sup.18B is unsubstituted tert-butyl.
[0410] In embodiments, R.sup.18B is hydrogen. In embodiments, R.sup.18B is CX.sub.3. In embodiments, R.sup.18B is CN. In embodiments, R.sup.18C is COOH. In embodiments, R.sup.18B is CONH.sub.2. In embodiments, R.sup.18C is CHX.sub.2. In embodiments, R.sup.18C is CH.sub.2X. In embodiments, R.sup.18C is unsubstituted methyl. In embodiments, R.sup.18C is unsubstituted ethyl. In embodiments, R.sup.18C is unsubstituted propyl. In embodiments, R.sup.18C is unsubstituted isopropyl. In embodiments, R.sup.18C is unsubstituted butyl. In embodiments, R.sup.18C is unsubstituted tert-butyl.
[0411] In embodiments, R.sup.18D is hydrogen. In embodiments, R.sup.18D is CX.sub.3. In embodiments, R.sup.18 is CN. In embodiments, R.sup.18D is COOH. In embodiments, R.sup.18 is CONH.sub.2. In embodiments, R.sup.18D is CHX.sub.2. In embodiments, R.sup.18D is CH.sub.2X. In embodiments, R.sup.18D is unsubstituted methyl. In embodiments, R.sup.18D is unsubstituted ethyl. In embodiments, R.sup.18D is unsubstituted propyl. In embodiments, R.sup.18D is unsubstituted isopropyl. In embodiments, R.sup.18D is unsubstituted butyl. In embodiments, R.sup.18D is unsubstituted tert-butyl.
[0412] In embodiments, R.sup.18 is independently hydrogen, oxo,
halogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, OCH.sub.2X.sup.18, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.18.sub.3, OCHX.sup.18.sub.2, R.sup.81-substituted or unsubstituted alkyl, R.sup.81-substituted or unsubstituted heteroalkyl, R.sup.81-substituted or unsubstituted cycloalkyl, R.sup.81-substituted or unsubstituted heterocycloalkyl, R.sup.81-substituted or unsubstituted aryl, or R.sup.81-substituted or unsubstituted heteroaryl. X.sup.18 is halogen. In embodiments, X.sup.18 is F.
[0413] R.sup.8 is independently oxo,
halogen, CX.sup.81.sub.3, CHX.sup.81.sub.2, OCH.sub.2X.sup.81, OCHX.sup.81.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, S H, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.81.sub.3, OCHX.sup.81.sub.2, R.sup.82-substituted or unsubstituted alkyl, R.sup.82-substituted or unsubstituted heteroalkyl, R.sup.82-substituted or unsubstituted cycloalkyl, R.sup.82-substituted or unsubstituted heterocycloalkyl, R.sup.82-substituted or unsubstituted aryl, or R.sup.82-substituted or unsubstituted heteroaryl. X.sup.81 is halogen. In embodiments, X.sup.81 is F.
[0414] R.sup.82 is independently oxo,
halogen, CX.sup.82.sub.3, CHX.sup.82.sub.2, OCH.sub.2X.sup.82, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.82.sub.3, OCHX.sup.82.sub.2, R.sup.83-substituted or unsubstituted alkyl, R.sup.83-substituted or unsubstituted heteroalkyl, R.sup.83-substituted or unsubstituted cycloalkyl, R.sup.83-substituted or unsubstituted heterocycloalkyl, R.sup.83-substituted or unsubstituted aryl, or R.sup.83-substituted or unsubstituted heteroaryl. X.sup.82 is halogen. In embodiments, X.sup.82 is F.
[0415] In embodiments, R.sup.18A is independently hydrogen, oxo,
halogen, CX.sup.18A.sub.3, CHX.sup.18A.sub.2, OCH.sub.2X.sup.18A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.18A.sub.3, OCHX.sup.18A.sub.2, R.sup.81A-substituted or unsubstituted alkyl, R.sup.81A-substituted or unsubstituted heteroalkyl, R.sup.81A-substituted or unsubstituted cycloalkyl, R.sup.81A-substituted or unsubstituted heterocycloalkyl, R.sup.81A-substituted or unsubstituted aryl, or R.sup.81A-substituted or unsubstituted heteroaryl. X.sup.18A is halogen. In embodiments, X.sup.18A is F.
[0416] R.sup.81A is independently oxo,
halogen, CX.sup.81A.sub.3, CHX.sup.81A.sub.2, OCH.sub.2X.sup.81A, OCHX.sup.81A.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.81A.sub.3, OCHX.sup.81A.sub.2, R.sup.82A-substituted or unsubstituted alkyl, R.sup.82A-substituted or unsubstituted heteroalkyl, R.sup.82A-substituted or unsubstituted cycloalkyl, R.sup.82A-substituted or unsubstituted heterocycloalkyl, R.sup.82A-substituted or unsubstituted aryl, or R.sup.82A-substituted or unsubstituted heteroaryl. X.sup.81A is halogen. In embodiments, X.sup.81A is F.
[0417] R.sup.82A is independently oxo,
halogen, CX.sup.82A.sub.3, CHX.sup.82A.sub.2, OCH.sub.2X.sup.82A, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.82A.sub.3, OCHX.sup.82A.sub.2, R.sup.83A-substituted or unsubstituted alkyl, R.sup.83A-substituted or unsubstituted heteroalkyl, R.sup.83A-substituted or unsubstituted cycloalkyl, R.sup.83A-substituted or unsubstituted heterocycloalkyl, R.sup.83A-substituted or unsubstituted aryl, or R.sup.83A-substituted or unsubstituted heteroaryl. X.sup.82A is halogen. In embodiments, X.sup.82A is F.
[0418] In embodiments, R.sup.18B is independently hydrogen, oxo,
halogen, CX.sup.18B.sub.3, CHX.sup.18B.sub.2, OCH.sub.2X.sup.18B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.18B.sub.3, OCHX.sup.18B.sub.2, R.sup.81B-substituted or unsubstituted alkyl, R.sup.81B-substituted or unsubstituted heteroalkyl, R.sup.81B-substituted or unsubstituted cycloalkyl, R.sup.81B-substituted or unsubstituted heterocycloalkyl, R.sup.81B-substituted or unsubstituted aryl, or R.sup.81B-substituted or unsubstituted heteroaryl. X.sup.18B is halogen. In embodiments, X.sup.18B is F.
[0419] R.sup.81B is independently oxo,
halogen, CX.sup.81B.sub.3, CHX.sup.81B.sub.2, OCH.sub.2X.sup.81B, OCHX.sup.81B.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.81B.sub.3, OCHX.sup.81B.sub.2, R.sup.82B-substituted or unsubstituted alkyl, R.sup.82B-substituted or unsubstituted heteroalkyl, R.sup.82B-substituted or unsubstituted cycloalkyl, R.sup.82B-substituted or unsubstituted heterocycloalkyl, R.sup.82B-substituted or unsubstituted aryl, or R.sup.82B-substituted or unsubstituted heteroaryl. X.sup.81B is halogen. In embodiments, X.sup.81B is F.
[0420] R.sup.82B is independently oxo,
halogen, CX.sup.82B.sub.3, CHX.sup.82B.sub.2, OCH.sub.2X.sup.82B, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.82B.sub.3, OCHX.sup.82B.sub.2, R.sup.83B-substituted or unsubstituted alkyl, R.sup.83B-substituted or unsubstituted heteroalkyl, R.sup.83B-substituted or unsubstituted cycloalkyl, R.sup.83B-substituted or unsubstituted heterocycloalkyl, R.sup.83B-substituted or unsubstituted aryl, or R.sup.83B-substituted or unsubstituted heteroaryl. X.sup.82B is halogen. In embodiments, X.sup.82B is F.
[0421] In embodiments, R.sup.18C is independently hydrogen, oxo,
halogen, CX.sup.18C.sub.3, CHX.sup.18C.sub.2, OCH.sub.2X.sup.18C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.18C.sub.3, OCHX.sup.18C.sub.2, R.sup.81C-substituted or unsubstituted alkyl, R.sup.81C-substituted or unsubstituted heteroalkyl, R.sup.81C-substituted or unsubstituted cycloalkyl, R.sup.81C-substituted or unsubstituted heterocycloalkyl, R.sup.81C-substituted or unsubstituted aryl, or R.sup.81C-substituted or unsubstituted heteroaryl. X.sup.18C is halogen. In embodiments, X.sup.18C is F.
[0422] R.sup.81C is independently oxo,
halogen, CX.sup.81C.sub.3, CHX.sup.81C.sub.2, OCH.sub.2X.sup.81C, OCHX.sup.81C.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.81C.sub.3, OCHX.sup.81C.sub.2, R.sup.82C-substituted or unsubstituted alkyl, R.sup.82C-substituted or unsubstituted heteroalkyl, R.sup.82C-substituted or unsubstituted cycloalkyl, R.sup.82C-substituted or unsubstituted heterocycloalkyl, R.sup.82C-substituted or unsubstituted aryl, or R.sup.82C-substituted or unsubstituted heteroaryl. X.sup.81C is halogen. In embodiments, X.sup.81C is F.
[0423] R.sup.82C is independently oxo,
halogen, CX.sup.82C.sub.3, CHX.sup.82C.sub.2, OCH.sub.2X.sup.82C, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.82C.sub.3, OCHX.sup.82C.sub.2, R.sup.83C-substituted or unsubstituted alkyl, R.sup.83C-substituted or unsubstituted heteroalkyl, R.sup.83C-substituted or unsubstituted cycloalkyl, R.sup.83C-substituted or unsubstituted heterocycloalkyl, R.sup.83C-substituted or unsubstituted aryl, or R.sup.83C-substituted or unsubstituted heteroaryl. X.sup.82C is halogen. In embodiments, X.sup.82C is F.
[0424] In embodiments, R.sup.18D is independently hydrogen, oxo,
halogen, CX.sup.18D.sub.3, CHX.sup.18D.sub.2, OCH.sub.2X.sup.18D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.18D.sub.3, OCHX.sup.18D.sub.2, R.sup.81D-substituted or unsubstituted alkyl, R.sup.81D substituted or unsubstituted heteroalkyl, R.sup.81D substituted or unsubstituted cycloalkyl, R.sup.81D-substituted or unsubstituted heterocycloalkyl, R.sup.81D substituted or unsubstituted aryl, or R.sup.81D-substituted or unsubstituted heteroaryl. X.sup.18D is halogen. In embodiments, X.sup.18D is F.
[0425] R.sup.18D is independently oxo,
halogen, CX.sup.81D.sub.3, CHX.sup.81D.sub.2, OCH.sub.2X.sup.81D, OCHX.sup.81D.sub.2, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.81D.sub.3, OCHX.sup.81D.sub.2, R.sup.82D-substituted or unsubstituted alkyl, R.sup.82D-substituted or unsubstituted heteroalkyl, R.sup.82D-substituted or unsubstituted cycloalkyl, R.sup.82D-substituted or unsubstituted heterocycloalkyl, R.sup.82D-substituted or unsubstituted aryl, or R.sup.82D-substituted or unsubstituted heteroaryl. X.sup.81D is halogen. In embodiments, X.sup.81D is F.
[0426] R.sup.82D is independently oxo,
halogen, CX.sup.82D.sub.3, CHX.sup.82D.sub.2, OCH.sub.2X.sup.82D, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCX.sup.82D.sub.3, OCHX.sup.82D.sub.2, R.sup.83D-substituted or unsubstituted alkyl, R.sup.83D-substituted or unsubstituted heteroalkyl, R.sup.83D-substituted or unsubstituted cycloalkyl, R.sup.83D-substituted or unsubstituted heterocycloalkyl, R.sup.83D-substituted or unsubstituted aryl, or R.sup.83D-substituted or unsubstituted heteroaryl. X.sup.82D is halogen. In embodiments, X.sup.82D is F.
[0427] R.sup.74, R.sup.77, R.sup.80, R.sup.83, R.sup.74A, R.sup.77A, R.sup.80A, R.sup.83A, R.sup.74B, R.sup.77B, R.sup.80B, R.sup.83B, R.sup.74C, R.sup.77C, R.sup.80C, R.sup.83C, R.sup.74D, R.sup.77D, R.sup.80D, R.sup.83D, R.sup.86, R.sup.89, R.sup.92, and R.sup.98 are independently hydrogen, oxo, halogen, CF.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCF.sub.3, OCHF.sub.2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In R.sup.74, R.sup.77, R.sup.80, R.sup.83, R.sup.74A, R.sup.77A, R.sup.80A, R.sup.83A, R.sup.74B, R.sup.77B, R.sup.80B, R.sup.83B, R.sup.74C, R.sup.77C, R.sup.80C, R.sup.83C, R.sup.74D, R.sup.77D, R.sup.80D, R.sup.83D, R.sup.86, R.sup.89, R.sup.92, and R.sup.98 are independently hydrogen, oxo, halogen, CF.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCF.sub.3, OCHF.sub.2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R.sup.74, R.sup.77, R.sup.80, R.sup.83, R.sup.74A, R.sup.77A, R.sup.80A, R.sup.83A, R.sup.74B, R.sup.77B, R.sup.80B, R.sup.83B, R.sup.74C, R.sup.77C, R.sup.80C, R.sup.83C, R.sup.74D, R.sup.77D, R.sup.80D, R.sup.83D, R.sup.86, R.sup.89, R.sup.92, and R.sup.98 are independently hydrogen, oxo, halogen, CF.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, SO.sub.3H, SO.sub.4H, SO.sub.2NH.sub.2, NHNH.sub.2, ONH.sub.2, NHC(O)NHNH.sub.2, NHC(O)NH.sub.2, NHSO.sub.2H, NHC(O)H, NHC(O)OH, NHOH, OCF.sub.3, OCHF.sub.2, unsubstituted C.sub.1-C.sub.8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C.sub.3-C.sub.8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
[0428] In embodiments, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen.
[0429] In embodiments, E is:
##STR00036##
In embodiments, E is:
##STR00037##
##STR00038##
[0430] In embodiments, E is:
##STR00039##
In embodiments, E is:
##STR00040##
In embodiments, E is:
##STR00041##
In embodiments, E is:
##STR00042##
[0431] In embodiments, E is:
##STR00043##
[0432] In some embodiments, a compound as described herein may include multiple instances of R.sup.1 or R.sup.2, and/or other variables. In such embodiments, each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each R.sup.1 and/or R.sup.2, is different, they may be referred to, for example, as R.sup.1.1, R.sup.1.2, R.sup.1.3, R.sup.1.4, R.sup.1.5, R.sup.2.1, R.sup.2.2, R.sup.2.3, or R.sup.2.4, respectively, wherein the definition of R.sup.1 is assumed by R.sup.1.1, R.sup.1.2, R.sup.1.3, R.sup.1.4, R.sup.1.5; and/or R.sup.2 is assumed by R.sup.2.1, R.sup.2.2, R.sup.2.3, R.sup.2.4. The variables used within a definition of R.sup.1 and/or R.sup.2, and/or other variables that appear at multiple instances and are different may similarly be appropriately labeled to distinguish each group for greater clarity. In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure).
[0433] In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a single stereoisomer. In embodiments, unless otherwise indicated, a compound described herein is a single enantiomer. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim).
[0434] In an aspect is provided a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, 51079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097 of human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of human reticulon 4.
[0435] In an aspect is provided a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of SEQ ID NO:331.
[0436] In embodiments, the compound has the formula:
##STR00044##
wherein R.sup.1, L.sup.2, and E are as described herein, including embodiments. In embodiments, the compound has the formula:
##STR00045##
wherein R.sup.1, L.sup.1, and E are as described herein, including embodiments. In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CN, OH, NH.sub.2, COOH, CONH.sub.2, NO.sub.2, SH, OCX.sup.1.sub.3, OCHX.sup.1.sub.2, OCH.sub.2X.sup.1, CHX.sup.1.sub.2, CH.sub.2X.sup.1, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R.sup.1 is independently halogen, CX.sup.1.sub.3, CN, unsubstituted C.sub.1-C.sub.4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl. In embodiments, R.sup.1 is independently unsubstituted methyl. In embodiments, R.sup.1 is independently unsubstituted ethyl. In embodiments, R.sup.1 is independently unsubstituted propyl. In embodiments, R.sup.1 is independently unsubstituted n-propyl. In embodiments, R.sup.1 is independently unsubstituted isopropyl. In embodiments, R.sup.1 is independently unsubstituted butyl. In embodiments, R.sup.1 is independently unsubstituted n-butyl. In embodiments, R.sup.1 is independently unsubstituted isobutyl. In embodiments, R.sup.1 is independently unsubstituted tert-butyl. In embodiments, R.sup.1 is independently unsubstituted pentyl. In embodiments, R.sup.1 is independently unsubstituted hexyl. In embodiments, R.sup.1 is independently unsubstituted heptyl. In embodiments, R.sup.1 is independently unsubstituted octyl. In embodiments, R.sup.1 is independently CF.sub.3. In embodiments, R.sup.1 is independently CCl.sub.3. In embodiments, R.sup.1 is independently unsubstituted phenyl. In embodiments, R.sup.1 is independently unsubstituted pyridyl. In embodiments, R.sup.1 is independently halogen. In embodiments, R.sup.1 is independently CN. In embodiments, R.sup.1 is independently OH. In embodiments, R.sup.1 is independently NH.sub.2. In embodiments, R.sup.1 is independently COOH. In embodiments, R.sup.1 is independently CONH.sub.2. In embodiments, R.sup.1 is independently NO.sub.2. In embodiments, R.sup.1 is independently SH. In embodiments, R.sup.1 is independently SO.sub.3H. In embodiments, R.sup.1 is independently SO.sub.4H. In embodiments, R.sup.1 is independently SO.sub.2NH.sub.2. In embodiments, R.sup.1 is independently NHNH.sub.2. In embodiments, R.sup.1 is independently ONH.sub.2. In embodiments, R.sup.1 is independently NHC(O)NHNH.sub.2. In embodiments, R.sup.1 is independently NHC(O)NH.sub.2. In embodiments, R.sup.1 is independently NHSO.sub.2H. In embodiments, R.sup.1 is independently NHC(O)H. In embodiments, R.sup.1 is independently NHC(O)OH. In embodiments, R.sup.1 is independently NHOH. In embodiments, R.sup.1 is independently substituted or unsubstituted alkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted heteroalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted cycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted aryl. In embodiments, R.sup.1 is independently substituted or unsubstituted heteroaryl. In embodiments, R.sup.1 is independently substituted alkyl. In embodiments, R.sup.1 is independently substituted heteroalkyl. In embodiments, R.sup.1 is independently substituted cycloalkyl. In embodiments, R.sup.1 is independently substituted heterocycloalkyl. In embodiments, R.sup.1 is independently substituted aryl. In embodiments, R.sup.1 is independently substituted heteroaryl. In embodiments, R.sup.1 is independently unsubstituted alkyl. In embodiments, R.sup.1 is independently unsubstituted heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted cycloalkyl. In embodiments, R.sup.1 is independently unsubstituted heterocycloalkyl. In embodiments, R.sup.1 is independently unsubstituted aryl. In embodiments, R.sup.1 is independently unsubstituted heteroaryl. In embodiments, R.sup.1 is independently substituted or unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.1 is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R.sup.1 is independently substituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.1 is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.1 is independently substituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.1 is independently substituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.1 is independently substituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.1 is independently substituted 5 to 10 membered heteroaryl. In embodiments, R.sup.1 is independently unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.1 is independently unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.1 is independently unsubstituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.1 is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R.sup.1 is independently substituted or unsubstituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.1 is independently substituted or unsubstituted phenyl. In embodiments, R.sup.1 is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R.sup.1 is independently substituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.1 is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.1 is independently substituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.1 is independently substituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.1 is independently substituted phenyl. In embodiments, R.sup.1 is independently substituted 5 to 6 membered heteroaryl. In embodiments, R.sup.1 is independently unsubstituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.1 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.1 is independently unsubstituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.1 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.1 is independently unsubstituted phenyl. In embodiments, R.sup.1 is independently unsubstituted 5 to 6 membered heteroaryl. In embodiments, R.sup.1 is independently OH. In embodiments, R.sup.1 is independently NH.sub.2. In embodiments, R.sup.1 is independently COOH. In embodiments, R.sup.1 is independently CONH.sub.2. In embodiments, R.sup.1 is independently NO.sub.2. In embodiments, R.sup.1 is independently SH. In embodiments, R.sup.1 is independently CF.sub.3. In embodiments, R.sup.1 is independently CHF.sub.2. In embodiments, R.sup.1 is independently CH.sub.2F. In embodiments, R.sup.1 is independently OCF.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2F. In embodiments, R.sup.1 is independently OCHF.sub.2. In embodiments, R.sup.1 is independently OCH.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently OCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently OCH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently OC(CH.sub.3).sub.3. In embodiments, R.sup.1 is independently SCH.sub.3. In embodiments, R.sup.1 is independently SCH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently SCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently SCH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently SC(CH.sub.3).sub.3. In embodiments, R.sup.1 is independently CH.sub.3. In embodiments, R.sup.1 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.1 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.1 is independently C(CH.sub.3).sub.3. In embodiments, R.sup.1 is independently F. In embodiments, R.sup.1 is independently Cl. In embodiments, R.sup.1 is independently Br. In embodiments, R.sup.1 is independently I.
[0437] In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted methyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.2 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.3 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.4 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.5 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.6 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.7 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted or unsubstituted C.sub.8 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted methyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.2 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.3 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.4 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.5 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.6 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.7 alkyl. In embodiments, R.sup.1 is R.sup.20-substituted C.sub.8 alkyl. In embodiments, R.sup.1 is an unsubstituted methyl. In embodiments, R.sup.1 is an unsubstituted C.sub.2 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.3 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.4 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.5 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.6 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.7 alkyl. In embodiments, R.sup.1 is an unsubstituted C.sub.8 alkyl.
[0438] In embodiments, the compound has the formula:
##STR00046##
X.sup.1, L.sup.1, L.sup.2, and E are as described herein.
[0439] In embodiments, the compound has the formula:
##STR00047##
R.sup.1 and R.sup.4 are as described herein.
[0440] In embodiments, the compound has the formula:
##STR00048##
R.sup.4 is as described herein.
[0441] In embodiments, the compound has the formula:
##STR00049##
R.sup.1, R.sup.5, and L.sup.1 are as described herein.
[0442] In embodiments, the compound has the formula:
##STR00050##
L.sup.1 and R.sup.5 are as described herein.
[0443] In embodiments, R.sup.4 is independently substituted or unsubstituted alkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted heteroalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted cycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted heterocycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted aryl. In embodiments, R.sup.4 is independently substituted or unsubstituted heteroaryl. In embodiments, R.sup.4 is independently substituted alkyl. In embodiments, R.sup.4 is independently substituted heteroalkyl. In embodiments, R.sup.4 is independently substituted cycloalkyl. In embodiments, R.sup.4 is independently substituted heterocycloalkyl. In embodiments, R.sup.4 is independently substituted aryl. In embodiments, R.sup.4 is independently substituted heteroaryl. In embodiments, R.sup.4 is independently unsubstituted alkyl. In embodiments, R.sup.4 is independently unsubstituted heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted cycloalkyl. In embodiments, R.sup.4 is independently unsubstituted heterocycloalkyl. In embodiments, R.sup.4 is independently unsubstituted aryl. In embodiments, R.sup.4 is independently unsubstituted heteroaryl. In embodiments, R.sup.4 is independently substituted or unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.4 is independently substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R.sup.4 is independently substituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.4 is independently substituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.4 is independently substituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.4 is independently substituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.4 is independently substituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.4 is independently substituted 5 to 10 membered heteroaryl. In embodiments, R.sup.4 is independently unsubstituted C.sub.1-C.sub.8 alkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted C.sub.3-C.sub.8 cycloalkyl. In embodiments, R.sup.4 is independently unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R.sup.4 is independently unsubstituted C.sub.6-C.sub.10 aryl. In embodiments, R.sup.4 is independently unsubstituted 5 to 10 membered heteroaryl. In embodiments, R.sup.4 is independently substituted or unsubstituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.4 is independently substituted or unsubstituted phenyl. In embodiments, R.sup.4 is independently substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R.sup.4 is independently substituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.4 is independently substituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.4 is independently substituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.4 is independently substituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.4 is independently substituted phenyl. In embodiments, R.sup.4 is independently substituted 5 to 6 membered heteroaryl. In embodiments, R.sup.4 is independently unsubstituted C.sub.1-C.sub.4 alkyl. In embodiments, R.sup.4 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R.sup.4 is independently unsubstituted C.sub.3-C.sub.6 cycloalkyl. In embodiments, R.sup.4 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R.sup.4 is independently unsubstituted phenyl. In embodiments, R.sup.4 is independently unsubstituted 5 to 6 membered heteroaryl.
[0444] In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted methyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.2 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.3 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.4 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.5 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.6 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.7 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted or unsubstituted C.sub.8 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted methyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.2 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.3 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.4 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.8 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.6 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.7 alkyl. In embodiments, R.sup.4 is R.sup.29-substituted C.sub.8 alkyl. In embodiments, R.sup.4 is an unsubstituted methyl. In embodiments, R.sup.4 is an unsubstituted C.sub.2 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.3 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.4 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.5 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.6 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.7 alkyl. In embodiments, R.sup.4 is an unsubstituted C.sub.8 alkyl.
[0445] In embodiments, R.sup.4 is independently OH. In embodiments, R.sup.4 is independently NH.sub.2. In embodiments, R.sup.4 is independently COOH. In embodiments, R.sup.4 is independently CONH.sub.2. In embodiments, R.sup.4 is independently CF.sub.3. In embodiments, R.sup.4 is independently CHF.sub.2. In embodiments, R.sup.4 is independently CH.sub.2F. In embodiments, R.sup.4 is independently OCF.sub.3. In embodiments, R.sup.4 is independently OCH.sub.2F. In embodiments, R.sup.4 is independently OCHF.sub.2. In embodiments, R.sup.4 is independently OCH.sub.3. In embodiments, R.sup.4 is independently OCH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently OCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently OCH(CH.sub.3).sub.2. In embodiments, R.sup.4 is independently OC(CH.sub.3).sub.3. In embodiments, R.sup.4 is independently SCH.sub.3. In embodiments, R.sup.4 is independently SCH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently SCH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently SCH(CH.sub.3).sub.2. In embodiments, R.sup.4 is independently SC(CH.sub.3).sub.3. In embodiments, R.sup.4 is independently CH.sub.3. In embodiments, R.sup.4 is independently CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently CH.sub.2CH.sub.2CH.sub.3. In embodiments, R.sup.4 is independently CH(CH.sub.3).sub.2. In embodiments, R.sup.4 is independently C(CH.sub.3).sub.3. In embodiments, R.sup.4 is independently hydrogen.
[0446] In an aspect is provided a compound having the formula:
##STR00051##
R.sup.1, R.sup.2, L.sup.1, L.sup.2, E, z1 and z2 are as described herein.
[0447] In embodiments, the compound has the formula:
##STR00052##
R.sup.1, R.sup.2, z1 and z2 are as described herein.
[0448] In embodiments, the compound has the formula:
##STR00053##
[0449] In embodiments, the compound is a compound described herein, including in an aspect, embodiment, claim, figure, table, example, or scheme.
[0450] In embodiments, the compound has the formula:
##STR00054##
[0451] In embodiments, the compound has the formula:
##STR00055##
[0452] In embodiments, the compound has the formula:
##STR00056##
[0453] In embodiments, the compound has the formula:
##STR00057##
[0454] In embodiments, the compound has the formula:
##STR00058##
[0455] In embodiments, the compound has the formula:
##STR00059##
[0456] In embodiments, the compound has the formula:
##STR00060##
[0457] In embodiments, the compound has the formula:
##STR00061##
[0458] In embodiments, the compound has the formula:
##STR00062##
[0459] In embodiments, the compound has the formula:
##STR00063##
[0460] In embodiments, the compound has the formula:
##STR00064##
##STR00065##
[0461] In embodiments, the compound has the formula:
##STR00066##
[0462] In embodiments, the compound has the formula:
##STR00067##
III. Pharmaceutical Compositions
[0463] In an aspect is provided a pharmaceutical composition including a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount.
[0464] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0465] In embodiments of the pharmaceutical compositions, the compound, or pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount.
[0466] In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-inflammatory agent.
IV. Methods of Treatment
[0467] In an aspect is provided a method of treating cancer, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. In embodiments, the Reticulon 4 inhibitor is an antisense nucleic acid.
[0468] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is liver cancer. In embodiments, the cancer is hepatocellular cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is estrogen receptor positive breast cancer. In embodiments, the cancer is estrogen receptor (ER) negative breast cancer. In embodiments, the cancer is tamoxifen resistant breast cancer. In embodiments, the cancer is HER2 negative breast cancer. In embodiments, the cancer is HER2 positive breast cancer. In embodiments, the cancer is low grade (well differentiated) breast cancer. In embodiments, the cancer is intermediate grade (moderately differentiated) breast cancer. In embodiments, the cancer is high grade (poorly differentiated) breast cancer. In embodiments, the cancer is stage 0 breast cancer. In embodiments, the cancer is stage I breast cancer. In embodiments, the cancer is stage II breast cancer. In embodiments, the cancer is stage III breast cancer. In embodiments, the cancer is stage IV breast cancer. In embodiments, the cancer is triple negative breast cancer.
[0469] In an aspect is provided a method of treating a neurodegenerative disease, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating nerve damage, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating a traumatic brain injury, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating a spinal cord injury, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In an aspect is provided a method of treating stroke, the method including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount. In embodiments, the neurodegenerative disease is ALS. In embodiments, the neurodegenerative disease is multiple sclerosis.
[0470] In an aspect is provided a method of treating neurodegenerative disease including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating nerve damage including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating traumatic brain injury including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating spinal cord injury including administering to a subject in need thereof an effective amount of a compound described herein. In an aspect is provided a method of treating stroke including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the neurodegenerative disease is ALS. In embodiments, the neurodegenerative disease is multiple sclerosis.
[0471] In an aspect is provided a method of treating a disease associated with reticulon 4 activity including administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the disease is associated with aberrant reticulon 4 activity.
[0472] In an aspect is provided a method of increasing nerve growth (e.g., neurite growth, neuron growth), the method including administering to a subject (e.g., contacting the nerve or neurite) in need thereof an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is included in a therapeutically effective amount.
[0473] In an aspect is provided a method of increasing nerve growth (e.g., neurite growth, neuron growth) including administering to a subject (e.g., contacting the nerve or neurite) in need thereof an effective amount of a compound described herein.
[0474] In embodiments, the method includes administering a second agent (e.g. therapeutic agent). In embodiments, the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In embodiments, the second agent is an agent for promoting nerve growth. In embodiments, the second agent is an agent for treating traumatic brain injury. In embodiments, the second agent is an agent for treating nerve damage. In embodiments, the second agent is an agent for treating spinal cord injury. In embodiments, the second agent is an agent for treating stroke.
V. Methods of Inhibition
[0475] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a Reticulon 4 inhibitor. In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is provided in a therapeutically effective amount.
[0476] In embodiments, the reticulon 4 is SEQ ID NO:333, SEQ ID NO:334, SEQ ID NO:335, SEQ ID NO:336, SEQ ID NO:337, SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:340, SEQ ID NO:331, SEQ ID NO:341, or SEQ ID NO:342. In embodiments, the reticulon 4 is SEQ ID NO:333. In embodiments, the reticulon 4 is SEQ ID NO:334. In embodiments, the reticulon 4 is SEQ ID NO:335. In embodiments, the reticulon 4 is SEQ ID NO:336. In embodiments, the reticulon 4 is SEQ ID NO:337. In embodiments, the reticulon 4 is SEQ ID NO:338. In embodiments, the reticulon 4 is SEQ ID NO:339. In embodiments, the reticulon 4 is SEQ ID NO:340. In embodiments, the reticulon 4 is SEQ ID NO:331. In embodiments, the reticulon 4 is SEQ ID NO:341. In embodiments, the reticulon 4 is SEQ ID NO:342.
[0477] In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4 (e.g., SEQ ID NO:331). In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 of SEQ ID NO:331 in human reticulon 4. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331.
[0478] In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of SEQ ID NO:331.
[0479] In an aspect is provided a method of inhibiting reticulon 4 activity including contacting the reticulon 4 with a compound described herein. In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the compound is provided in an effective amount. In embodiments, the compound is provided in a therapeutically effective amount. In embodiments, the method includes contacting the reticulon 4 protein with an effective amount of a compound described herein. In embodiments, compound is covalently bonded to the amino acid corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to G1097 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to H1098 of SEQ ID NO:331.
[0480] In embodiments, the compound contacts a cysteine in a sequence described herein. In embodiments, the sequence is (SEQ ID NO:1). In embodiments, the sequence is (SEQ ID NO:2). In embodiments, the sequence is (SEQ ID NO:3). In embodiments, the sequence is (SEQ ID NO:4). In embodiments, the sequence is (SEQ ID NO:5). In embodiments, the sequence is (SEQ ID NO:6). In embodiments, the sequence is (SEQ ID NO:7). In embodiments, the sequence is (SEQ ID NO:8). In embodiments, the sequence is (SEQ ID NO:9). In embodiments, the sequence is (SEQ ID NO:10). In embodiments, the sequence is (SEQ ID NO:11). In embodiments, the sequence is (SEQ ID NO:12). In embodiments, the sequence is (SEQ ID NO:13). In embodiments, the sequence is (SEQ ID NO:14). In embodiments, the sequence is (SEQ ID NO:15). In embodiments, the sequence is (SEQ ID NO:16). In embodiments, the sequence is (SEQ ID NO:17). In embodiments, the sequence is (SEQ ID NO:18). In embodiments, the sequence is (SEQ ID NO:19). In embodiments, the sequence is (SEQ ID NO:20). In embodiments, the sequence is (SEQ ID NO:21). In embodiments, the sequence is (SEQ ID NO:22). In embodiments, the sequence is (SEQ ID NO:23). In embodiments, the sequence is (SEQ ID NO:24). In embodiments, the sequence is (SEQ ID NO:25). In embodiments, the sequence is (SEQ ID NO:26). In embodiments, the sequence is (SEQ ID NO:27). In embodiments, the sequence is (SEQ ID NO:28). In embodiments, the sequence is (SEQ ID NO:29). In embodiments, the sequence is (SEQ ID NO:30). In embodiments, the sequence is (SEQ ID NO:31). In embodiments, the sequence is (SEQ ID NO:32). In embodiments, the sequence is (SEQ ID NO:33). In embodiments, the sequence is (SEQ ID NO:34). In embodiments, the sequence is (SEQ ID NO:35). In embodiments, the sequence is (SEQ ID NO:36). In embodiments, the sequence is (SEQ ID NO:37). In embodiments, the sequence is (SEQ ID NO:38). In embodiments, the sequence is (SEQ ID NO:39). In embodiments, the sequence is (SEQ ID NO:40). In embodiments, the sequence is (SEQ ID NO:41). In embodiments, the sequence is (SEQ ID NO:42). In embodiments, the sequence is (SEQ ID NO:43). In embodiments, the sequence is (SEQ ID NO:44). In embodiments, the sequence is (SEQ ID NO:45). In embodiments, the sequence is (SEQ ID NO:46). In embodiments, the sequence is (SEQ ID NO:47). In embodiments, the sequence is (SEQ ID NO:48). In embodiments, the sequence is (SEQ ID NO:49). In embodiments, the sequence is (SEQ ID NO:50). In embodiments, the sequence is (SEQ ID NO:51). In embodiments, the sequence is (SEQ ID NO:52). In embodiments, the sequence is (SEQ ID NO:53). In embodiments, the sequence is (SEQ ID NO:54). In embodiments, the sequence is (SEQ ID NO:55). In embodiments, the sequence is (SEQ ID NO:56). In embodiments, the sequence is (SEQ ID NO:57). In embodiments, the sequence is (SEQ ID NO:58). In embodiments, the sequence is (SEQ ID NO:59). In embodiments, the sequence is (SEQ ID NO:60). In embodiments, the sequence is (SEQ ID NO:61). In embodiments, the sequence is (SEQ ID NO:62). In embodiments, the sequence is (SEQ ID NO:63). In embodiments, the sequence is (SEQ ID NO:64). In embodiments, the sequence is (SEQ ID NO:65). In embodiments, the sequence is (SEQ ID NO:66). In embodiments, the sequence is (SEQ ID NO:67). In embodiments, the sequence is (SEQ ID NO:68). In embodiments, the sequence is (SEQ ID NO:69). In embodiments, the sequence is (SEQ ID NO:70). In embodiments, the sequence is (SEQ ID NO:71). In embodiments, the sequence is (SEQ ID NO:72). In embodiments, the sequence is (SEQ ID NO:73). In embodiments, the sequence is (SEQ ID NO:74). In embodiments, the sequence is (SEQ ID NO:75). In embodiments, the sequence is (SEQ ID NO:76). In embodiments, the sequence is (SEQ ID NO:77). In embodiments, the sequence is (SEQ ID NO:78). In embodiments, the sequence is (SEQ ID NO:79). In embodiments, the sequence is (SEQ ID NO:80). In embodiments, the sequence is (SEQ ID NO:81). In embodiments, the sequence is (SEQ ID NO:82). In embodiments, the sequence is (SEQ ID NO:83). In embodiments, the sequence is (SEQ ID NO:84). In embodiments, the sequence is (SEQ ID NO:85). In embodiments, the sequence is (SEQ ID NO:86). In embodiments, the sequence is (SEQ ID NO:87). In embodiments, the sequence is (SEQ ID NO:88). In embodiments, the sequence is (SEQ ID NO:89). In embodiments, the sequence is (SEQ ID NO:90). In embodiments, the sequence is (SEQ ID NO:91). In embodiments, the sequence is (SEQ ID NO:92). In embodiments, the sequence is (SEQ ID NO:93). In embodiments, the sequence is (SEQ ID NO:94). In embodiments, the sequence is (SEQ ID NO:95). In embodiments, the sequence is (SEQ ID NO:96). In embodiments, the sequence is (SEQ ID NO:97). In embodiments, the sequence is (SEQ ID NO:98). In embodiments, the sequence is (SEQ ID NO:99). In embodiments, the sequence is (SEQ ID NO:100). In embodiments, the sequence is (SEQ ID NO:101). In embodiments, the sequence is (SEQ ID NO:102). In embodiments, the sequence is (SEQ ID NO:103). In embodiments, the sequence is (SEQ ID NO:104). In embodiments, the sequence is (SEQ ID NO:105). In embodiments, the sequence is (SEQ ID NO:106). In embodiments, the sequence is (SEQ ID NO:107). In embodiments, the sequence is (SEQ ID NO:108). In embodiments, the sequence is (SEQ ID NO:109). In embodiments, the sequence is (SEQ ID NO:110). In embodiments, the sequence is (SEQ ID NO:111). In embodiments, the sequence is (SEQ ID NO:112). In embodiments, the sequence is (SEQ ID NO:113). In embodiments, the sequence is (SEQ ID NO:114). In embodiments, the sequence is (SEQ ID NO:115). In embodiments, the sequence is (SEQ ID NO:116). In embodiments, the sequence is (SEQ ID NO:117). In embodiments, the sequence is (SEQ ID NO:118). In embodiments, the sequence is (SEQ ID NO:119). In embodiments, the sequence is (SEQ ID NO:120). In embodiments, the sequence is (SEQ ID NO:121). In embodiments, the sequence is (SEQ ID NO:122). In embodiments, the sequence is (SEQ ID NO:123). In embodiments, the sequence is (SEQ ID NO:124). In embodiments, the sequence is (SEQ ID NO:125). In embodiments, the sequence is (SEQ ID NO:126). In embodiments, the sequence is (SEQ ID NO:127). In embodiments, the sequence is (SEQ ID NO:128). In embodiments, the sequence is (SEQ ID NO:129). In embodiments, the sequence is (SEQ ID NO:130). In embodiments, the sequence is (SEQ ID NO:131). In embodiments, the sequence is (SEQ ID NO:132). In embodiments, the sequence is (SEQ ID NO:133). In embodiments, the sequence is (SEQ ID NO:134). In embodiments, the sequence is (SEQ ID NO:135). In embodiments, the sequence is (SEQ ID NO:136). In embodiments, the sequence is (SEQ ID NO:137). In embodiments, the sequence is (SEQ ID NO:138). In embodiments, the sequence is (SEQ ID NO:139). In embodiments, the sequence is (SEQ ID NO:140). In embodiments, the sequence is (SEQ ID NO:141). In embodiments, the sequence is (SEQ ID NO:142). In embodiments, the sequence is (SEQ ID NO:143). In embodiments, the sequence is (SEQ ID NO:144). In embodiments, the sequence is (SEQ ID NO:145). In embodiments, the sequence is (SEQ ID NO:146). In embodiments, the sequence is (SEQ ID NO:147). In embodiments, the sequence is (SEQ ID NO:148). In embodiments, the sequence is (SEQ ID NO:149). In embodiments, the sequence is (SEQ ID NO:150). In embodiments, the sequence is (SEQ ID NO:151). In embodiments, the sequence is (SEQ ID NO:152). In embodiments, the sequence is (SEQ ID NO:153). In embodiments, the sequence is (SEQ ID NO:154). In embodiments, the sequence is (SEQ ID NO:155). In embodiments, the sequence is (SEQ ID NO:156). In embodiments, the sequence is (SEQ ID NO:157). In embodiments, the sequence is (SEQ ID NO:158). In embodiments, the sequence is (SEQ ID NO:159). In embodiments, the sequence is (SEQ ID NO:160). In embodiments, the sequence is (SEQ ID NO:161). In embodiments, the sequence is (SEQ ID NO:162). In embodiments, the sequence is (SEQ ID NO:163). In embodiments, the sequence is (SEQ ID NO:164). In embodiments, the sequence is (SEQ ID NO:165). In embodiments, the sequence is (SEQ ID NO:166). In embodiments, the sequence is (SEQ ID NO:167). In embodiments, the sequence is (SEQ ID NO:168). In embodiments, the sequence is (SEQ ID NO:169). In embodiments, the sequence is (SEQ ID NO:170). In embodiments, the sequence is (SEQ ID NO:171). In embodiments, the sequence is (SEQ ID NO:172). In embodiments, the sequence is (SEQ ID NO:173). In embodiments, the sequence is (SEQ ID NO:174). In embodiments, the sequence is (SEQ ID NO:175). In embodiments, the sequence is (SEQ ID NO:176). In embodiments, the sequence is (SEQ ID NO:177). In embodiments, the sequence is (SEQ ID NO:178). In embodiments, the sequence is (SEQ ID NO:179). In embodiments, the sequence is (SEQ ID NO:180). In embodiments, the sequence is (SEQ ID NO:181). In embodiments, the sequence is (SEQ ID NO:182). In embodiments, the sequence is (SEQ ID NO:183). In embodiments, the sequence is (SEQ ID NO:184). In embodiments, the sequence is (SEQ ID NO:185). In embodiments, the sequence is (SEQ ID NO:186). In embodiments, the sequence is (SEQ ID NO:187). In embodiments, the sequence is (SEQ ID NO:188). In embodiments, the sequence is (SEQ ID NO:189). In embodiments, the sequence is (SEQ ID NO:190). In embodiments, the sequence is (SEQ ID NO:191). In embodiments, the sequence is (SEQ ID NO:192). In embodiments, the sequence is (SEQ ID NO:193). In embodiments, the sequence is (SEQ ID NO:194). In embodiments, the sequence is (SEQ ID NO:195). In embodiments, the sequence is (SEQ ID NO:196). In embodiments, the sequence is (SEQ ID NO:197). In embodiments, the sequence is (SEQ ID NO:198). In embodiments, the sequence is (SEQ ID NO:199). In embodiments, the sequence is (SEQ ID NO:200). In embodiments, the sequence is (SEQ ID NO:201). In embodiments, the sequence is (SEQ ID NO:202). In embodiments, the sequence is (SEQ ID NO:203). In embodiments, the sequence is (SEQ ID NO:204). In embodiments, the sequence is (SEQ ID NO:205). In embodiments, the sequence is (SEQ ID NO:206). In embodiments, the sequence is (SEQ ID NO:207). In embodiments, the sequence is (SEQ ID NO:208). In embodiments, the sequence is (SEQ ID NO:209). In embodiments, the sequence is (SEQ ID NO:210). In embodiments, the sequence is (SEQ ID NO:211). In embodiments, the sequence is (SEQ ID NO:212). In embodiments, the sequence is (SEQ ID NO:213). In embodiments, the sequence is (SEQ ID NO:214). In embodiments, the sequence is (SEQ ID NO:215). In embodiments, the sequence is (SEQ ID NO:216). In embodiments, the sequence is (SEQ ID NO:217). In embodiments, the sequence is (SEQ ID NO:218). In embodiments, the sequence is (SEQ ID NO:219). In embodiments, the sequence is (SEQ ID NO:220). In embodiments, the sequence is (SEQ ID NO:221). In embodiments, the sequence is (SEQ ID NO:222). In embodiments, the sequence is (SEQ ID NO:223). In embodiments, the sequence is (SEQ ID NO:224). In embodiments, the sequence is (SEQ ID NO:225). In embodiments, the sequence is (SEQ ID NO:226). In embodiments, the sequence is (SEQ ID NO:227). In embodiments, the sequence is (SEQ ID NO:228). In embodiments, the sequence is (SEQ ID NO:229). In embodiments, the sequence is (SEQ ID NO:230). In embodiments, the sequence is (SEQ ID NO:231). In embodiments, the sequence is (SEQ ID NO:232). In embodiments, the sequence is (SEQ ID NO:233). In embodiments, the sequence is (SEQ ID NO:234). In embodiments, the sequence is (SEQ ID NO:235). In embodiments, the sequence is (SEQ ID NO:236). In embodiments, the sequence is (SEQ ID NO:237). In embodiments, the sequence is (SEQ ID NO:238). In embodiments, the sequence is (SEQ ID NO:239). In embodiments, the sequence is (SEQ ID NO:240). In embodiments, the sequence is (SEQ ID NO:241). In embodiments, the sequence is (SEQ ID NO:242). In embodiments, the sequence is (SEQ ID NO:243). In embodiments, the sequence is (SEQ ID NO:244). In embodiments, the sequence is (SEQ ID NO:245). In embodiments, the sequence is (SEQ ID NO:246). In embodiments, the sequence is (SEQ ID NO:247). In embodiments, the sequence is (SEQ ID NO:248). In embodiments, the sequence is (SEQ ID NO:249). In embodiments, the sequence is (SEQ ID NO:250). In embodiments, the sequence is (SEQ ID NO:251). In embodiments, the sequence is (SEQ ID NO:252). In embodiments, the sequence is (SEQ ID NO:253). In embodiments, the sequence is (SEQ ID NO:254). In embodiments, the sequence is (SEQ ID NO:255). In embodiments, the sequence is (SEQ ID NO:256). In embodiments, the sequence is (SEQ ID NO:257). In embodiments, the sequence is (SEQ ID NO:258). In embodiments, the sequence is (SEQ ID NO:259). In embodiments, the sequence is (SEQ ID NO:260). In embodiments, the sequence is (SEQ ID NO:261). In embodiments, the sequence is (SEQ ID NO:262). In embodiments, the sequence is (SEQ ID NO:263). In embodiments, the sequence is (SEQ ID NO:264). In embodiments, the sequence is (SEQ ID NO:265). In embodiments, the sequence is (SEQ ID NO:266). In embodiments, the sequence is (SEQ ID NO:267). In embodiments, the sequence is (SEQ ID NO:268). In embodiments, the sequence is (SEQ ID NO:269). In embodiments, the sequence is (SEQ ID NO:270). In embodiments, the sequence is (SEQ ID NO:271). In embodiments, the sequence is (SEQ ID NO:272). In embodiments, the sequence is (SEQ ID NO:273). In embodiments, the sequence is (SEQ ID NO:274). In embodiments, the sequence is (SEQ ID NO:275). In embodiments, the sequence is (SEQ ID NO:276). In embodiments, the sequence is (SEQ ID NO:277). In embodiments, the sequence is (SEQ ID NO:278). In embodiments, the sequence is (SEQ ID NO:279). In embodiments, the sequence is (SEQ ID NO:280). In embodiments, the sequence is (SEQ ID NO:281). In embodiments, the sequence is (SEQ ID NO:282). In embodiments, the sequence is (SEQ ID NO:283). In embodiments, the sequence is (SEQ ID NO:284). In embodiments, the sequence is (SEQ ID NO:285). In embodiments, the sequence is (SEQ ID NO:286). In embodiments, the sequence is (SEQ ID NO:287). In embodiments, the sequence is (SEQ ID NO:288). In embodiments, the sequence is (SEQ ID NO:289). In embodiments, the sequence is (SEQ ID NO:290). In embodiments, the sequence is (SEQ ID NO:291). In embodiments, the sequence is (SEQ ID NO:292). In embodiments, the sequence is (SEQ ID NO:293). In embodiments, the sequence is (SEQ ID NO:294). In embodiments, the sequence is (SEQ ID NO:295). In embodiments, the sequence is (SEQ ID NO:296). In embodiments, the sequence is (SEQ ID NO:297). In embodiments, the sequence is (SEQ ID NO:298). In embodiments, the sequence is (SEQ ID NO:299). In embodiments, the sequence is (SEQ ID NO:300). In embodiments, the sequence is (SEQ ID NO:301). In embodiments, the sequence is (SEQ ID NO:302). In embodiments, the sequence is (SEQ ID NO:303). In embodiments, the sequence is (SEQ ID NO:304). In embodiments, the sequence is (SEQ ID NO:305). In embodiments, the sequence is (SEQ ID NO:306). In embodiments, the sequence is (SEQ ID NO:307). In embodiments, the sequence is (SEQ ID NO:308). In embodiments, the sequence is (SEQ ID NO:309). In embodiments, the sequence is (SEQ ID NO:310). In embodiments, the sequence is (SEQ ID NO:311). In embodiments, the sequence is (SEQ ID NO:312). In embodiments, the sequence is (SEQ ID NO:313). In embodiments, the sequence is (SEQ ID NO:314). In embodiments, the sequence is (SEQ ID NO:315). In embodiments, the sequence is (SEQ ID NO:316). In embodiments, the sequence is (SEQ ID NO:317). In embodiments, the sequence is (SEQ ID NO:318). In embodiments, the sequence is (SEQ ID NO:319). In embodiments, the sequence is (SEQ ID NO:320). In embodiments, the sequence is (SEQ ID NO:321). In embodiments, the sequence is (SEQ ID NO:322). In embodiments, the sequence is (SEQ ID NO:323). In embodiments, the sequence is (SEQ ID NO:324). In embodiments, the sequence is (SEQ ID NO:325). In embodiments, the sequence is (SEQ ID NO:326). In embodiments, the sequence is (SEQ ID NO:327). In embodiments, the sequence is (SEQ ID NO:328). In embodiments, the sequence is (SEQ ID NO:329). In embodiments, the sequence is (SEQ ID NO:330). In embodiments, the sequence is (SEQ ID NO:331). In embodiments, the sequence is (SEQ ID NO:332). In embodiments, the sequence is (SEQ ID NO:333). In embodiments, the sequence is (SEQ ID NO:334). In embodiments, the sequence is (SEQ ID NO:335). In embodiments, the sequence is (SEQ ID NO:336). In embodiments, the sequence is (SEQ ID NO:337). In embodiments, the sequence is (SEQ ID NO:338). In embodiments, the sequence is (SEQ ID NO:339). In embodiments, the sequence is (SEQ ID NO:340). In embodiments, the sequence is (SEQ ID NO:341). In embodiments, the sequence is (SEQ ID NO:342). In embodiments, the sequence is (SEQ ID NO:343).
[0481] In embodiments, the inhibition is competitive inhibition. In embodiments, the inhibition is irreversible. In embodiments, the inhibition is reversible. In embodiments, the compound covalently binds to the reticulon 4 protein.
[0482] Where the compound covalently binds to the reticulon 4 a reticulon 4 protein (e.g., human reticulon 4) covalently bonded to a reticulon 4 inhibitor is formed (also referred to herein as a reticulon 4-compound adduct), as described below. In embodiments, the resulting covalent bond is reversible. Where the resulting covalent bond is reversible, the bonding reverses upon denaturation of the protein. Thus, in embodiments, the reversibility of a covalent bond between the compound and the reticulon 4 upon denaturation of the reticulon 4 avoids or decreases autoimmune response in a subject subsequent to administration of the compound (relative to irreversibility). Moreover, in embodiments, the reversibility of a covalent bond between the compound and the reticulon 4 upon denaturation of the reticulon 4 avoids or decreases the toxicity (e.g. liver toxicity) of the compound in a subject (relative to irreversibility).
[0483] In embodiments, the reticulon 4 activity is endoplasmic reticulum (ER) tubule formation. In embodiments, the reticulon 4 activity is an increase in endoplasmic reticulum (ER) tubule formation. In embodiments, the reticulon 4 activity is RTN 4 membrane associate. In embodiments, the reticulon 4 activity is RTN 4 membrane contact. In embodiments, the reticulon 4 activity is increasing ER tubule networks. In embodiments, the reticulon 4 activity is nuclear envelope assembly (e.g., during mitosis). In embodiments, the reticulon 4 activity is nuclear envelope formation (e.g., during mitosis). In embodiments, the reticulon 4 activity is nuclear envelope disassembly (e.g., during mitosis). In embodiments, the reticulon 4 activity is increasing cell division. In embodiments, the reticulon 4 activity is increasing the rate of cell divisional. In embodiments, the reticulon 4 activity is promoting cell division. In embodiments, the reticulon 4 activity is completing cell division. In embodiments, the reticulon 4 activity is maintaining natural nuclear envelope morphology (e.g., during mitosis). In embodiments, the reticulon 4 activity is maintaining natural interphase nuclear envelope morphology. In embodiments, the reticulon 4 activity is nuclear envelope remodeling (e.g., during mitosis). In embodiments, the reticulon 4 activity is inhibition of neurite cell growth. In embodiments, the reticulon 4 activity is neuron growth. In embodiments, the reticulon 4 activity is neuron survival. In embodiments, the reticulon 4 activity is neuron proliferation. In embodiments, the reticulon 4 activity is completing mitosis. In embodiments, the reticulon 4 activity is increasing the rate of mitosis (e.g, compared to lack of RTN 4 activity).
[0484] In an aspect is provided a method of inhibiting cell divisional (e.g., cancer cell division, cancer proliferation), the method including contacting a cell (e.g., cancer cell) with an effective amount of a Reticulon 4 inhibitor. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein).
[0485] In an aspect is provided a method of inhibiting cell divisional (e.g., cancer cell division, cancer proliferation) including contacting a cell (e.g., cancer cell) with an effective amount of a compound described herein.
VI. Reticulon 4 Protein
[0486] In an aspect is provided a reticulon 4 protein covalently bonded to a Reticulon 4 inhibitor (a reticulon 4 protein-reticulon 4 inhibitor complex). In embodiments, the reticulon 4 is a human reticulon 4. In embodiments, the reticulon 4 is has the sequence SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor is a compound described herein. In embodiments, the Reticulon 4 inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-Reticulon 4 antibody, anti-Reticulon 4 binding antibody fragment), or compound (e.g., compound described herein). In embodiments, the Reticulon 4 inhibitor is provided in a therapeutically effective amount. In embodiments, the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to G1097 of SEQ ID NO:331. In embodiments, the Reticulon 4 inhibitor contacts an amino acids corresponding to H1098 of SEQ ID NO:331.
[0487] In an aspect is provided a reticulon 4 protein covalently bonded to a compound described herein. In embodiments, compound is covalently bonded to the amino acid corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound covalently binds an amino acid corresponding to C1101 in SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1105 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to C1101 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to E1078 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1079 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to A1082 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to I1083 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to K1090 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to Y1091 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to S1094 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to G1097 of SEQ ID NO:331. In embodiments, the compound contacts an amino acids corresponding to H1098 of SEQ ID NO:331.
[0488] In embodiments, the compound is bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is reversibly covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the compound is irreversibly covalently bonded to a cysteine residue of the reticulon 4 protein. In embodiments, the cysteine residue corresponds to C1101 of SEQ ID NO:331.
[0489] In an embodiment, the reticulon 4 protein is covalently bonded (e.g., reversibly or irreversibly) to a portion of a compound described herein (e.g., portion of a reticulon 4 inhibitor or portion of a compound described herein).
[0490] In an aspect is provided a reticulon 4 protein (e.g., human reticulon 4) covalently bonded to a reticulon 4 inhibitor (e.g., reticulon 4 inhibitor, compound described herein, or a portion of a compound described herein).
[0491] In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is irreversibly covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is reversibly covalently bonded to a reticulon 4 inhibitor (e.g., compound described herein or a portion of a compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is irreversibly covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 protein (e.g., human reticulon 4) is reversibly covalently bonded to a portion of a reticulon 4 inhibitor (e.g., compound described herein). In embodiments, the reticulon 4 inhibitor (e.g., compound described herein) is bonded to a cysteine residue (e.g., Cys1101 of human reticulon 4 or cysteine corresponding to Cys1101 of human reticulon 4) of the reticulon 4 protein (e.g., human reticulon 4). In embodiments, the portion of a reticulon 4 inhibitor (e.g., compound described herein) is bonded to a cysteine residue (e.g., Cys1101 of SEQ ID NO:331 or cysteine corresponding to Cys1101 of SEQ ID NO:331) of the reticulon 4 protein (e.g., human reticulon 4).
[0492] In embodiments, the RTN4 protein covalently bonded to a RTN4 inhibitor or compound described herein is the product of a reaction between the RTN4 protein and a RTN4 inhibitor or compound described herein. It will be understood that the covalently bonded RTN4 protein and RTN4 inhibitor (e.g., compound described herein) are the remnants of the reactant RTN4 protein and RTN4 inhibitor or compound, wherein each reactant now participates in the covalent bond between the RTN4 protein and RTN4 inhibitor or compound. In embodiments of the covalently bonded RTN4 protein and compound described herein, the remnant of the E substitutent is a linker including a covalent bond between the RTN4 protein and the remainder of the compound described herein. It will be understood by a person of ordinary skill in the art that when a RTN4 protein is covalently bonded to a RTN4 inhibitor (e.g., compound described herein), the RTN4 inhibitor (e.g., compound described herein) forms a remnant of the pre-reacted RTN4 inhibitor (e.g., compound described herein) wherein a bond connects the remnant of the RTN4 inhibitor (e.g., compound described herein) to the remnant of the RTN4 protein (e.g., cysteine sulfur, sulfur of amino acid corresponding to C1101 of human RTN4, sulfur of C1101 of human RTN4). The remnant of the RTN4 inhibitor (compound described herein) may also be called a portion of the RTN4 inhibitor. In embodiments, the remnant of the E substituent is a linker selected from a bond, S(O).sub.2, NH, O, S, C(O), C(O)NH, NHC(O), NHC(O)NH, NHC(O)NH, C(O)O, OC(O), CH.sub.2NH, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C.sub.1-C.sub.8, C.sub.1-C.sub.6, C.sub.1-C.sub.4, or C.sub.1-C.sub.2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C.sub.3-C.sub.8, C.sub.3-C.sub.6, C.sub.4-C.sub.6, or C.sub.5-C.sub.6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C.sub.6-C.sub.10 or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula:
##STR00068##
wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R.sup.1, R.sup.2, L.sup.1, L.sup.2, z1, and z2 are as described herein. As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula:
##STR00069##
wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R.sup.1, R.sup.2, R.sup.15, R.sup.17, L.sup.1, L.sup.2, z1, and z2 are as described herein. As a non-limiting example, the RTN4 protein covalently bonded to a RTN4 inhibitor may have the formula:
##STR00070##
wherein S is the sulfur of a reticulon 4 protein cysteine (e.g., corresponding to C1101 of human reticulon 4), which is bonded to the remainder of the reticulon 4 protein and wherein R.sup.1, R.sup.2, R.sup.16, R.sup.17, L.sup.1, L.sup.2, z1, and z2 are as described herein.
VII. Embodiments
Embodiment P1
[0493] A compound having the formula:
##STR00071##
[0494] wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 5;
[0495] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 4; L.sup.1 is a bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene; R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene; R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; E is an electrophilic moiety; Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently
hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; [0496] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I; [0497] n1, n2, n4, and n5 are independently an integer from 0 to 4; and [0498] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment P2
[0499] The compound of embodiment P1 having the formula:
##STR00072##
Embodiment P3
[0500] The compound of embodiment P1 having the formula:
##STR00073##
Embodiment P4
[0501] The compound of embodiment P1 having the formula:
##STR00074##
Embodiment P5
[0502] The compound of embodiment P1 having the formula:
##STR00075##
Embodiment P6
[0503] The compound of one of embodiments P1 to P5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SR.sup.1D, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment P7
[0504] The compound of one of embodiments P1 to P5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
Embodiment P8
[0505] The compound of one of embodiments P1 to P5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
Embodiment P9
[0506] The compound of one of embodiments P1 to P5, wherein R.sup.1 is independently Cl.
Embodiment P10
[0507] The compound of embodiment P1, wherein two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment P11
[0508] The compound of embodiment P1, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted cycloalkyl.
Embodiment P12
[0509] The compound of embodiment P1, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
Embodiment P13
[0510] The compound of one of embodiments P1 to P12, wherein L.sup.1 is a bond, substituted or unsubstituted C.sub.1-C.sub.8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
Embodiment P14
[0511] The compound of one of embodiments P1 to P12, wherein L.sup.1 is a bond.
Embodiment P15
[0512] The compound of one of embodiments P1 to P14, wherein L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.
Embodiment P16
[0513] The compound of one of embodiments P1 to P14, wherein L.sup.2 is NR.sup.5.
Embodiment P17
[0514] The compound of embodiment P16, wherein R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
Embodiment P18
[0515] The compound of embodiment P16, wherein R.sup.5 is hydrogen or unsubstituted C.sub.1-C.sub.3 alkyl.
Embodiment P19
[0516] The compound of embodiment P16, wherein R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl.
Embodiment P20
[0517] The compound of embodiment P16, wherein R.sup.5 is hydrogen.
Embodiment P21
[0518] The compound of one of embodiments P1 to P20, wherein E is a covalent cysteine modifier moiety.
Embodiment P22
[0519] The compound of one of embodiments P1 to P20, wherein E is:
##STR00076##
[0520] R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B, NHC(O)NHNR.sup.15AR.sup.15B, NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0521] R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2,
CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, ONR.sup.16AR.sup.16B, NHC(O)NHNR.sup.16AR.sup.16B,
NHC(O)NR.sup.16AR.sup.16B, N(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0522] R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B,
NHC(O)NHNR.sup.17AR.sup.17B,
NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0523] R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0524] R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, are independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0525] each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I;
[0526] n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and
[0527] m15, m16, and m17 are independently and integer from 1 to 2.
Embodiment P23
[0528] The compound of embodiment P22, wherein R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen.
Embodiment P24
[0529] The compound of one of embodiments P22 to P23, wherein E is:
##STR00077##
Embodiment P25
[0530] A pharmaceutical composition comprising a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient.
Embodiment P26
[0531] A pharmaceutical composition comprising the compound of any one of embodiments P1 to P24 and a pharmaceutically acceptable excipient.
Embodiment P27
[0532] A method of inhibiting reticulon 4 protein activity, said method comprising contacting the reticulon 4 protein with a Reticulon 4 inhibitor.
Embodiment P28
[0533] The method of embodiment P27, wherein the Reticulon 4 inhibitor is an siRNA, antibody, or compound.
Embodiment P29
[0534] The method of embodiment P30, wherein the Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, 51079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of human reticulon 4.
Embodiment P30
[0535] A method of inhibiting reticulon 4 protein activity, said method comprising contacting the reticulon 4 protein with an effective amount of a compound of one of embodiments P1 to P24.
Embodiment P31
[0536] The method of embodiment P30, wherein the compound is covalently bonded to the amino acid corresponding to C1101 of human reticulon 4.
Embodiment P32
[0537] The method of embodiment P30, wherein the compound contacts one or more amino acids corresponding to E1105, C1101, E1078, 51079, A1082, I1083, K1090,
[0538] Y1091, S1094, G1097, and H1098 of human reticulon 4.
Embodiment P33
[0539] A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a Reticulon 4 inhibitor.
Embodiment P34
[0540] A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of one of embodiments P1 to P24.
Embodiment P35
[0541] The method of one of embodiments P33 to P34, wherein the cancer is colorectal cancer.
Embodiment P36
[0542] A reticulon 4 protein covalently bonded to a compound of one of embodiments P1 to P24.
Embodiment P37
[0543] The Reticulon 4 protein of embodiment P36, wherein the compound is bonded to a cysteine residue of the protein.
Embodiment P38
[0544] The reticulon 4 protein of embodiment P36, covalently bonded to a portion of a compound of one of embodiments 1 to 24.
Embodiment P39
[0545] The reticulon 4 protein of embodiment P36, irreversibly covalently bonded to a portion of a compound of one of embodiments 1 to 24.
Embodiment P40
[0546] The reticulon 4 protein of one of embodiments P36 to P39, wherein the compound or portion of the compound is covalently bonded to an amino acid corresponding to C1101 of human reticulon 4.
VIII. Additional Embodiments
Embodiment 1
[0547] A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound having the
##STR00078##
[0548] formula:
[0549] wherein, R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0550] z1 is an integer from 0 to 5;
[0551] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(OR.sup.2CC(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0552] z2 is an integer from 0 to 4;
[0553] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0554] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0555] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0556] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0557] E is an electrophilic moiety;
[0558] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0559] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0560] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0561] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment 2
[0562] The method of embodiment 1, wherein the compound has the formula:
##STR00079##
Embodiment 3
[0563] The method of embodiment 1, wherein the compound has the formula:
##STR00080##
Embodiment 4
[0564] The method of embodiment 1, wherein the compound has the formula:
##STR00081##
Embodiment 5
[0565] The method of embodiment 1, wherein the compound has the formula:
##STR00082##
Embodiment 6
[0566] The method of one of embodiments 1 to 5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SR.sup.1D, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 7
[0567] The method of one of embodiments 1 to 5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
Embodiment 8
[0568] The method of one of embodiments 1 to 5, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
Embodiment 9
[0569] The method of one of embodiments 1 to 5, wherein R.sup.1 is independently Cl.
Embodiment 10
[0570] The method of embodiment 1, wherein two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 11
[0571] The method of embodiment 1, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted cycloalkyl.
Embodiment 12
[0572] The method of embodiment 1, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
Embodiment 13
[0573] The method of one of embodiments 1 to 12, wherein L.sup.1 is a bond, substituted or unsubstituted C.sub.1-C.sub.8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
Embodiment 14
[0574] The method of one of embodiments 1 to 12, wherein L.sup.1 is a bond.
Embodiment 15
[0575] The method of one of embodiments 1 to 14, wherein L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.
Embodiment 16
[0576] The method of one of embodiments 1 to 14, wherein L.sup.2 is NR.sup.5.
Embodiment 17
[0577] The method of embodiment 16, wherein R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
Embodiment 18
[0578] The method of embodiment 16, wherein R.sup.5 is hydrogen or unsubstituted C.sub.1-C.sub.3 alkyl.
Embodiment 19
[0579] The method of embodiment 16, wherein R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl.
Embodiment 20
[0580] The method of embodiment 16, wherein R.sup.5 is hydrogen.
Embodiment 21
[0581] The method of one of embodiments 1 to 20, wherein E is a covalent cysteine modifier moiety.
Embodiment 22
[0582] The method of one of embodiments 1 to 20, wherein E is:
##STR00083##
[0583] R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B, NHC(O)NHNR.sup.15AR.sup.15B,
NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0584] R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2, CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, NR.sup.16AR.sup.16B,
NHC(O)NHNR.sup.16AR.sup.16B,
NHC(O)NR.sup.16AR.sup.16B, N(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0585] R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B,
NHC(O)NHNR.sup.17AR.sup.17B,
NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0586] R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2,
CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0587] R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, are independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0588] each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I;
[0589] n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and
[0590] m15, m16, and m17 are independently and integer from 1 to 2.
Embodiment 23
[0591] The method of embodiment 22, wherein R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen.
Embodiment 24
[0592] The method of one of embodiments 22 to 23, wherein E is:
##STR00084##
Embodiment 25
[0593] The method of embodiment 1, having the formula:
##STR00085##
Embodiment 26
[0594] The method of one of embodiments 1 to 25, wherein the cancer is colorectal cancer.
Embodiment 27
[0595] The use of a compound for the preparation of a medicament for the treatment of cancer, wherein the compound has the formula:
##STR00086##
[0596] wherein,
[0597] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0598] z1 is an integer from 0 to 5;
[0599] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3,
OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(OR.sup.2CC(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0600] z2 is an integer from 0 to 4; [0601] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O)NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0602] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0603] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0604] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0605] E is an electrophilic moiety;
[0606] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0607] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0608] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0609] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment 28
[0610] The compound of embodiment 27, wherein the compound has the formula:
##STR00087##
Embodiment 29
[0611] The compound of embodiment 27, wherein the compound has the formula:
##STR00088##
Embodiment 30
[0612] The compound of embodiment 27, wherein the compound has the formula:
##STR00089##
Embodiment 31
[0613] The compound of embodiment 27, wherein the compound has the formula:
##STR00090##
Embodiment 32
[0614] The compound of embodiment 27, wherein the compound has the formula:
##STR00091##
Embodiment 33
[0615] The compound of one of embodiments 27 to 32, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SR.sup.1D, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 34
[0616] The compound of one of embodiments 27 to 32, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
Embodiment 35
[0617] The compound of one of embodiments 27 to 32, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
Embodiment 36
[0618] The compound of one of embodiments 27 to 32, wherein R.sup.1 is independently Cl.
Embodiment 37
[0619] The compound of embodiment 27, wherein two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 38
[0620] The compound of embodiment 27, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted cycloalkyl.
Embodiment 39
[0621] The compound of embodiment 27, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
Embodiment 40
[0622] The compound of one of embodiments 27 to 39, wherein L.sup.1 is a bond, substituted or unsubstituted C.sub.1-C.sub.8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
Embodiment 41
[0623] The compound of one of embodiments 27 to 39, wherein L.sup.1 is a bond.
Embodiment 42
[0624] The compound of one of embodiments 27 to 41, wherein L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.
Embodiment 43
[0625] The compound of one of embodiments 27 to 41, wherein L.sup.2 is NR.sup.5.
Embodiment 44
[0626] The compound of embodiment 43, wherein R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
Embodiment 45
[0627] The compound of embodiment 43, wherein R.sup.5 is hydrogen or unsubstituted C.sub.1-C.sub.3 alkyl.
Embodiment 46
[0628] The compound of embodiment 43, wherein R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl.
Embodiment 47
[0629] The compound of embodiment 43, wherein R.sup.5 is hydrogen.
Embodiment 48
[0630] The compound of one of embodiments 27 to 47, wherein E is a covalent cysteine modifier moiety.
Embodiment 49
[0631] The compound of one of embodiments 27 to 47, wherein E is:
##STR00092##
[0632] R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B,
NHC(O)NHNR.sup.15AR.sup.15B,
NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0633] R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2,
CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, ONR.sup.16AR.sup.16B,
NHC(O)NHNR.sup.16AR.sup.16B,
NHC(O)NR.sup.16AR.sup.16B,
NHC(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0634] R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2,
CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B,
NHC(O)NHNR.sup.17AR.sup.17B,
NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3, OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0635] R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0636] R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, are independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0637] each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I;
[0638] n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and
[0639] m15, m16, and m17 are independently and integer from 1 to 2.
Embodiment 50
[0640] The compound of embodiment 49, wherein R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen.
Embodiment 51
[0641] The compound of one of embodiments 49 to 50, wherein E is:
##STR00093##
Embodiment 52
[0642] The compound of embodiment 27, having the formula:
##STR00094##
Embodiment 53
[0643] A pharmaceutical composition comprising a Reticulon 4 inhibitor and a pharmaceutically acceptable excipient.
Embodiment 54
[0644] The pharmaceutical composition of embodiment 53, wherein the Reticulon 4 inhibitor is the compound has the formula:
##STR00095##
[0645] wherein,
[0646] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0647] z1 is an integer from 0 to 5; R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0648] z2 is an integer from 0 to 4;
[0649] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, , NR.sup.4(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
[0650] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0651] L.sup.2 is a bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
[0652] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0653] E is an electrophilic moiety;
[0654] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0655] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0656] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0657] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment 55
[0658] A method of inhibiting reticulon 4 protein activity, said method comprising contacting a reticulon 4 protein with an effective amount of a Reticulon 4 inhibitor, wherein said Reticulon 4 inhibitor contacts one or more amino acids corresponding to E1105, C1101, E1078, S1079, A1082, I1083, K1090, Y1091, S1094, G1097, and H1098 of SEQ ID NO:331.
Embodiment 56
[0659] The method of embodiment 55, wherein the Reticulon 4 inhibitor is an antisense nucleic acid, antibody, or a compound.
Embodiment 57
[0660] The method of embodiment 55 or 56, wherein said Reticulon 4 inhibitor is a compound having the formula:
##STR00096##
[0661] wherein,
[0662] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0663] z1 is an integer from 0 to 5;
[0664] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0665] z2 is an integer from 0 to 4;
[0666] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0667] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O), OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0668] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0669] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0670] E is an electrophilic moiety;
[0671] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0672] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0673] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0674] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment 58
[0675] The method of embodiment 57, wherein the compound is covalently bonded to the amino acid corresponding to C1101 of SEQ ID NO:331.
Embodiment 59
[0676] A reticulon 4 protein covalently bonded to a compound having the formula:
##STR00097##
[0677] wherein,
[0678] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1R.sup.1D, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0679] z1 is an integer from 0 to 5;
[0680] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0681] z2 is an integer from 0 to 4;
[0682] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0683] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0684] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0685] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0686] E is an electrophilic moiety;
[0687] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0688] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0689] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0690] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2;
[0691] wherein the reticulon 4 protein is covalently bonded to said compound through said reacted electrophilic moiety.
Embodiment 60
[0692] The Reticulon 4 protein of embodiment 59, wherein the compound is bonded to a cysteine residue of the protein.
Embodiment 61
[0693] The reticulon 4 protein of one of embodiments 59 to 60, wherein the compound is covalently bonded to an amino acid corresponding to C1101 of SEQ ID NO:331.
Embodiment 62
[0694] A compound having the formula:
##STR00098##
[0695] wherein,
[0696] R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SO.sub.n1NR.sup.1AR.sup.1B, SO.sub.v1NR.sup.1AR.sup.1B, NHC(O)NR.sup.1AR.sup.1B, N(O).sub.m1, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, NR.sup.1ASO.sub.2R.sup.1D, NR.sup.1AC(O)R.sup.1C, NR.sup.1AC(O)OR.sup.1C, NR.sup.1AOR.sup.1C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0697] z1 is an integer from 0 to 5;
[0698] R.sup.2 is independently halogen, CX.sup.2.sub.3, CHX.sup.2.sub.2, CH.sub.2X.sup.2, OCX.sup.2.sub.3, OCH.sub.2X.sup.2, OCHX.sup.2.sub.2, CN, SO.sub.n2R.sup.2D, SO.sub.v2NR.sup.2AR.sup.2B, NHC(O)NR.sup.2AR.sup.2B, N(O).sub.m2, NR.sup.2AR.sup.2B, C(O)R.sup.2C, C(O)OR.sup.2C, C(O)NR.sup.2AR.sup.2B, OR.sup.2D, NR.sup.2ASO.sub.2R.sup.2D, NR.sup.2AC(O)R.sup.2C, NR.sup.2AC(O)OR.sup.2C, NR.sup.2AOR.sup.2C, N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0699] z2 is an integer from 0 to 4;
[0700] L.sup.1 is a
bond, S(O).sub.2, NR.sup.4, O, S, C(O), C(O)NR.sup.4, NR.sup.4C(O), NR.sup.4C(O)NH, NHC(O)NR.sup.4, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0701] R.sup.4 is hydrogen, CX.sup.4.sub.3, CHX.sup.4.sub.2, CH.sub.2X.sup.4, OCX.sup.4.sub.3, OCH.sub.2X.sup.4, OCHX.sup.4.sub.2, CN, C(O)R.sup.4A, C(O)OR.sup.4A, C(O)NR.sup.4AR.sup.4B, OR.sup.4A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0702] L.sup.2 is a
bond, S(O).sub.2, NR.sup.5, O, S, C(O), C(O)NR.sup.5, NR.sup.5C(O), NR.sup.5C(O)NH, NHC(O)NR.sup.5, C(O)O, OC(O), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
[0703] R.sup.5 is hydrogen, CX.sup.5.sub.3, CHX.sup.5.sub.2, CH.sub.2X.sup.5, OCX.sup.5.sub.3, OCH.sub.2X.sup.5, OCHX.sup.5.sub.2, CN, C(O)R.sup.5A, C(O)OR.sup.5A, C(O)NR.sup.5AR.sup.5B, OR.sup.5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0704] E is an electrophilic moiety;
[0705] Each R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D, R.sup.2A, R.sup.2B, R.sup.2C, R.sup.2D, R.sup.4A, R.sup.4B, R.sup.5A, and R.sup.5B is independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0706] each X, X.sup.1, X.sup.2, X.sup.4, and X.sup.5 is independently F, Cl, Br, or I;
[0707] n1, n2, n4, and n5 are independently an integer from 0 to 4; and
[0708] m1, m2, m4, m5, v1, v2, v4, and v5 are independently an integer from 1 to 2.
Embodiment 63
[0709] The compound of embodiment 62, wherein the compound has the formula:
##STR00099##
Embodiment 64
[0710] The compound of embodiment 1, wherein the compound has the formula:
##STR00100##
Embodiment 65
[0711] The compound of embodiment 1, wherein the compound has the formula:
##STR00101##
Embodiment 66
[0712] The compound of embodiment 1, wherein the compound has the formula:
##STR00102##
Embodiment 67
[0713] The compound of one of embodiments 62 to 66, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SR.sup.1D, NR.sup.1AR.sup.1B, C(O)R.sup.1C, C(O)OR.sup.1C, C(O)NR.sup.1AR.sup.1B, OR.sup.1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 68
[0714] The compound of one of embodiments 62 to 66, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C.sub.6-C.sub.12 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
Embodiment 69
[0715] The compound of one of embodiments 62 to 66, wherein R.sup.1 is independently halogen, CX.sup.1.sub.3, CHX.sup.1.sub.2, CH.sub.2X.sup.1, OCX.sup.1.sub.3, OCH.sub.2X.sup.1, OCHX.sup.1.sub.2, CN, SH, NH.sub.2, C(O)OH, C(O)NH.sub.2, OH, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
Embodiment 70
[0716] The compound of one of embodiments 62 to 66, wherein R.sup.1 is independently Cl.
Embodiment 71
[0717] The compound of embodiment 62, wherein two adjacent R.sup.1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Embodiment 72
[0718] The compound of embodiment 62, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted cycloalkyl.
Embodiment 73
[0719] The compound of embodiment 62, wherein two adjacent R.sup.1 substituents are joined to form an unsubstituted C.sub.3-C.sub.6 cycloalkyl.
Embodiment 74
[0720] The compound of one of embodiments 62 to 73, wherein L.sup.1 is a bond, substituted or unsubstituted C.sub.1-C.sub.8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
Embodiment 75
[0721] The compound of one of embodiments 62 to 73, wherein L.sup.1 is a bond.
Embodiment 76
[0722] The compound of one of embodiments 62 to 75, wherein L.sup.2 is NR.sup.5 or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.
Embodiment 77
[0723] The compound of one of embodiments 62 to 75, wherein L.sup.2 is NR.sup.5.
Embodiment 78
[0724] The compound of embodiment 77, wherein R.sup.5 is hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.
Embodiment 79
[0725] The compound of embodiment 77, wherein R.sup.5 is hydrogen or unsubstituted C.sub.1-C.sub.3 alkyl.
Embodiment 80
[0726] The compound of embodiment 77, wherein R.sup.5 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl, or unsubstituted benzyl.
Embodiment 81
[0727] The compound of embodiment 77, wherein R.sup.5 is hydrogen.
Embodiment 82
[0728] The compound of one of embodiments 62 to 81, wherein E is a covalent cysteine modifier moiety.
Embodiment 83
[0729] The compound of one of embodiments 62 to 81, wherein E is:
##STR00103##
[0730] R.sup.15 is independently hydrogen, halogen, CX.sup.15.sub.3, CHX.sup.15.sub.2, CH.sub.2X.sup.15, CN, SO.sub.n15R.sup.15D, SO.sub.v15NR.sup.15AR.sup.15B, NHNR.sup.15AR.sup.15B, ONR.sup.15AR.sup.15B,
NHC(O)NHNR.sup.15AR.sup.15B,
NHC(O)NR.sup.15AR.sup.15B, N(O).sub.m15, NR.sup.15AR.sup.15B, C(O)R.sup.15C, C(O)OR.sup.15C, C(O)NR.sup.15AR.sup.15B, OR.sup.15D, NR.sup.15ASO.sub.2R.sup.15D, NR.sup.15AC(O)R.sup.15C, NR.sup.15AC(O)OR.sup.15C, NR.sup.15AOR.sup.15C, OCX.sup.15.sub.3, OCHX.sup.15.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0731] R.sup.16 is independently hydrogen, halogen, CX.sup.16.sub.3, CHX.sup.16.sub.2, CH.sub.2X.sup.16, CN, SO.sub.n16R.sup.16D, SO.sub.v16NR.sup.16AR.sup.16B, NHNR.sup.16AR.sup.16B, ONR.sup.16AR.sup.16B,
NHC(O)NHNR.sup.16AR.sup.16B,
NHC(O)NR.sup.16AR.sup.16B, N(O).sub.m16, NR.sup.16AR.sup.16B, C(O)R.sup.16C, C(O)OR.sup.16C, C(O)NR.sup.16AR.sup.16B, OR.sup.16D, NR.sup.16ASO.sub.2R.sup.16D, NR.sup.16AC(O)R.sup.16C, NR.sup.16AC(O)OR.sup.16C, NR.sup.16AOR.sup.16C, OCX.sup.16.sub.3, OCHX.sup.16.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0732] R.sup.17 is independently hydrogen, halogen, CX.sup.17.sub.3, CHX.sup.17.sub.2, CH.sub.2X.sup.17, CN, SO.sub.n17R.sup.17D, SO.sub.v17NR.sup.17AR.sup.17B, NHNR.sup.17AR.sup.17B, ONR.sup.17AR.sup.17B,
NHC(O)NHNR.sup.17AR.sup.17B,
NHC(O)NR.sup.17AR.sup.17B, N(O).sub.m17, NR.sup.17AR.sup.17B, C(O)R.sup.17C, C(O)OR.sup.17C, C(O)NR.sup.17AR.sup.17B, OR.sup.17D, NR.sup.17ASO.sub.2R.sup.17D, NR.sup.17AC(O)R.sup.17C, NR.sup.17AC(O)OR.sup.17C, NR.sup.17AOR.sup.17C, OCX.sup.17.sub.3,
OCHX.sup.17.sub.2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0733] R.sup.18 is independently hydrogen, CX.sup.18.sub.3, CHX.sup.18.sub.2, CH.sub.2X.sup.18, C(O)R.sup.18C, C(O)OR.sup.18C, C(O)NR.sup.18AR.sup.18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0734] R.sup.15A, R.sup.15B, R.sup.15C, R.sup.15D, R.sup.16A, R.sup.16B, R.sup.16C, R.sup.16D, R.sup.17A, R.sup.17B, R.sup.17C, R.sup.17D, R.sup.18A, R.sup.18B, R.sup.18C, and R.sup.18D, are independently hydrogen, CX.sub.3, CN, COOH, CONH.sub.2, CHX.sub.2, CH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
[0735] each X, X.sup.15, X.sup.16, X.sup.17 and X.sup.18 is independently F, Cl, Br, or I;
[0736] n15, n16, n17, v15, v16, and v17, are independently an integer from 0 to 4; and
[0737] m15, m16, and m17 are independently and integer from 1 to 2.
Embodiment 84
[0738] The compound of embodiment 83, wherein R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen.
Embodiment 85
[0739] The compound of one of embodiments 82 to 83, wherein E is:
##STR00104##
Embodiment 86
[0740] The compound of embodiment 62, having the formula:
##STR00105##
IX. Examples
I. Chemoproteomics-Enabled Covalent Ligand Screen Reveals a Cysteine Hotspot in Reticulon 4 that Impairs ER Morphology and Cancer Pathogenicity
[0741] Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck in chemical genetics is identifying the targets of leads that arise from screens. Here, we generated and screened a library of cysteine-reactive fragment-based covalent ligands for agents that impair colorectal cancer pathogenicity and coupled the discovery of lead compounds with target identification using isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) platforms. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). This protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology and colorectal cancer pathogenicity. RTN4 is a novel colorectal cancer therapeutic target and we determined a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
[0742] Traditional strategies for cancer target discovery oftentimes involve searching for proteins or genes that may be dysregulated or mutated in tumors, which may miss promising therapeutic targets that may not necessarily be changing in expression or activity. Screening chemical libraries for anti-cancer small-molecules using chemical genetics strategies have arisen as a powerful complementary approach to traditional target discovery approaches for mining druggable nodes that can be pharmacologically interrogated in cancer.sup.3,4. However, a major challenge with chemical genetics is identifying the targets of leads that arise from screens. Oftentimes, lead compounds must be derivatized to either bear bioorthogonal and/or photoaffinity handles or conjugated to beads to facilitate chemoproteomic target identification.sup.4. However, these approaches oftentimes require additional synthetic efforts to make analogs of the lead molecule and alter the structure of the molecule, which hinder or may prevent target identification.
[0743] Here, we have generated a library of 75 cysteine-reactive fragment-based covalent ligands and coupled the screening of this library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) platform to rapidly couple the identification of covalent ligands that impair colorectal cancer pathogenicity with the identification of its direct targets and druggable hotspots within these targets (
[0744] There are several advantages to this overall approach. First, our library already introduces specific covalent interactions through the incorporation of cysteine-reactive acrylamide and chloroacetamide warheads, thus avoiding the necessity for introducing photoaffinity handles for target identification. Recent studies have shown that the reactivity of these scaffolds can be tempered and made to confer substantial selectivity through appending small-molecular weight fragments.sup.6. Also, because these compounds are small molecular weight fragment-based covalent ligands, they can sample more macromolecular protein space and enable interrogation of more druggable nodes, a notion explored by many pharmaceutical companies with fragment-based ligand discovery.sup.8. Second, the advantage of this approach is that the lead molecule itself can be directly competed against reactivity-based probes for target identification without the need for additional derivatization or synthetic efforts.
[0745] We screened our cysteine-reactive ligand library of acrylamides and chloroacetamides to identify compounds that impair colorectal cancer cell survival and proliferation in the highly metastatic and tumorigenic SW620 colorectal cancer cells (
TABLE-US-00014 TABLE 1 Covalent ligand screening data. SW620 cells were treated with either DMSO or cysteine-reactive fragment (50 M) for 48 h after which serum-free cell survival or proliferation were assessed by Hoescht staining. Shown are average and sem values from n = 3/group. SW620 survival Ave sem p value DKM 3-30 0.31 0.06 2.21E02 DKM 3-16 0.34 0.04 2.28E02 DKM 2-40 0.36 0.03 3.11E03 DKM 2-91 0.38 0.03 8.97E04 DKM 2-101 0.39 0.06 7.57E03 DKM 3-10 0.41 0.06 7.05E03 DKM 2-94 0.43 0.05 2.39E03 DKM 2-76 0.44 0.07 7.08E03 DKM 2-80 0.47 0.08 9.35E03 TRH 1-55 0.47 0.04 2.37E03 TRH 1-12 0.49 0.03 7.24E03 DKM 3-7 0.51 0.04 5.46E02 DKM 2-95 0.52 0.10 3.89E02 DKM 3-43 0.52 0.08 7.87E02 DKM 2-98 0.52 0.13 3.64E02 DKM 3-36 0.54 0.09 9.56E02 TRH 1-32 0.55 0.10 1.00E01 DKM 3-41 0.55 0.09 9.87E02 DKM 3-70 0.57 0.11 1.26E01 DKM 2-37 0.57 0.18 1.09E01 TRH 1-50 0.58 0.07 9.26E02 DKM 3-5 0.59 0.04 1.21E02 DKM 2-108 0.61 0.02 1.36E02 DKM 3-31 0.65 0.08 1.64E01 DKM 2-83 0.66 0.07 3.18E02 DKM 2-59 0.66 0.07 4.92E02 TRH 1-53 0.69 0.07 4.08E02 DKM 3-32 0.70 0.07 2.03E01 DKM 2-93 0.74 0.06 4.79E02 DKM 2-84 0.74 0.07 7.66E02 DKM 2-113 0.75 0.03 6.08E02 DKM 3-9 0.75 0.03 2.44E01 DKM 2-114 0.76 0.03 7.42E02 DKM 3-13 0.77 0.06 2.89E01 DKM 2-34 0.78 0.02 8.76E02 DKM 2-47 0.78 0.05 1.16E01 DKM 3-29 0.79 0.05 3.11E01 DKM 2-49 0.80 0.06 1.60E01 DKM 2-71 0.81 0.08 3.96E01 DKM 2-43 0.84 0.06 2.27E01 DKM 2-107 0.86 0.05 2.62E01 DKM 2-67 0.87 0.14 6.20E01 DKM 2-50 0.89 0.02 3.05E01 DKM 2-31 0.89 0.04 3.69E01 DKM 2-48 0.90 0.05 4.00E01 DKM 2-32 0.91 0.11 5.55E01 DKM 2-33 0.92 0.08 5.36E01 DKM 2-52 0.92 0.10 7.25E01 DKM 2-39 0.93 0.05 5.71E01 TRH 1-13 0.94 0.05 6.20E01 DKM 2-72 0.96 0.06 8.49E01 DKM 2-58 0.98 0.05 8.50E01 TRH 1-19 1.01 0.06 9.16E01 DKM 2-120 1.02 0.06 8.83E01 DKM 3-42 1.04 0.21 9.09E01 DKM 2-42 1.04 0.04 7.11E01 DKM 2-97 1.06 0.27 8.33E01 DKM 2-60 1.08 0.16 7.51E01 DKM 2-86 1.09 0.13 6.45E01 DKM 2-110 1.12 0.17 5.54E01 TRH 1-20 1.14 0.05 2.66E01 DKM 2-62 1.15 0.09 2.76E01 DKM 3-11 1.20 0.18 5.32E01 DKM 3-4 1.22 0.03 8.53E02 DKM 2-116 1.23 0.20 3.58E01 DKM 2-102 1.24 0.05 9.50E02 DKM 3-12 1.29 0.09 2.49E01 DKM 2-111 1.33 0.23 2.40E01 DKM 2-103 1.35 0.06 4.12E02 DKM 2-100 1.38 0.03 1.54E02 DKM 2-109 1.40 0.02 1.17E02 TRH 1-27 1.44 0.24 2.79E01 DKM 2-106 1.44 0.25 1.75E01 DKM 3-8 1.52 0.09 6.85E02 TRH 1-54 1.75 0.24 1.01E01 DKM 2-94 0.32 0.03 2.69E04 DKM 2-71 0.41 0.01 4.06E06 DKM 2-98 0.42 0.02 6.51E06 DKM 2-83 0.48 0.03 9.33E04 DKM 2-80 0.48 0.02 5.02E04 DKM 2-76 0.50 0.03 1.02E03 DKM 3-70 0.53 0.02 2.15E05 DKM 2-52 0.53 0.02 5.63E05 TRH 1-55 0.53 0.09 1.68E02 DKM 3-30 0.54 0.03 1.50E02 DKM 2-93 0.57 0.04 2.66E03 DKM 2-91 0.59 0.03 2.18E03 DKM 3-16 0.60 0.03 2.62E02 TRH 1-53 0.72 0.06 3.32E02 DKM 2-67 0.73 0.01 3.21E06 DKM 2-37 0.73 0.02 1.45E03 DKM 2-59 0.74 0.03 3.06E03 TRH 1-50 0.76 0.04 8.71E03 DKM 3-10 0.79 0.10 2.12E01 DKM 3-5 0.82 0.03 3.03E03 DKM 2-84 0.84 0.05 3.17E02 DKM 2-48 0.85 0.04 3.85E02 DKM 2-95 0.85 0.01 6.52E02 TRH 1-12 0.89 0.07 1.86E01 DKM 2-116 0.90 0.03 2.11E02 DKM 3-41 0.93 0.05 6.18E01 DKM 3-13 0.94 0.03 6.02E01 DKM 3-43 0.94 0.01 6.04E01 DKM 3-32 0.95 0.03 6.55E01 DKM 2-62 0.95 0.02 5.64E02 DKM 2-110 0.95 0.06 5.12E01 DKM 2-108 0.95 0.11 7.80E01 DKM 2-120 0.96 0.01 4.87E02 DKM 2-109 0.96 0.02 1.74E01 DKM 2-97 0.96 0.05 5.01E01 DKM 2-101 0.96 0.05 6.87E01 DKM 3-36 0.97 0.04 8.31E01 DKM 2-40 0.98 0.01 4.54E01 DKM 2-107 0.99 0.09 9.13E01 DKM 3-31 0.99 0.04 9.63E01 DKM 2-100 1.00 0.04 9.31E01 DKM 3-7 1.00 0.01 9.83E01 TRH 1-32 1.00 0.03 9.60E01 DKM 2-72 1.00 0.03 9.74E01 DKM 3-9 1.00 0.10 9.91E01 DKM 2-106 1.00 0.02 9.02E01 DKM 2-60 1.00 0.05 9.64E01 DKM 2-86 1.02 0.13 8.97E01 DKM 3-8 1.05 0.00 6.93E01 DKM 2-34 1.05 0.07 5.50E01 DKM 2-111 1.06 0.01 2.53E02 DKM 3-12 1.06 0.06 6.44E01 DKM 2-49 1.09 0.02 6.51E02 DKM 2-39 1.10 0.03 6.16E02 DKM 2-114 1.11 0.08 4.12E01 DKM 2-47 1.12 0.02 2.38E02 DKM 2-103 1.12 0.11 4.76E01 DKM 3-42 1.12 0.07 2.68E01 DKM 2-32 1.14 0.12 3.13E01 DKM 2-33 1.15 0.11 2.44E01 DKM 2-58 1.16 0.04 2.34E02 DKM 2-31 1.16 0.09 1.75E01 DKM 3-11 1.18 0.02 1.79E01 TRH 1-19 1.19 0.07 1.47E01 DKM 3-4 1.20 0.10 2.19E01 DKM 3-29 1.21 0.04 1.76E02 TRH 1-20 1.21 0.11 2.47E01 TRH 1-27 1.25 0.08 6.96E02 DKM 2-43 1.28 0.03 2.17E03 TRH 1-13 1.28 0.04 4.17E03 DKM 2-50 1.30 0.01 4.14E04 DKM 2-102 1.33 0.05 1.65E02 DKM 2-42 1.37 0.00 1.52E04 TRH 1-54 1.39 0.01 1.49E06 DKM 2-113 1.47 0.07 1.23E02
[0746] We next performed isoTOP-ABPP studies to identify the direct targets of these lead compounds. We competed either vehicle or DKM 3-30 against labeling of SW620 proteomes with a broad cysteine-reactive probe, iodoacetamide-alkyne (IAyne), followed by appending probe-labeled proteins with a biotin-azide tag bearing a TEV protease recognition site and an isotopically light (for vehicle-treated) or heavy (for fragment-treated) tags via copper catalyzed azide-alkyne cycloaddition (CuAAC).sup.6,9. We then combined control and treated proteomes in a 1:1 ratio, enriched probe-labeled proteins with avidin, and digested proteomes with trypsin. Avidin-enriched probe-modified tryptic peptides were released by TEV protease digestion for subsequent quantitative proteomic analysis. Through these studies, we identified the top hit for DKM 3-30 as C1101 in reticulon 4 (RTN4, Uniprot ID Q9NQC3-1) with a light to heavy ratio of 3.0 (
TABLE-US-00015 TABLE2 IsoTOP-ABPPanalysesofDKM3-5andDKM3-30inSW620cells.SW620cellproteomes werepre-treatedwithDMSOorDKM3-5(50M)orDKM3-30(50M)for30minat 37 C.priortolabelingofproteomeswithIAyne(100M)for1hatroomtemperature. Proteomeswerethensubjectedtocopper-catalyzedazide-alkynecycloadditionwith abiotin-azidetagbearinganisotopicallylight(forDMSO-treated)versusheavy (forligand-treated)valineandaTEVproteaserecognitionsite.Proteomeswere thenmixedina1:1ratioandprobe-modifiedpeptideswereenrichedandreleased byTEVproteaseforsubsequentquantitativeproteomicanalysis.Thedatawas filteredforonlythoseprobe-modifiedpeptidesthatwereidentifiedinatleast 2outof3runs.Ratiosforthesameredundantprobe-modifiedpeptidesandpeptides acrossrunswereaveraged.Tophitsofcovalentligandswereconfirmedtohavemore thanonelighttoheavyratiogreaterthan2.Shownbelowarethefinalconsolidated andaveragedlighttoheavyratiosforthosepeptidesonlyobservedinatleast2outof 3biologicalreplicatesforisoTOP-ABPPstudieswithDKM3-5andDKM3-30,respectively. Cys Avearea # of Peptide SeqIDNumber Index ratio UniProt runs YSNSALGHVNC*TIK (SEQIDNO:1) C1101 3.04 Q9NQC3F8W914 3 AYEYVEC*PIR (SEQIDNO:2) 2.54 P53701 2 APPWVPAMGFTLAPS (SEQIDNO:3) C19 2.51 B1AH87P30536 2 LGC*FVGSR YYGGAEVVDEIELLC*QR (SEQIDNO:4) 2.43 G3V5L0 2 KVIGIEC*SSISDYAVK (SEQIDNO:5) C101 2.40 Q99873 2 TYDPSGDSTLPTC*SK (SEQIDNO:6) 2.35 Q9Y2X3 2 FTTSC*MTGYSPQLQGLSSGGSGSYSPGVTYSPVSGYNK (SEQIDNO:7) C158 2.31 Q965K2Q965K2 2 C157 SLVQNNCLSRPNIFLC*PEIEPK (SEQIDNO:8) C145 2.28 Q8TAQ2Q8TAQ2 2 Q8TAQ2F8VXC8 LWNTLGVC*K (SEQIDNO:9) 2.22 P63244 2 SLPSAVYC*IEDK (SEQIDNO:10) C674 2.20 O43290 2 EGGQYGLVAAC*AAGGQGHAMIVEAYPK (SEQIDNO:11) C436 2.14 P55084P55084 2 AAIGC*GIVESILNWVK (SEQIDNO:12) C486 2.14 P11388P11388 2 C431 P11388P11388 LC*PLKDEPWPIHPWEPGSFR (SEQIDNO:13) C105 2.11 E7ETU7H0Y9G6 2 C78 E9PF06P09001 VIEASDVVLEVLDARDPLGC*R (SEQIDNO:14) C144 2.08 Q9BVP2Q9BVP2 2 YVAAAFPSAC*GK (SEQIDNO:15) C172 2.07 B4DW73Q16822 3 VC*TLAIIDPGDSDIIR (SEQIDNO:16) C92 2.06 P62888E5RI99 2 STPYEC*GFDPMSPAR (SEQIDNO:17) C39 2.01 P03897 2 VALEGLRPTIPPGISPHVC*K (SEQIDNO:18) C361 2.00 Q13418Q13418 2 C453 A0A0A0MTH3 Q13418 LLEETGIC*VVPGSGFGQR (SEQIDNO:19) C477 1.94 Q8TD30 2 FGVIC*LEDLIHEIAFPGK (SEQIDNO:20) 1.92 Q6DKI1 2 ASC*LYGQLPK (SEQIDNO:21) 1.89 P09211 3 ATGHSGGGC*ISQGR (SEQIDNO:22) 1.84 I3L407I3L139 3 Q9HA64I3L3W5 HVVC*AAETGSGK (SEQIDNO:23) 1.82 Q9NUL7 3 STFFNVLTNSQASAENFPFC*TIDPNESRVPVPDER (SEQIDNO:24) 1.78 J3KQ32Q9NTK5 2 VDDEILGFISEATPLGGIQAASTESC*NQQLDLALCR (SEQIDNO:25) 1.78 P42166 2 IDRYTQQGFGNLPIC*MAK (SEQIDNO:26) C841 1.77 A0A087WVM4 2 C906 Q6UB35B7ZM99 C907 AVC*MLSNTTAIAEAWAR (SEQIDNO:27) C376 1.77 P68366Q13748 3 Q9NY65C9J2C0 Q71U36Q9NY65 P68366 LC*YVALDFENEMATAASSSSLEK (SEQIDNO:28) C219 1.74 P68133P68032 3 YATSCYSCC*PR (SEQIDNO:29) C173 1.71 Q13057Q13057 2 VIGSGC*NLDSAR (SEQIDNO:30) C192 1.71 P00338P07195 2 P00338 VLPMNTGVEAGETAC*K (SEQIDNO:31) 1.71 P04181 2 AVLLVGLC*DSGK (SEQIDNO:32) C73 1.70 Q9Y5M8 3 VTDDLVC*LVYK (SEQIDNO:33) 1.70 P49458 2 VC*EEIAIIPSKK (SEQIDNO:34) C35 1.69 H0YN88 2 A0A075B716 P08708 VQENSAYIC*SR (SEQIDNO:35) C585 1.67 Q9Y3T9 2 NCAVSC*AGEK (SEQIDNO:36) C141 1.67 Q15813Q15813 2 GC*STVLSPEGSAQFAAQIFGLSNHLVWSK (SEQIDNO:37) C374 1.66 P22234 2 TIQFVDWC*PTGFK (SEQIDNO:38) C347 1.66 Q13748Q9BQE3 2 Q9NY65C9J2C0 Q71U36Q9NY65 AGQPHSSSDAAQAPAEQPHSSSDAAQAPC*PR (SEQIDNO:39) C51 1.66 P29372P29372 2 A2IDA3P29372 P29372 LALFNPDVC*WDRNNPEPWNK (SEQIDNO:40) C44 1.65 O00483 2 AVASQLDC*NFLK (SEQIDNO:41) 1.65 A0A087X2I1 2 P62333 C*SGIGDNPGSETAAPR (SEQIDNO:42) C1317 1.64 H0YAC6P50851 2 QPAIMPGQSYGLEDGSC*SYK (SEQIDNO:43) 1.64 M0QXS5P14866 2 GNVAGDSKNDPPMEAAGFTAQVIILNHPGQISAGYAPVLDC* (SEQIDNO:44) 1.64 P68104 2 HTAHIACK A0A087WVQ9 YWLC*AATGPSIK (SEQIDNO:45) 1.64 P63244 2 LQSGIC*HLFR (SEQIDNO:46) 1.64 P14868 2 TIYAGNALC*TVK (SEQIDNO:47) C155 1.63 P13804 3 TSC*GSPNYAAPEVISGR (SEQIDNO:48) C200 1.63 Q13131Q13131 2 TFC*GTPEYLAPEVLEDNDYGR (SEQIDNO:49) C310 1.62 P31749P31751 2 Q9Y243Q9Y243 M0R0P9 ISC*MSKPPAPNPTPPR (SEQIDNO:50) 1.62 P46734P46734 2 RPYGVGLLIAGYDDMGPHIFQTC*PSANYFDCR (SEQIDNO:51) C123 1.60 P25786P25786 3 C154 F5GX11 LADQC*TGLQGFLVFHSFGGGTGSGFTSLLMER (SEQIDNO:52) C129 1.59 Q9BQE3P68363 2 C199 F5H5D3Q71U36 LNLSC*IHSPVVNELMR (SEQIDNO:53) 1.59 Q9Y2X3 2 LVVPATQC*GSLIGK (SEQIDNO:54) C109 1.58 Q15365 2 NLSDLIDLVPSLC*EDLLSSVDQPLK (SEQIDNO:55) C65 1.58 P47756P47756 2 C24 B1AK88B1AK87 B1AK85 SVHYC*PATK (SEQIDNO:56) C193 1.57 P25205P25205 2 NFYGGNGIVGAQVPLGAGIALAC*K (SEQIDNO:57) C188 1.57 P08559P08559 2 C219 P08559 HISPTAPDTLGC*YPFYK (SEQIDNO:58) C384 1.56 A0A087WWF6 2 C419 P49005 QGEYGLASIC*NGGGGASAMLIQKL (SEQIDNO:59) 1.56 P24752 3 HSMNPFC*EIAVEEAVR (SEQIDNO:60) C133 1.56 P38117P38117 2 LGMLSPEGTC*K (SEQIDNO:61) C212 1.56 P49327 2 GLC*GAIHSSIAK (SEQIDNO:62) C103 1.56 P36542P36542 2 LVAFC*PFASSQVALENANAVSEGVVHEDLR (SEQIDNO:63) 1.55 O00567 2 GSDC*GIVNVNIPTSGAEIGGAFGGEK (SEQIDNO:64) C450 1.55 P49419P49419 2 LNQQQHPDC*K (SEQIDNO:65) C239 1.55 Q5T280 3 C*LHNFLTDGVPAEGAFTEDFQGLR (SEQIDNO:66) C268 1.54 G3V1A6P57764 2 C316 TPC*NAGTFSQPEK (SEQIDNO:67) C129 1.54 O43684J3QT28 2 O43684 CPEALFQPSFLGMESC*GIHETTFNSIMK (SEQIDNO:68) 1.54 P63261P60709 2 SWC*PDCVQAEPVVR (SEQIDNO:69) 1.54 Q9BRA2 2 KLDTNSDGQLDFSEFLNLIGGLAMAC*HDSFLK (SEQIDNO:70) 1.53 2 SIQFVDWC*PTGFK (SEQIDNO:71) C347 1.53 P68366P68363 2 P68366 SGGSGGC*SGAGGASNCGTGSGR (SEQIDNO:72) 1.53 E9PI68 3 A0A087WUC6 Q15005 FTLDC*THPVEDGIMDAANFEQFLQER (SEQIDNO:73) 1.53 P35268 2 DLNYC*FSGMSDHR (SEQIDNO:74) C267 1.53 P31943G8JLB6 3 P55795 C*EFEEVQGFLDQVAHK (SEQIDNO:75) 1.53 E9PI14Q9NX20 2 NLPFPTYFPDGDEEELPEDLYDENVC*QPGAPSITFA (SEQIDNO:76) C365 1.53 E7ETU7H0Y9G6 2 C338 P09001 GQVC*LPVISAENWKPATK (SEQIDNO:77) C144 1.52 P68036P68036 2 P68036 C*FGTGAAGNR (SEQIDNO:78) 1.52 P78527 3 ADPDGPEAQAEAC*SGER (SEQIDNO:79) C18 1.52 Q9NX24 2 VHPAMATAAGGC*R (SEQIDNO:80) 1.52 H7C0N4H7C561 3 EMFPYEASTPTGISASC*R (SEQIDNO:81) C323 1.51 G5E972P42167 2 P42167 LNIISNLDC*VNEVIGIR (SEQIDNO:82) C357 1.51 P30154P30154 2 C402 P30154P30153 C390 YMACC*LLYR (SEQIDNO:83) C386 1.51 P68366Q9BQE3 2 C316 P68363F5H5D3 Q71U36P68366 SC*SGVEFSTSGSSNTDTGK (SEQIDNO:84) C36 1.51 A0A0A0MR02 P45880 3 AGSDGESIGNC*PFSQR (SEQIDNO:85) C35 1.51 Q9Y696 3 GC*EVVVSGK (SEQIDNO:86) 1.50 P23396 2 NILGGTVFREPIIC*K (SEQIDNO:87) C154 1.50 P48735P48735 3 AGAIAPC*EVTVPAQNTGLGPEK (SEQIDNO:88) 1.50 P05388 3 TIGGGDDSFTTFFC*ETGAGK (SEQIDNO:89) 1.49 P68366P68366 2 FNNWGGSLSLGHPFGATGC*R (SEQIDNO:90) C413 1.49 P55084P55084 2 NWYVQPSC*ATSGDGLYEGLTWLTSNYKS (SEQIDNO:91) C155 1.49 P62330 2 APC*QAGDLR (SEQIDNO:92) 1.49 P48431 2 QVLMGPYNPDTC*PEVGFFDVLGNDR (SEQIDNO:93) 1.49 Q9H3P7 3 VTEDENDEPIEIPSEDDGTVLLSTVTAQFPGAC*GLR (SEQIDNO:94) C39 1.49 A0A087X260 2 A0A087WYY0 B1AKP7Q13148 G3V162 IQCTLQDVGSALATPC*SSAR (SEQIDNO:95) C80 1.49 Q96EY854R3P5 2 NLSFFLTPPC*AR (SEQIDNO:96) C492 1.48 P42224P42224 2 J3KPM9 LLACIASRPGQC*GR (SEQIDNO:97) 1.48 P62241 2 C*SDNSSYEEPLSPISASSSTSR (SEQIDNO:98) C205 1.48 Q8IXK0 2 C711 A0A0A0MSI2 C346 Q8IXK0Q8IXK0 Q8IXK0B3KPJ4 Q8IXK0 C*LAQEVNIPDWIVDLR (SEQIDNO:99) 1.48 Q9Y4W2Q9Y4W2 2 HEEFEEGC*K (SEQIDNO:100) C41 1.48 I3L3Q4Q9HC38 2 C245 Q9HC38F6TLX2 GLDYEGGGC*R (SEQIDNO:101) C691 1.48 O60568 2 LLQC*DPSSASQF (SEQIDNO:102) 1.47 P37235 3 TVPFLPLLGGC*IDDTILSR (SEQIDNO:103) C180 1.47 Q7Z7H8Q7Z7H8 3 IINDNATYC*R (SEQIDNO:104) 1.47 O00567 2 SLLINAVEASC*IR (SEQIDNO:105) C262 1.47 E2QRB3P32322 2 C188 P32322 A0A087WTV6 P32322J3KR12 Q96C36 PPMEAAGFTAQVIILNHPGQISAGYAPVLDCHTAHIAC*K (SEQIDNO:106) 1.47 P68104 2 A0A087WVQ9 HPLTQELKEC*EGIVPVPLAEK (SEQIDNO:107) 1.46 P82932 2 HTGPGILSMANAGPNTNGSQFFIC*TAK (SEQIDNO:108) C115 1.46 P62937 2 IISDNLTYC*K (SEQIDNO:109) 1.46 Q9Y2X3 3 LIDFLEC*GK (SEQIDNO:110) C234 1.45 P17844J3KTA4 2 KAVVVC*PK (SEQIDNO:111) C588 1.45 Q00839Q00839 2 LTTPTYGDLNHLVSATMSGVTTC*LR (SEQIDNO:112) C239 1.45 Q13885P68371 3 C221 Q9BVA1P04350 Q5JP53 VCETDGC*SSEAK (SEQIDNO:113) C10 1.45 D6RF24H0Y9L0 3 C14 P53582 VC*PPHMLPEDGANLSSAR (SEQIDNO:114) C29 1.44 Q9GZY8 2 A0A0A0MS29 Q9GZY8H7C433 E9PQX8 TFVDFFSQC*LHEEYR (SEQIDNO:115) 1.44 Q53GQ0 2 FALAC*NASDKIIEPIQSR (SEQIDNO:116) 1.44 P35250P35250 2 TIAEC*LADELINAAK (SEQIDNO:117) C172 1.44 P46782M0R0R2 3 M0R0F0 FMTPVIQDNPSGWGPC*AVPEQFR (SEQIDNO:118) C19 1.44 O15371O15371 3 O15371 SVLLCGIEAQAC*ILNTTLDLLDR (SEQIDNO:119) C114 1.44 K7ENV7K7EKW4 2 Q96AB3 AVAILC*NHQR (SEQIDNO:120) 1.44 P11387 3 GNFTLPEVAEC*FDEITYVELQKEEAQK (SEQIDNO:121) C629 1.44 Q00839Q00839 2 TIIPLISQC*TPK (SEQIDNO:122) C212 1.44 P40926 3 DVQIGDIVTVGEC*RPLSK (SEQIDNO:123) C131 1.44 P62280 2 LLDLVQQSC*NYK (SEQIDNO:124) C30 1.43 B1AHD1P55769 3 C*MTNTPVVVR (SEQIDNO:125) C120 1.43 P32322P32322 2 P32322 VLGLGLGC*LR (SEQIDNO:126) 1.43 Q9BRJ7K7EIN2 3 VC*ISILHAPGDDPMGYESSAER (SEQIDNO:127) 1.43 P60604P60604 2 AYHEQLSVAEITNAC*FEPANQMVK (SEQIDNO:128) 1.43 P68366Q13748 3 Q71U36P68366 AGQC*VIGLQMGTNK (SEQIDNO:129) C153 1.43 Q99439B4DDF4 3 C155 B4DUT8 C164 A0A087X271 SGDAAIVDMVPGKPMC*VESFSDYPPLGR (SEQIDNO:130) 1.42 P68104 2 A0A087WVQ9 VSDTVVEPYNATLSVHQLVENTDETYC*IDNEALYDICFR (SEQIDNO:131) C201 1.42 P68371Q9BVA1 2 C183 P04350Q5JP53 Q9BUF5 C*EFQDAYVLLSEKK (SEQIDNO:132) 1.42 P10809 2 SSQC*HTGSSPR (SEQIDNO:133) C439 1.42 O15226O15226 2 LNISFPATGC*QK (SEQIDNO:134) 1.42 P62753 3 FHADSVC*K (SEQIDNO:135) 1.42 Q9BW61 2 C*MQLTDFILK (SEQIDNO:136) C54 1.42 E7EPB3P50914 2 ELEVLLMC*NK (SEQIDNO:137) C91 1.42 P62910F8W727 2 C109 D3YTB1 NHLLPDIVTC*VQSSR (SEQIDNO:138) C184 1.42 Q9BSD7 2 VNGTTPC*AFPTHYEEALKDEEK (SEQIDNO:139) 1.41 O15479 2 LTEGC*SFR (SEQIDNO:140) C93 1.41 H0YMV8Q71UM5 2 C77 P42677 C*ALSSPSLAFTPPIK (SEQIDNO:141) C120 Q8NFH5Q8NFH5 2 Q8NFH5 SSVQEEC*VSTISSSKDEDPLAATR (SEQIDNO:142) 1.41 Q7L0Y3 3 TQNLPNC*QLISR (SEQIDNO:143) 1.41 P37268 2 C*SEGSFLLTTFPRPVTVEPMDQLDDEEGLPEK (SEQIDNO:144) C119 1.41 Q15233Q15233 3 SMVSPVPSPTGTISVPNSC*PASPR (SEQIDNO:145) 1.41 P85037 2 EITSLDTENIDEILNNADVALVNFYADWC*R (SEQIDNO:146) C58 1.40 Q9B526 2 GHSSDSNPAIC*R (SEQIDNO:147) C31 1.40 Q5JTH9 2 FC*IWTESAFR (SEQIDNO:148) C250 1.40 P36578 2 SLC*NLEESITSAGRDDLESFQLEISGFLK (SEQIDNO:149) 1.40 Q52LJ0Q52LJ0 2 IDC*FSEVPTSVFGEK (SEQIDNO:150) 1.40 O00567 2 NMSVHLSPC*FR (SEQIDNO:151) C116 1.40 P62280 3 GLPC*TELFVAPVGVASKR (SEQIDNO:152) C79 1.40 H0Y901E9PDI4 3 C428 O00515 VAC*ITEQVLTLVNKR (SEQIDNO:153) 1.40 P04843 3 NSQWVPTLPNSSHHLDAVPC*STTINR (SEQIDNO:154) C138 1.40 Q12824Q12824 2 G5E975 NVQLLSQFVSPFTGC*IYGR (SEQIDNO:155) 1.40 Q9Y3D5 2 LC*SSSSSDTSSR (SEQIDNO:156) C385 1.40 Q86WB0Q86WB0 2 C9J0I9 LVVPASQC*GSLIGK (SEQIDNO:157) C109 1.40 Q15366Q15366 3 Q15366Q15366 VNAAGTDPSSPVGFVLGVDLLHIFPLEGATFLC*PADVTDPR (SEQIDNO:158) 1.39 Q9UI43 2 C*PFTGNVSIR (SEQIDNO:159) C60 1.39 P62280 2 LTALDYHNPAGFNC*KDETEFR (SEQIDNO:160) C19 1.39 Q9Y224 3 VPTANVSVVDLTC*R (SEQIDNO:161) C247 1.39 P04406 2 DSGYGDIWC*PERGEFLAPPR (SEQIDNO:162) C176 1.39 J3KP06F8WD26 2 C228 Q8WWI1Q8WWI1 C213 Q8WWI1Q8WWI1 NFNYHILSPC*DLSNYTDLAMSTVK (SEQIDNO:163) C461 1.39 G5E9W3Q9UKF6 3 AC*QSIYPLHDVFVR (SEQIDNO:164) C201 1.39 D6RB09D6RAT0 P61247D6RG13 WC*EYGLTFTEK (SEQIDNO:165) C65 1.38 A0A0A0MR02 2 P45880 KTPC*GEGSK (SEQIDNO:166) C70 1.38 P60866P60866 2 NC*LTNFHGMDLTR (SEQIDNO:167) C96 1.38 D6RB09D6RAT0 2 P61247D6RG13 YGIIC*MEDLIHEIYTVGKR (SEQIDNO:168) C186 1.38 P18124A8MUD9 3 C*ASQAGMTAYGTR (SEQIDNO:169) C127 1.38 E9PDU6Q15417 2 C132 Q15417 KAQC*PIVER (SEQIDNO:170) C66 1.38 P46782M0R0R2 2 M0R0F0 NGDIC*ETSGKPK (SEQIDNO:171) C60 1.38 Q16637E7EQZ4 2 Q16637Q16637 Q16637B4DP61 KGAGNPQASTLALQSNITQC*LLGQPWPLNEAQVQASVVK (SEQIDNO:172) C1260 1.38 E7ETY2Q13428 3 C1261 Q13428Q13428 C1299 Q13428Q13428 Q13428Q13428 J3KQ96 FCSFSPC*IEQVQR (SEQIDNO:173) C209 1.37 Q96FX7 2 IHMGSC*AENTAK (SEQIDNO:174) 1.37 P24752 3 GC*IVDANLSVLNLVIVK (SEQIDNO:175) 1.37 P62753 3 IAILTC*PFEPPKPK (SEQIDNO:176) C253 1.37 E9PCA1B7ZAR1 2 P48643 TLTSC*FLSCVVCVEGIVTK (SEQIDNO:177) C164 1.37 P25205P25205 2 LGYILTC*PSNLGTGLR (SEQIDNO:178) C347 1.37 P12532P12532 2 LMWLFGC*PLLLDDVAR (SEQIDNO:179) 1.37 O15067 2 INISEGNC*PER (SEQIDNO:180) C54 1.37 Q15366Q15366 3 Q15366Q15366 Q15365 SGQGAFGNMC*R (SEQIDNO:181) C96 1.37 P36578 3 GLC*AIAQAESLR (SEQIDNO:182) 1.37 P23396 3 IIPTLEEGLQLPSPTATSQLPLESDAVEC*LNYQHYK (SEQIDNO:183) 1.37 P61978P61978 3 C*PEALFQPSFLGMESCGIHETTFNSIMK (SEQIDNO:184) 1.37 P60709P63261 2 LC*FSTAQHAS (SEQIDNO:185) 1.37 M0QXS5P14866 2 LGTLAPFC*CPWEQLTQDWESR (SEQIDNO:186) C705 1.37 Q99575 2 AAVEEGIVLGGGC*ALLR (SEQIDNO:187) 1.37 P10809 3 LDSLGLCSVSC*ALEFIPNSK (SEQIDNO:188) C256 1.36 Q9BSH4 2 VC*NFLASQVPFPSR (SEQIDNO:189) C205 1.36 Q99714 3 VTDGALVVVDCVSGVC*VQTETVLR (SEQIDNO:190) C136 1.36 P13639 2 YAIC*SALAASALPALVMSK (SEQIDNO:191) C125 1.36 P36578 3 TATAVAHC*K (SEQIDNO:192) C25 1.36 MOR210P62249 3 GC*TATLGNFAK (SEQIDNO:193) 1.36 P15880 2 VC*NYGLTFTQK (SEQIDNO:194) C66 1.36 Q9Y277Q9Y277 2 SLHDALC*VLAQTVK (SEQIDNO:195) C348 1.36 P78371 2 AWVWNTHADFADEC* (SEQIDNO:196) C209 1.36 C9JXG8P43487 2 PKPELLAIR C132 C9JJ34F6WQW2 C9JGV6P43487 C*HTPPLYR (SEQIDNO:197) 1.36 M0R117Q02543 2 YIGENLQLLVDRPDGTYC*FR (SEQIDNO:198) 1.36 Q9Y221 2 ALANVNIGSLIC*NVGAGGPAPAAGAAPAGGPAPSTAAAPAE (SEQIDNO:199) 1.36 P05386 2 EK ANC*IDSTASAEAVFASEVKK (SEQIDNO:200) C268 1.36 M0QXL5M0R299 2 C183 P22087M0R2Q4 NC*IVLIDSTPYR (SEQIDNO:201) 1.35 P62241 2 YSTGSDSASFPHTTPSMC*LNPDLEGPPLEAYTIQGQY (SEQIDNO:202) C217 1.35 Q15366Q15366 2 LGEWVGLC*K (SEQIDNO:203) 1.35 P25398 2 C*ASQVGMTAPGTR (SEQIDNO:204) C215 1.35 Q99439B4DDF4 2 C204 B4DUT8 TTSSANNPNLMYQDEC*DR (SEQIDNO:205) C586 1.35 Q92841H3BLZ8 2 C507 Q92841Q92841 C505 Q92841 ISLGLPVGAVINC*ADNTGAK (SEQIDNO:206) 1.35 P62829 2 AYGGSMC*AK (SEQIDNO:207) 1.35 P49207 2 VVNSETPVVVDFHAQWC*GPCK (SEQIDNO:208) C90 1.35 Q99757F8WDN2 2 GVPGAIVNVSSQC*SQR (SEQIDNO:209) C137 1.34 Q7Z4W1J3QS36 2 J3KS22 GC*LWALNPAKIDK (SEQIDNO:210) 1.34 O15353 2 DLC*FSPGLMEASHVVNDVNEAVQLVFR (SEQIDNO:211) C362 1.34 Q9BXW7Q9BXW7 2 HGFC*GIPITDTGR (SEQIDNO:212) 1.34 P12268 3 ASDHGWVC*DQR (SEQIDNO:213) C309 1.34 Q9HC36 2 AVC*MLSNTTAVAEAWAR (SEQIDNO:214) C376 1.33 Q9BQE3 3 HIGDGC*CLTR (SEQIDNO:215) C202 1.33 A0A087WZT2 3 Q6UX53 SDLGPC*EK (SEQIDNO:216) 1.33 D6RDI2J3KPP4 2 O95232 LPITVLNGAPGFINLC*DALNAWQLVK (SEQIDNO:217) C240 1.33 P31939P31939 2 VDEFPLC*GHMVSDEYEQLSSEALEAAR (SEQIDNO:218) C49 1.33 X1WI28P27635 3 IISNASC*TTNCLAPLAK (SEQIDNO:219) C152 1.33 P04406 3 DLTTAGAVTQC*YR (SEQIDNO:220) 1.33 Q02543 2 SAC*SLESNLEGLAGVLEADLPNYK (SEQIDNO:221) C44 1.32 Q09161 2 KITAFVPNDGC*LNFIEENDEVLVAGFGR (SEQIDNO:222) 1.32 P62266 2 TGC*TFPEKPDFH (SEQIDNO:223) C318 1.32 P55263P55263 3 C336 P55263 NQSFC*PTVNLDKLWTLVSEQTR (SEQIDNO:224) C70 1.32 P46776E9PLL6 3 E9PJD9 SGEEDFESLASQFSDC*SSAK (SEQIDNO:225) C113 1.32 K7EN45K7EMU7 2 Q13526 SPWLAGNELTVADVVLWSVLQQIGGC*SVTVPANVQR (SEQIDNO:226) 1.32 Q13155 2 VNQAIWLLC*TGAR (SEQIDNO:227) C155 1.32 P46782M0R0R2 3 M0R0F0 AC*DLPAWVHFPDTER (SEQIDNO:228) 1.32 H7BXI1 2 YYALCGFGGVLSC*GLTHTAVVPLDLVK (SEQIDNO:229) 1.31 Q00325 2 EC*LPLIIFLR (SEQIDNO:230) 1.31 P62701 3 VLVTTNVC*AR (SEQIDNO:231) C392 1.31 Q9UMR2Q9UMR2 2 C393 Q9NUU7Q9NUU7 C367 H3BQK0F6QDS0 C310 I3L352 SYC*AEIAHNVSSK (SEQIDNO:232) C114 1.31 P62910F8W727 2 C96 D3YTB1 TAFQEALDAAGDKLVVVDFSATWC*GPCK (SEQIDNO:233) 1.31 P10599 2 LC*YVALDFEQEMATAASSSSLEK (SEQIDNO:234) 1.30 P60709P63261 3 Q658J3 VRPSTGNSASTPQSQC*LPSEIEVK (SEQIDNO:235) C131 1.30 Q9UJX3Q9UJX3 2 AATGEEVSAEDLGGADLHC*R (SEQIDNO:236) 1.30 Q9HCCO 2 PGHLQEGFGC*VVTNRFDQLFDDESDPFEVLK (SEQIDNO:237) C11 1.30 Q8NC51Q8NC51 3 Q8NC51Q8NC51 C*ASQSGMTAYGTR (SEQIDNO:238) C166 1.30 Q99439B4DDF4 3 C164 B4DUT8 C175 A0A087X271 LC*VQNSPQEAR (SEQIDNO:239) C150 1.30 P33240P33240 3 E7EWR4E9PID8 A0A0A0MT56 PC*SEETPAISPSKR (SEQIDNO:240) C3 1.30 P33316H0YNJ9 2 LDINLLDNVVNC*LYHGEGAQQR (SEQIDNO:241) 1.30 O14980 2 NMMAAC*DPR (SEQIDNO:242) C285 1.29 Q13509Q13885 3 C650 P68371A6NNZ2 C303 A0A0B4J269 C266 Q9BVA1Q3ZCM7 P04350K7ESM5 Q5JP53Q9BUF5 IAVHC*TVR (SEQIDNO:243) C72 1.29 P62913Q5VVC8 2 P62913 C*PQVEEAIVQSGQKK (SEQIDNO:244) C146 1.29 Q9BVP2Q9BVP2 2 SQAPC*ANKDEADLSSK (SEQIDNO:245) C300 1.29 Q96SK2Q96SK2 2 C*LGHPEEFYNLVR (SEQIDNO:246) 1.29 P37268 2 NTVLC*NVVEQFLQADLAR (SEQIDNO:247) C70 1.29 Q14258 2 AFQYVETHGEVC*PANWTPDSPTIKPSPAASK (SEQIDNO:248) 1.29 P30048 3 QAVLGAGLPISTPC*TTINK (SEQIDNO:249) C119 1.29 P24752 3 GTPEQPQC*GFSNAVVQILR (SEQIDNO:250) C67 1.29 Q86SX6 3 ADHQPLTEASYVNLPTIALC*NTDSPLR (SEQIDNO:251) C148 1.29 A0A0C4DG17 3 C9J9K3P08865 GSDELFSTC*VTNGPFIIVISSNSASAANGNDSKK (SEQIDNO:252) C23 1.29 A0A0U1RRM4 3 P26599P26599 P26599 AYHEQLTVAEITNAC*FEPANQMVK (SEQIDNO:253) C295 1.28 Q9BQE3F5H5D3 2 C365 INPYMSSPC*HIEMILTEK (SEQIDNO:254) C106 1.28 J3KRX5J3QLC8 2 C144 A0A087WXM6 P18621 A0A0A6YYL6 J3QQT2P18621 YIYDQC*PAVAGYGPIEQLPDYNR (SEQIDNO:255) C453 1.28 P31930 2 C*ELSSSVQTDINLPYLTMDSSGPK (SEQIDNO:256) 1.28 P38646 3 GC*LLYGPPGTGK (SEQIDNO:257) 1.27 A0A087X2I1 3 P62333 ALNALC*DGLIDELNQALK (SEQIDNO:258) 1.27 P30084 3 NTPSFLIAC*NK (SEQIDNO:259) C179 1.27 Q9Y5M8 2 C*MPTFQFFK (SEQIDNO:260) 1.27 P10599 3 TGNGPMSVC*GR (SEQIDNO:261) C493 1.27 O95793O95793 2 O95793 A0A087X1A5 Q5JW30 HELQANC*YEEVKDR (SEQIDNO:262) C139 1.27 E9PK25G3V1A4 3 C177 P23528 AFAFVTFADDQIAQSLC*GEDLIIK (SEQIDNO:263) C244 1.27 A0A087X260 2 A0A087WYY0 B1AKP7Q13148 G3V162 LTPGC*EAEAETEAICFFVQQFTDMEHNR (SEQIDNO:264) C2359 1.26 P49327 2 LECVEPNC*R (SEQIDNO:265) 1.26 Q969Q0 2 SYC*NDQSTGDIK (SEQIDNO:266) C106 1.26 P00492 2 ATC*APQHGAPGPGPADASK (SEQIDNO:267) C2516 1.26 P21333 2 C2535 A0A087WWY3 Q60FE5P21333 ATYDKLC*K (SEQIDNO:268) 1.26 P62851 2 GSC*STEVEKETQEK (SEQIDNO:269) C69 1.26 O75348 2 TVDSQGPTPVC*TPTFLER (SEQIDNO:270) 1.26 Q9BYG3 2 LC*YVALDFEQEMAMVASSSSLEK (SEQIDNO:271) C880 1.26 P0CG39 3 VFIMDSC*DELIPEYLNFIR (SEQIDNO:272) C366 1.25 P08238 3 HC*SQVDSVR (SEQIDNO:273) C112 1.25 Q14247Q14247 2 Q14247 AAAPAPEEEMDEC*EQALAAEPK (SEQIDNO:274) C266 1.25 P26641P26641 2 EKTAC*AINK (SEQIDNO:275) C293 1.25 Q8NCA5E9PH82 2 Q52LJ0Q8NCA5 Q52LJ0 SGTIC*SSELPGAFEAAGFHLNEHLYNMIIR (SEQIDNO:276) C200 1.24 A0A0C4DGQ5 2 P04632K7ELJ7 TASISSSPSEGTPTVGSYGC*TPQSLPK (SEQIDNO:277) C787 1.24 Q6PKG0Q6PKG0 3 EVIAVSCGPAQC*QETIR (SEQIDNO:278) C162 1.24 P38117P38117 2 NC*PHVVVGTPGR (SEQIDNO:279) C164 1.24 O00148 3 SC*PSFSASSEGTR (SEQIDNO:280) C9 1.24 D6RCP9P27707 2 D6RFG8D6RG38 GLIAAIC*AGPTALLAHEIGFGSK (SEQIDNO:281) C86 1.23 Q99497K7ELW0 2 K7EN27 LYYFQYPC*YQEGLR (SEQIDNO:282) 1.23 Q9NRW3 3 GC*WDSIHVVEVQEK (SEQIDNO:283) C135 1.22 P47756P47756 2 C176 B1AK88B1AK87 B1AK85 SCYDLSC*HAR (SEQIDNO:284) 1.22 P41250 2 VGSFC*LSEAGAGSDSFALK (SEQIDNO:285) C73 1.21 P45954P45954 2 AINC*ATSGVVGLVNCLR (SEQIDNO:286) C1448 1.21 P49327 2 TSAVPSPC*GK (SEQIDNO:287) C260 1.21 P49748P49748 2 P49748 INEIVYFLPFC*HSELIQLVNK (SEQIDNO:288) C513 1.21 Q9H078Q9H078 2 C371 Q9H078Q9H078 C572 Q9H078H0YGM0 IGFPETTEEELEEIASENSDC*IFPSAPDVK (SEQIDNO:289) C353 1.21 Q9Y3F4Q9Y3F4 2 IVGYFVSGC*DPSIMGIGPVPAISGALK (SEQIDNO:290) C287 1.21 A0A0B4J2A4 2 P42765 RGPC*IIYNEDNGIIK (SEQIDNO:291) C208 1.21 P36578 2 AALVTSFC*MFKYMALYSMIQR (SEQIDNO:292) C542 1.20 H0Y4Z2 2 ESLNASIVDAINQAADC*WGIR (SEQIDNO:293) C167 1.20 Q9UJZ1 2 EEHLC*TQR (SEQIDNO:294) 1.20 J3KN67 2 GC*GVVKFESPEVAER (SEQIDNO:295) 1.20 P52272P52272 3 A0A087X0X3 KC*SASNR (SEQIDNO:296) C17 1.19 Q8WVC2Q9BYK1 2 P63220 TPC*SSLLPLLNAHAATSGK (SEQIDNO:297) C307 1.18 B8ZZZ7Q9NUQ6 2 C367 A0A0A0MSG5 C397 Q9NUQ6Q9NUQ6 Q9NUQ6 VSLDPELEEALTSASDTELC*DLAAILGMHNLITNTK (SEQIDNO:298) C132 1.17 Q9NYL9 3 FDPTQFQDC*IIQGLTETGTDLEAVAK (SEQIDNO:299) C35 1.17 Q7L1Q6C9IZ80 2 C39 Q7L1Q6Q7L1Q6 Q7L1Q6 LGGSLIVAFEGC*PV (SEQIDNO:300) C146 1.16 P60981P60981 2 TQYSCYC*CK (SEQIDNO:301) C229 1.15 Q9UGI8Q9UGI8 2 IC*PVEFNPNFVAR (SEQIDNO:302) 1.15 Q9UI30F5GX77 2 TPSYSISSTLNPQAPEFILGC*TASK (SEQIDNO:303) C142 1.15 Q14694H3BQC6 2 Q14694Q14694 ASVGFGGSC*FQK (SEQIDNO:304) C209 1.14 O60701O60701 2 NTGQTC*VCSNQFLVQR (SEQIDNO:305) 1.13 C9J8Q5P01763 2 P51649P51649 FQSSAVMALQEASEAYLVGLFEDTNLC*AIHAK (SEQIDNO:306) 1.12 Q71DI3 2 AGAVVAVPTDTLYGLACAASC*SAALR (SEQIDNO:307) C99 1.11 Q86U90 3 AVLLASDAQEC*TLEEVVER (SEQIDNO:308) C332 1.10 Q27J81Q27J81 2 FQSSAVMALQEACEAYLVGLFEDTNLC*AIHAK (SEQIDNO:309) C111 1.08 P68431 2 NMITGTSQADC*AVLIVAAGVGEFEAGISK (SEQIDNO:310) 1.08 P68104Q05639 2 A0A087WVQ9 GNHEC*ASINR (SEQIDNO:311) C83 1.05 P62136P62140 3 C126 P62136 LC*DFGVSGQLIDSMANSFVGTR (SEQIDNO:312) C207 1.04 G5E9C7Q02750 2 C211 P36507Q02750 C114 SC*GSSTPDEFPTDIPGTK (SEQIDNO:313) 1.02 P41091 2 GTLTLC*PYHSDR (SEQIDNO:314) C620 1.00 Q13200Q13200 2 Q13200 LSLDGQNIYNAC*CTLR (SEQIDNO:315) C250 0.95 A0A0U1RRM4 2 C281 P26599P26599 P26599 ADASSTPSFQQAFASSC*TISSNGPGQR (SEQIDNO:316) C688 0.94 Q68CZ2Q68CZ2 2 STLTDSLVC*K (SEQIDNO:317) C41 0.94 P13639 3 SDITKLEVDAIVNAA (SEQIDNO:318) C186 0.91 Q9BQ69 2 NSSLLGGGGVDGC*IHR LC*EPEVLNSLEETYSPFFR (SEQIDNO:319) C261 0.90 H0YJA2Q6PJT7 2 C177 Q6PJT7G3V5I6 C224 Q6PJT7G3V256 Q6PJT7Q6PJT7 Q6PJT7Q6PJT7 Q6PJT7 C*PAPPRGPPAPAPEVEELAR (SEQIDNO:320) C161 0.81 P48681 2 AAC*LESAQEPAGAWGNK (SEQIDNO:321) C53 0.76 A0A024R4E5 2 LHTGPLPEQC*R (SEQIDNO:322) C163 0.68 A0JLT2J3KR33 2 A0JLT2 FQSAAIGALQEASEAYLVGLFEDTNLC*A (SEQIDNO:323) 0.66 K7EK07P84243 2 FQSSAVMALQEAREAYLVGLFEDTNLC*AIRAK (SEQIDNO:324) C111 0.65 Q5TEC6 2 HLNEIDLFHC*IDPNDSK (SEQIDNO:325) C62 0.59 A0A087WYT3 2 C58 Q15185Q15185 QC*PIMDPAWEAPEGVPIDAIIFGGR (SEQIDNO:326) C297 0.29 B4DW73Q16822 3 SEC*DQDYIPETDQDC*SMSPCPQRTPDSGLAQHPFQNEDYR (SEQIDNO:327) C1290 0.12 Q9P2N4Q9P2N4 2 C1250 H0Y859Q9P2N4 C1278 C1262
[0747] To determine the relevance of RTN4 in colorectal cancer, we performed isoTOP-ABPP analysis to quantitatively map proteome-wide reactivity of cysteines in pooled primary human colorectal tumors through comparative ratiometric analysis of IAyne labeling at 100 (heavy) versus 10 M (light) concentrations. Previous studies by Weerapana et al. have shown that hyper-reactive cysteines, which show saturated IAyne labeling at lower concentrations and thus exhibit a lower (<3) heavy to light ratio, are highly enriched in functional cysteines, compared to those sites that are not hyper-reactive that show heavy to light ratios of 10.sup.10. We identify RTN4 labeling of C1101 in primary human colorectal tumors. RTN4 C1101 shows a ratio of 6.2 indicating that this cysteine is not hyper-reactive (
[0748] We further confirm the relevance of RTN4 in colorectal cancer by showing that transient or stable knockdown of RTN4 by RNA interference phenocopies the impaired survival, proliferation, and anti-tumorigenic effects observed with DKM 3-30 in SW620 colorectal cancer cells (
[0749] RTN4 is known to be a critical mediator of endoplasmic reticulum (ER) tubule formation.sup.11-13. Interestingly, Voeltz et al. found that tubular ER network formation in a reconstituted in vitro system was disrupted by thiol modifying agents and discovered that Xenopus RTN4 was responsible for this action.sup.15. Intriguingly, one of these cysteines, C952 of Xenopus RTN4.sup.12, corresponds to C1101 of human RTN4 identified in our study (
[0750] We postulated that covalent modification of RTN4(C1101) by DKM 3-30 would impact the formation of ER tubular networks in cells. We attempted to analyze the effects of
[0751] DKM 3-30 in SW620 colorectal cancer cells, and while the images suggest alterations in the ER morphology (
[0752] Cell division requires elaborate rearrangements in the ER and the nuclear envelope to ensure correct inheritance of DNA and segregation of DNA within a single nucleus.sup.15. During prophase the nuclear envelope retracts into the ER and then reforms during telophase. The reticulon family of proteins, and the transition between ER tubules and sheets, have been implicated in nuclear envelope assembly and disassembly during mitosis.sup.16-18 Time-lapse imaging of mitotic cells revealed that control cells divided rapidly (50-60 min) (
[0753] We also synthesized analogs of DKM 3-30 and showed that YP 1-46 demonstrated less displacement of IAyne labelling of RTN4, whereas AMR 1-125 exhibited 7-fold improved potency compared to DKM 3-30. We further showed that AMR 1-125, but not YP 1-46, impaired cell survival in U2OS and SW620 cells and ER morphology in U2OS cells (
[0754] In summary, we identify RTN4 as a novel colorectal cancer therapeutic target, and reveal a unique druggable hotspot within this classically undruggable protein, which can be targeted by cysteine-reactive ligands such as DKM 3-30 to impair ER and nuclear envelope morphology and colorectal cancer pathogenicity. We also show that DKM 3-30 impairs osteosarcoma cell survival as well, suggesting that RTN4 may have broader impacts upon other types of cancers. We recognize that DKM 3-30 may have additional off-targets that may contribute its anti-cancer activity, but nonetheless show compelling evidence that DKM 3-30 and its analogs phenocopy what is observed with RTN4 knockdown and that DKM 3-30 confers sensitivity in MEF cells only when expressing human RTN4. DKM 3-30 and AMR 1-125 may serve as initial starting points for subsequent medicinal chemistry to develop a more potent and selective RTN4 inhibitors for cancer therapy. Overall, we highlight the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
[0755] Methods.
[0756] Materials. IAyne was obtained from CHESS Gmbh. Heavy and light TEV-biotin tags were synthesized per previously described methods 5,21
[0757] Synthesis of Cysteine Fragment Library. The synthesis of the cysteine-reactive ligand library is described below. All compounds in the library were confirmed to be >95% pure.
[0758] Cell Culture. SW620 cells were purchased from ATCC. SW620 cells were grown in L-15 media with 10% fetal bovine serum (FBS) in ambient CO.sub.2. U2OS cells were grown in DMEM media supplemented with 10% FBS at 37 C. with 5% CO.sub.2.
[0759] Survival and Proliferation Assays. Cells were plated the evening before the experiment, and allowed to adhere overnight. For serum-free cell survival assays, cells were plated in media not containing FBS. For cell proliferation assays, cells were plated in regular media. For the chemical genetics screen, cells were treated with either DMSO or the cysteine-reactive fragment for 48 h and cell viability was assessed by Hoescht stain using our previously described methods
[0760] Tumor Xenograft Growth Studies. C.B17 SCID male mice (6-8 weeks old) were injected subcutaneously into the flank with 2,000,000 cells in serum-free media. For pharmacological treatments, mice were exposed by intraperitoneal (ip) injection with either vehicle (18:1:1 PBS/ethanol/PEG40) or 50 mg/kg DKM 3-30 once per day starting ten days after the initiation of the xenograft experiment and until the completion of the study. Tumors were measured every 7 days by caliper measurements. Animal experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of California, Berkeley.
[0761] IsoTOP-ABPP Analysis. IsoTOP-ABPP analyses were performed as previously described.sup.5-7. For competitive IsoTOP-ABPP, SW620 cell lysates were pre-incubated with DMSO vehicle or DKM 3-30 (50 M) for 30 min at 37 C. in phosphate-buffered saline (PBS), and then labeled with IAyne (100 M) for 1 h at room temperature. They were subsequently treated with isotopically light (control) or heavy (treated) TEV-biotin (100 M) and CuAAC was performed as previously described.sup.5,6. For analysis of cysteine reactivity in primary colorectal tumor tissue, tumors were pooled and incubated with either 100 M IAyne and isotopically heavy TEV-biotin or 10 M IAyne and isotopically light TEV-biotin followed by CuAAC. Proteins were precipitated over one hour and pelleted by centrifugation at 6500g. Proteins were washed 3 times with cold methanol then denatured and resolubilized by heating in 1.2% SDS/PBS to 85 C. for 5 min. Insoluble components were precipitated by centrifugation at 6500g and soluble proteome was diluted in 5 ml PBS, for a final concentration of 0.2% SDS. Labeled proteins were bound to avidin-agarose beads (170 L resuspended beads/sample, Thermo Pierce) while rotating overnight at 4 C. Bead-linked proteins were enriched by washing three times each in PBS and water, then resuspended in 6 M urea/PBS (Sigma-Aldrich) and reduced in dithiothreitol (1 mM, Sigma-Aldrich), alkylated with iodoacetamide (18 mM, Sigma-Aldrich), then washed and resuspended in 2 M urea/PBS with 1 mM calcium chloride and trypsinized overnight with 0.5 g/1 sequencing grade trypsin (Promega). Tryptic peptides were discarded and beads were washed three times each in PBS and water, then washed with one wash of TEV buffer containing 1 M DTT. TEV-biotin tag was digested overnight in TEV buffer containing 1 M DTT and 5 L Ac-TEV protease at 29 C. Peptides were diluted in water and acidified with final concentration of 5% formic acid (1.2 M, Spectrum).
[0762] Peptides from all proteomic experiments were pressure-loaded onto a 250 mm inner diameter fused silica capillary tubing packed with 4 cm of Aqua C18 reverse-phase resin (Phenomenex #04A-4299) which was previously equilibrated on an Agilent 600 series HPLC using gradient from 100% buffer A to 100% buffer B over 10 min, followed by a 5 min wash with 100% buffer B and a 5 min wash with 100% buffer A. The samples were then attached using a MicroTee PEEK 360 m fitting (Thermo Fisher Scientific # p-888) to a 13 cm laser pulled column packed with 10 cm Aqua C18 reverse-phase resin and 3 cm of strong-cation exchange resin for isoTOP-ABPP studies. Samples were analyzed using an Q Exactive Plus mass spectrometer (Thermo Fisher Scientific) using a 5-step Multidimensional Protein Identification Technology (MudPIT) program, using 0%, 25%, 50%, 80%, and 100% salt bumps of 500 mM aqueous ammonium acetate and using a gradient of 5-55% buffer B in buffer A (buffer A: 95:5 water:acetonitrile, 0.1% formic acid; buffer B 80:20 acetonitrile:water, 0.1% formic acid). Data was collected in data-dependent acquisition mode with dynamic exclusion enabled (60 s). One full MS (MS1) scan (400-1800 m/z) was followed by 15 MS2 scans (ITMS) of the nth most abundant ions. Heated capillary temperature was set to 200 C. and the nanospray voltage was set to 2.75 kV.
[0763] Data were extracted in the form of MS1 and MS2 files using Raw Extractor 1.9.9.2 (Scripps Research Institute) and searched against the Uniprot mouse database using ProLuCID search methodology in IP2 v.3 (Integrated Proteomics Applications, Inc).sup.23. Cysteine residues were searched with a static modification for carboxyaminomethylation (+57.02146) and up to two differential modifications for methionine oxidation and either the light or heavy TEV tags (+464.28596 or +470.29977, respectively). Peptides were required to have at least one tryptic end and to contain the TEV modification. ProLUCID data was filtered through DTASelect to achieve a peptide false-positive rate below 1%.
[0764] Gel-Based ABPP. Gel-based ABPP methods were performed as previously described.sup.24. Recombinant RTN4 (0.06 g) protein (RTN4-Fisher Scientific) were pre-treated with DMSO or DKM 3-30, respectively, for 1 h at 37 C. in an incubation volume of 50 L PBS, and were subsequently treated with IAyne (10 M final concentration) for 30 min at 37 C. CuAAC was performed to append rhodamine-azide onto IAyne probe-labeled proteins. The samples were separated by SDS/PAGE and scanned using a ChemiDoc MP (Bio-Rad Laboratories, Inc). Inhibition of target labeling was assessed by densitometry using ImageStudio Light software.
[0765] RTN4 Knockdown. Targets were knocked down transiently with siRNA or stably with shRNA as previously described.sup.22,25. For siRNA studies, SW620 cells (200,000 cells/well) were seeded overnight after which siControl (non-targeting siRNA) or siRTN4 oligonucleotides (5 pooled siRNAs targeting each target purchased from Dharmacon) were transfected into cells using Dharmafect 1. Cells were harvested after 48 h for qPCR and for seeding for cell viability assays.
[0766] For shRNA studies, shControl (targeting GFP) or shRTN4 constructs (purchased from Sigma) were transfected into HEK293T cells alongside lentiviral vectors using FuGENE. Lentivirus was collected from filtered cultured medium 48 h post-transfection and used to infect the target cancer cell line with Polybrene (0.01 mg/ml) Target cells were selected over 3 days with 1 mg/ml puromycin. The short hairpin sequences for the generation of RTN4 knockdown lines were: CCGGGCAGTGTTGATGTGGGTATTTCTCGAGAAATACCCACATCAACACTGCTTTTT TG (SEQ ID NO:328) and CCGGGCTATATCTGAGGAGTTGGTTCTCGAGAACCAACTCCTCAGATATAGCTTTTT TG (SEQ ID NO:329). The control shRNA was targeted against GFP with the target sequence GCAAGCTGACCCTGAAGTTCAT (SEQ ID NO:330). Knockdown was confirmed by qPCR.
[0767] qPCR. qPCR was performed using the manufacturer's protocol for Fisher Maxima SYBR Green with 10 mM primer concentrations or for Bio-Rad SsoAdvanced Universal Probes Supermix. Primer sequences for Fisher Maxima SYBR Green were derived from Harvard Primer Bank. Primer sequences for Bio-Rad SsoAdvanced Universal Probes Supermix were designed with Primer 3 Plus.
[0768] Fluorescence microscopy. SW620 and U2OS cells were transiently transfected with a plasmid encoding GFP-tagged Sec61 using fuGENE6 (Roche) according to the manufacturer's instructions. Transfected cells plated on poly-L-lysine treated coverslips were treated, washed in PBS, and fixed by incubation in 4% paraformaldehyde in PBS for 10 min. Fixed cells were washed extensively in PBS and nuclei stained by addition of 4,6-diamidino-2-phenylindole (DAPI) (Thermo Fisher Scientific) for 10 min. Coverslips were mounted using Fluoromount-G (SouthernBiotech) and visualized using a DeltaVision Elite microscope outfitted with a 60 oil immersion objective. Acquired stacks of images of fixed cells were deconvolved and analyzed using SoftWoRx and ImageJ. For time-lapse imaging of live cells, transfected cells were plated on poly-L-lysine treated glass-bottom 4-well imaging chambers (Lab-Tek II; Thermo Fisher Scientific). Imaging was performed using a DeltaVision Elite microscope encased in a chamber that was maintained at 37 C. and was continuously perfused with humidified 5% CO2. Acquired images were analyzed using SoftWoRx and ImageJ.
[0769] Homology modeling and multiple sequence alignments. The threaded homology model of the human Rtn4 (amino acids 1054-1120 of Rtn4a) on the NMR solution structure of the corresponding region of mouse Rtn4 (PDB 2KO2) was generated using Protein Homology/analogY Recognition Engine V 2.0 (Phyre2). Figures were made using PyMOL. Multiple sequence alignments were generated using Clustal Omega and figures were made using BoxShade.
[0770] Primary Human Colorectal Tumors. Eligible patients completed written consent for our tissue banking protocol that is approved by the University of Alabama at Birmingham Institutional Review Board. During the colorectal tumor resection, a 1 cm.sup.3 portion of the tumor was dissected free of the fresh resection specimen, divided into 4-5 aliquots, placed into 1.5 mL cryovials, flash frozen, and stored at 80 C. Adjacent non-tumor bearing colorectal tissue was also collected and banked in a similar manner.
[0771] General Synthetic Methods
[0772] Chemicals and reagents were purchased from major commercial suppliers and used without further purification. Reactions were performed under a nitrogen atmosphere unless otherwise noted. Silica gel flash column chromatography was performed using EMD or Sigma Aldrich silica gel 60 (230-400 mesh). Proton and carbon nuclear magnetic resonance (.sup.1H NMR and .sup.13C NMR) data was acquired on a Bruker AVB 400, AVQ 400, or AV 600 spectrometer at the University of California, Berkeley. High resolution mass spectrum were obtained from the QB3 mass spectrometry facility at the University of California, Berkeley using positive or negative electrospray ionization (+ESI or ESI). Yields are reported as a single run.
[0773] General Procedure A. The amine (1 eq.) was dissolved in DCM (5 mL/mmol) and cooled to 0 C. To the solution was added acryloyl chloride (1.2 eq.) followed by triethylamine (1.2 eq.). The solution was warmed to room temperature and stirred overnight. The solution was then washed with brine and the crude product was purified by silica gel chromatography (and recrystallization if necessary) to afford the corresponding acrylamide.
[0774] General Procedure B. The amine (1 eq.) was dissolved in DCM (5 mL/mmol) and cooled to 0 C. To the solution was added chloroacetyl chloride (1.2 eq.) followed by triethylamine (1.2 eq.). The solution was warmed to room temperature and stirred overnight. The solution was then washed with brine and the crude product was purified by silica gel chromatography (and recrystallization if necessary) to afford the corresponding chloroacetamide.
##STR00106##
[0775] N-(4-benzoylphenyl)acrylamide (DKM 2-117). Following General Procedure A starting from 4-aminobenzophenone (587 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 37% yield as a yellow solid (275 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.77 (s, 1H), 7.80-7.73 (m, 6H), 7.57 (tt, J=1.5, 7.4 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 6.46 (dd, J=1.6 16.9 Hz, 1H), 6.37 (dd, J=9.9, 16.9 Hz, 1H), 5.75 (dd, J=1.6, 9.9 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3): 196.3, 164.4, 142.3, 137.8, 133.0, 132.5, 131.7, 131.0, 130.0, 128.8, 128.4, 119.3. HRMS (+ESI): Calculated: 252.1019 (C.sub.16H.sub.14NO.sub.2). Observed: 252.1014.
##STR00107##
[0776] N-([1,1-biphenyl]-4-ylmethyl)acrylamide (DKM 2-37). Following General Procedure A starting from 4-phenylbenzylamine (552 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 10% yield as an off-white solid (73 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.58-7.55 (m, 4H), 7.44 (t, J=7.5 Hz, 2H), 7.38-7.33 (m, 3H), 6.35 (dd, J=1.3, 17.0 Hz, 1H), 6.13 (dd, J=10.3, 17.0 Hz, 1H), 6.01 (s, 1H), 5.68 (dd, J=1.3, 10.3 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.5, 140.77, 140.73, 137.2, 130.7, 128.9, 128.5, 127.6, 127.5, 127.2, 127.1, 43.5. HRMS (+ESI): Calculated: 238.1226 (C.sub.16H.sub.16NO). Observed: 238.1224.
##STR00108##
[0777] 2-Chloro-N-(4-phenylbutan-2-yl)acetamide (DKM 2-76). Following General Procedure B starting from 1-methyl-3-phenylpropylamine (614 mg, 4.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 81% yield as a white solid (662 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34-7.31 (m, 2H), 7.24-7.21 (m, 3H), 6.55 (d, J=7.4 Hz, 1H), 4.15-4.07 (m, 1H), 4.04 (s, 2H), 2.70 (t, J=8.2 Hz, 2H), 1.89-1.83 (m, 2H), 1.26 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.1, 141.3, 128.4, 128.2, 125.9, 45.7, 42.7, 381, 32.3, 20.7. HRMS (+ESI): Calculated: 226.0993 (C.sub.12H.sub.17ClNO). Observed: 226.0992.
##STR00109##
[0778] 2-chloro-N-(4-fluorobenzyl)acetamide (DKM 2-80). Following General Procedure B starting from 4-fluorobenzylamine (369 mg, 2.9 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 77% yield as a white solid (452 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.28-7.24 (m, 2H), 7.05-7.01 (m, 2H), 6.97 (s, 1H), 4.45 (d, J=5.6 Hz, 2H), 4.09 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.1, 163.6, 161.2, 133.20, 133.17, 129.64, 129.56, 115.9, 115.7, 43.2, 42.7. HRMS (ESI): Calculated: 200.0284 (C.sub.9H.sub.8NOClF). Observed: 200.0284.
##STR00110##
[0779] N-(benzo[d][1,3]dioxol-5-yl)acrylamide (DKM 2-86). Following General Procedure A starting from 3,4-(methylenedioxy)aniline (486 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 68% yield as a white solid (438 mg). .sup.1H NMR (400 MHz, (CD.sub.3).sub.2SO): 10.05 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.02 (dd, J=2.0, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.38 (dd, J=10.1, 17.0 Hz, 1H), 6.22 (dd, J=2.1, 17.0 Hz, 1H), 5.99 (s, 2H), 5.72 (dd, J=2.1, 10.1 Hz, 1H). .sup.13C NMR (100 MHz, (CD.sub.3).sub.2SO): 162.8, 147.0, 143.1, 133.4, 131.8, 126.5, 112.1, 108.1, 101.4, 101.0. HRMS (+ESI): Calculated: 192.0655 (C.sub.10H.sub.10NO.sub.3). Observed: 192.0651.
##STR00111##
[0780] 2-chloro-N-(2,3-dihydro-1H-inden-4-yl)acetamide (DKM 2-91). Following General Procedure B starting from 4-aminoindan (372 mg, 2.8 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 49% yield as an off-white solid (289 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.19 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.16 (s, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.10 (quint, J=7.5 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 163.8, 145.5, 134.5, 132.8, 127.3, 121.6, 118.5, 43.1, 33.2, 29.8, 24.8. HRMS (+ESI): Calculated: 210.0680 (C.sub.11H.sub.13ClNO). Observed: 210.0680.
##STR00112##
[0781] 2-Chloro-N-(2-chlorobenzyl)acetamide (DKM 2-94). Following General Procedure B starting from 2-chlorobenzylamine (432 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 67% yield as a white solid (443 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.36-7.18 (m, 5H), 4.51 (d, J=6.4 Hz, 2H), 4.01 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.1, 134.7, 133.5 129.8, 129.5, 129.1, 127.1, 42.5, 41.6. HRMS (ESI): Calculated: 215.9988 (C.sub.9H.sub.8NOCl.sub.2). Observed: 215.9988.
##STR00113##
[0782] N-(4-cyano-[1,1-biphenyl]-4-yl)acrylamide (DKM 2-98). Following General Procedure A starting from 4-(4-aminophenyl)benzonitrile (387 mg, 2.0 mmol), product was obtained after silica gel chromatography (1% to 2% ethyl methanol in DCM) in 70% yield as a yellow solid (348 mg). .sup.1H NMR (600 MHz, (D.sub.3C).sub.2CO): 9.52 (s, 1H), 7.90-7.89 (m, 2H), 7.87-7.86 (m, 2H), 7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 6.49 (dd, J=10.0, 16.9 Hz, 1H), 6.39 (dd, J=2.0, 16.9 Hz, 1H), 5.76 (dd, J=2.0, 10.0 Hz, 1H). .sup.13C NMR (150 MHz, (D.sub.3C).sub.2CO): 164.3, 145.7, 140.9, 134.8, 133.6, 132.7, 128.5, 128.2, 127.6, 120.8, 119.5, 111.3. HRMS (ESI): Calculated: 247.0877 (C.sub.16H.sub.11N.sub.2O). Observed: 247.0875.
##STR00114##
[0783] N-(4-(methylthio)phenyl)acrylamide (DKM 3-10). Following General Procedure A starting from 4-(methylthio)aniline (405 mg, 2.9 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 64% yield as a clear oil (362 mg). .sup.1H NMR (400 MHz, MeOD): 7.59-7.56 (m, 2H), 7.26-7.22 (m, 2H), 6.42 (dd, J=9.6, 17.0 Hz, 1H), 6.34 (dd, J=2.3, 17.0 Hz, 1H), 5.75 (dd, J=2.3, 9.6 Hz, 1H), 2.45 (s, 3H). .sup.13C NMR (100 MHz, MeOD): 166.0, 137.2, 135.4, 132.4, 128.6, 127.7, 121.9, 16.4. HRMS (+ESI): Calculated: 194.0634 (C.sub.10H.sub.12NOS). Observed: 194.0631.
##STR00115##
[0784] N-(4-ethyl-[1,1-biphenyl]-4-yl)acrylamide (DKM 3-16). Following General Procedure A starting from 4-amino-4-ethylbiphenyl (386 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 70% ethyl acetate in hexanes) in 65% yield as a white solid (164 mg). 41 NMR (400 MHz, (CD.sub.3).sub.2CO): 7.82 (d, J=8.2 Hz, 2H), 7.62-7.59 (m, 2H), 7.58-7.54 (m, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.47 (dd, J=9.9, 16.9 Hz, 1H), 6.36 (dd, J=2.2, 16.9 Hz, 1H), 5.72 (dd, J=2.2, 9.9 Hz, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H). .sup.13C NMR (100 MHz, (CD.sub.3).sub.2CO): 164.1, 144.0, 139.5, 13.9, 137.1, 132.9, 129.3, 127.9, 127.4, 127.2, 120.7, 29.2, 16.2. HRMS (+ESI): Calculated: 252.1383 (C.sub.17H.sub.18NO). Observed: 252.1379.
##STR00116##
[0785] N,N-diphenylacrylamide (DKM 3-70). A solution of diphenylamine (347 mg, 2.1 mmol) in DCM (10 mL) was cooled to 0 C. To the solution was added acryloyl chloride (222 mg, 2.5 mmol) followed by triethylamine (279 mg, 2.8 mmol). The solution was allowed to warm to room temperature and stirred overnight. The solution was washed with brine and citric acid and the crude product was purified via silica gel chromatography (20% to 60% ethyl acetate in hexanes) to afford the product in 24% yield as a dark yellow oil (112 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.43-7.28 (m, 10H), 6.52 (dd, J=2.0, 16.8 Hz, 1H), 6.25 (dd, J=10.2, 16.8 Hz, 1H), 5.67 (dd, J=1.8, 10.2 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 142.6, 129.7, 129.3, 128.5, 127.0. HRMS (+ESI): Calculated: 246.0889 (C.sub.15H.sub.13NONa). Observed: 246.0887.
##STR00117##
[0786] 2-Chloro-N-(4-phenoxyphenyl)acetamide (TRH 1-23). Following General Procedure B starting from 4-phenoxyaniline (370 mg, 2.0 mmol) product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 46% yield as a white solid (315 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42 (s, 1H), 7.52-7.48 (m, 2H), 7.35-7.31 (m, 2H), 7.10 (t, J=7.3 Hz, 1H), 7.01-6.98 (m, 4H), 4.17 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.2, 157.2, 154.4, 132.1, 129.8, 123.4, 122.2, 119.4, 118.7, 42.9. HRMS (ESI): Calculated: 260.0484 (C.sub.14H.sub.11NO.sub.2Cl). Observed: 260.0482.
##STR00118##
[0787] N-(4-(trifluoromethyl)phenyl)acrylamide (TRH 1-50). Following General Procedure A starting from 4-(trifluoromethyl)aniline (328 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 55% yield as a white solid (239 mg). .sup.1H NMR (400 MHz, MeOD): 7.78 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 6.44-6.32 (m, 2H), 5.75 (dd, J=8.4, 2.8 Hz, 1H). .sup.13C NMR (100 MHz, MeOD): 166.3, 143.3, 132.1, 128.6, 127.04, 127.00, 126.97, 126.93, 126.6, 124.3, 120.9. HRMS (ESI): Calculated: 214.0485 (C.sub.10H.sub.7NOF.sub.3). Observed: 214.0484.
##STR00119##
[0788] 2-Chloro-N-(2-methylbenzyl)acetamide (TRH 1-55). Following General Procedure B starting from 2-methylbenzylamine (239 mg, 2.0 mmol) product was obtained after silica gel chromatography (30% ethyl acetate in hexanes) and recrystallization from 5% ethyl acetate in hexanes in 64% yield as a white solid (191 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.25-7.19 (m, 4H), 6.85 (s, 1H), 4.46 (d, J=5.6 Hz, 2H), 4.04 (s, 2H), 2.33 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 136.4, 135.0, 130.6, 128.4, 128.0, 126.3, 42.6, 42.0, 19.0. HRMS (ESI): Calculated: 196.0535 (C.sub.10H.sub.11NOCl). Observed: 196.0534.
##STR00120##
[0789] N-benzylacrylamide (DKM 2-31). Following General Procedure A starting from benzylamine (334 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 75% yield as a white solid (376 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.28-7.18 (m, 6H), 6.19-6.16 (m, 2H), 5.53 (dd, J=4.6, 7.3 Hz, 1H), 4.36 (d, J=5.9 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 138.1, 130.8, 128.6, 127.7, 127.3, 126.5, 43.5. HRMS (+ESI): Calculated: 162.0913 (C.sub.10H.sub.12NO). Observed: 162.0912.
##STR00121##
[0790] N-(4-phenylbutan-2-yl)acrylamide (DKM 2-32). Following General Procedure A starting from 1-methyl-3-phenylpropylamine (606 mg, 4.0 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 89% yield as a clear oil (735 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.32-7.29 (m, 2H), 7.23-7.20 (m, 3H), 6.84 (d, J=8.4 Hz, 1H), 6.36-6.24 (m, 2H), 5.64 (dd, J=2.8, 9.2 Hz, 1H), 4.21-4.14 (m, 1H), 2.70 (t, J=7.8 Hz, 2H), 1.93-1.77 (m, 2H), 1.24 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.1, 141.7, 131.3, 128.3, 128.2, 125.80, 125.77, 45.1, 38.4, 32.5, 20.8. HRMS (+ESI): Calculated: 204.1383 (C.sub.13H.sub.18NO). Observed: 204.1380.
##STR00122##
[0791] N-(4-methoxybenzyl)acrylamide (DKM 2-33). Following General Procedure A starting from 4-methoxybenzylamine (424 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 60% yield as a clear oil (343 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.14 (d, J=8.8 Hz, 2H), 6.85 (s, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.24-6.14 (m, 2H), 5.56 (dd, J=2.0, 9.6 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H), 3.73 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.6, 158.9, 130.9, 130.3, 129.1, 126.4, 113.9, 55.2, 42.9. HRMS (+ESI): Calculated: 192.1019 (C.sub.11H.sub.14NO.sub.2). Observed: 192.1017.
##STR00123##
[0792] N-(4-fluorobenzyl)acrylamide (DKM 2-34). Following General Procedure A starting from 4-fluorobenzylamine (368 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 60% ethyl acetate in hexanes) in 52% yield as an off-white solid (276 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.24-7.19 (m, 2H), 6.97 (t, J=8.5 Hz, 2H), 6.42 (s, 1H), 6.27 (d, J=17.0 Hz, 1H), 6.12 (dd, J=17.0, 10.2 Hz, 1H), 5.63 (d, J=10.2 Hz, 1H), 4.42 (d, J=5.8 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.7, 163.5, 134.0, 130.6, 129.6, 129.5, 127.0, 115.7, 115.5, 43.0. HRMS (+ESI): Calculated: 180.0819 (C.sub.10H.sub.11NOF). Observed: 180.0818.
##STR00124##
[0793] Ethyl 4-acryloylpiperazine-1-carboxylate (DKM 2-39). Following General Procedure A starting from ethyl 1-piperazinecarboxylate (477 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 70% ethyl acetate in hexanes) in 58% yield as a yellow oil (372 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.46 (dd, J=10.5, 16.8 Hz, 1H), 6.18 (dd, J=1.9, 16.8 Hz), 5.60 (dd, J=1.9, 10.5 Hz), 4.03 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 3.44 (s, 2H), 3.39-3.36 (m, 4H), 1.15 (t, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.3, 155.1, 128.2, 127.1, 61.5, 45.4, 43.6, 43.3, 41.5, 14.5. HRMS (+ESI): Calculated: 213.1234 (C.sub.10H.sub.17N.sub.2O.sub.3). Observed: 213.1232.
##STR00125##
[0794] N-(2,5-difluorophenyl)acrylamide (DKM 2-40). Following General Procedure A starting from 2,5-difluoroaniline (369 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 15% ethyl acetate in hexanes) in 27% yield as a white solid (141 mg). .sup.1H NMR (400 MHz, (CD.sub.3).sub.2CO): 9.26 (s, 1H), 8.29-8.24 (m, 1H), 7.24-7.18 (m, 1H), 6.90-6.84 (m, 1H), 6.67 (dd, J=10.2, 16.9 Hz, 1H), 6.41 (dd, J=1.9, 16.9 Hz, 1H), 5.79 (dd, J=1.9, 10.2 Hz, 1H). .sup.13C NMR (100 MHz, (CD.sub.3).sub.2CO): 164.6, 160.4, 151.0, 148.7, 132.0, 128.9, 128.8, 128.5, 116.7, 116.6, 116.5, 116.4, 111.1, 111.0, 110.8, 110.7, 110.0, 109.7. HRMS (+ESI): Calculated: 184.0568 (C.sub.9H.sub.8F.sub.2NO). Observed: 184.0567.
##STR00126##
[0795] N-phenethylacrylamide (DKM 2-42). Following General Procedure A starting from phenylethylamine (367 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 85% yield as a yellow oil (450 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.30-7.18 (m, 5H), 6.63 (s, 1H), 6.25 (dd, J=1.8, 17.0 Hz, 1H), 6.13 (dd, J=10.0, 17.0 Hz 1H), 5.59 (dd, J=1.6, 10.0 Hz, 1H), 3.56 (q, J=6.8 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 138.8, 131.0, 128.7, 128.6, 126.4, 126.1, 40.8, 35.6. HRMS (+ESI): Calculated: 176.1070 (C.sub.11H.sub.14NO). Observed: 176.1068.
##STR00127##
[0796] N-(4-bromobenzyl)acrylamide (DKM 2-43). Following General Procedure A starting from 4-bromobenzylamine (535 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 59% yield as a white solid (407 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.37 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (s, 1H), 6.24-6.10 (m, 2H), 5.59 (dd, J=2.0, 9.7 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 137.2, 131.7, 130.6, 129.4, 126.9, 121.2, 42.8. HRMS (+ESI): Calculated: 240.0019 (C.sub.10H.sub.11BrNO). Observed: 240.0016.
##STR00128##
[0797] N-(3,5-dimethylbenzyl)acrylamide (DKM 2-47). Following General Procedure A starting from 3,5-dimethylbenzylamine (257 mg, 1.9 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 77% yield as a white solid (276 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.89-6.87 (m, 4H), 6.26 (dd, J=2.1, 17.0 Hz, 1H), 6.18 (dd, J=9.7, 17.0 Hz, 1H) 5.59 (dd, J=2.1, 9.7 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.28 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.6, 138.1, 138.0, 130.9, 129.0, 126.3, 125.6, 43.4, 12.2. HRMS (+ESI): Calculated: 190.1226 (C.sub.12H.sub.16NO). Observed: 190.1225.
##STR00129##
[0798] 1-(pyrrolidin-1-yl)prop-2-en-1-one (DKM 2-48). Following General Procedure A starting from pyrrolidine (223 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 38% yield as a pale yellow oil (148 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.40 (dd, J=10.0, 16.8 Hz, 1H), 6.29 (dd, J=2.4, 16.8 Hz, 1H), 5.60 (dd, J=2.4, 10.0 Hz, 1H), 3.48 (t, J=6.8 Hz, 4H), 1.91 (quint, J=6.7 Hz, 2H), 1.82 (quint, J=6.7 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.4, 128.8, 127.2, 46.6, 45.9, 26.1, 24.3. HRMS (+ESI): Calculated: 126.0913 (C.sub.7H.sub.12NO). Observed: 126.0912.
##STR00130##
[0799] 1-morpholinoprop-2-en-1-one (DKM 2-49). Following General Procedure A starting from morpholine (273 mg, 3.1 mmol), product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 46% yield as a yellow oil (205 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.45 (dd, J=10.5, 16.8 Hz, 1H), 6.20 (dd, J=1.9, 16.8 Hz, 1H), 5.61 (dd, J=1.9, 10.5 Hz, 1H), 5.38 (s, 6H), 3.46 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.3, 128.1, 126.9, 66.6, 46.0, 42.1. HRMS (+ESI): Calculated: 142.0863 (C.sub.7H.sub.12NO.sub.2). Observed: 142.0861.
##STR00131##
[0800] N-(3-phenylpropyl)acrylamide (DKM 2-50). Following General Procedure A starting from 3-phenyl-1-propylamine (275 mg, 2.0 mmol), product was obtained after silica gel chromatography (0% to 60% ethyl acetate in hexanes) in 58% yield as a yellow oil (223 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.29-7.25 (m, 2H), 7.20-7.16 (m, 3H), 6.99 (s, 1H), 6.29-6.17 (m, 2H), 5.59 (dd, J=2.6, 9.0 Hz, 1H), 3.34 (q, J=6.7 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.87 (quint, J=7.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.0, 141.4, 131.1, 128.33, 128.26, 125.9, 39.2, 33.2, 31.0. HRMS (+ESI): Calculated: 190.1226 (C.sub.12H.sub.16NO). Observed: 190.1225.
##STR00132##
[0801] N-(2-(2-methoxyphenoxy)ethyl)acrylamide (DKM 2-58). Following General Procedure A starting from 2-(2-methoxyphenoxy)ethanamine (509 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 70% yield as a yellow oil (470 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.95-6.84 (m, 4H), 6.77 (s, 1H), 6.26 (d, J=17.1 Hz, 1H), 6.11 (dd, J=10.2, 17.1 Hz, 1H), 5.59 (d, J=10.2 Hz, 1H), 4.07 (t, J=5.2 Hz, 2H), 3.79 (s, 3H), 3.69 (q, J=5.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.7, 149.6, 147.7, 130.8, 126.4, 122.1, 121.0, 114.8, 111.8, 68.5, 55.7, 38.9. HRMS (+ESI): Calculated: 244.0944 (C.sub.12H.sub.15NO.sub.3Na). Observed: 244.0940.
##STR00133##
[0802] N-([1,1-biphenyl]-2-ylmethyl)acrylamide (DKM 2-59). Following General Procedure A starting from 2-phenylbenzylamine (202 mg, 1.1 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 70% yield as a yellow oil (184 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.41-7.22 (m, 9H), 6.16 (dd, J=1.2, 17.2 Hz, 1H), 6.03-5.97 (m, 2H), 5.55 (dd, J=1.2, 10.0 Hz, 1H), 4.44 (d, J=5.6 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.3, 141.6, 140.6, 135.2, 1306, 130.2, 129.0, 128.7, 128.4, 127.8, 127.4, 127.3, 126.4, 41.4. HRMS (+ESI): Calculated: 238.1226 (C.sub.16H.sub.16NO). Observed: 238.1223.
##STR00134##
[0803] N-(2-chlorobenzyl)acrylamide (DKM 2-60). Following General Procedure A starting from 2-chlorobenzylamine (406 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 34% yield as a white solid (162 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34-30 (m, 2H), 7.20-7.16 (m, 2H), 6.84 (s, 1H), 6.25 (dd, J=2.0, 17.0 Hz, 1H), 6.16 (dd, J=9.7, 17.0 Hz, 2H), 5.60 (dd, J=2.0, 9.7 Hz, 1H), 4.52 (d, J=6.1 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 135.5, 133.5, 130.6, 129.8, 129.5, 128.8, 127.1, 126.8, 41.4. HRMS (+ESI): Calculated: 196.0524 (C.sub.10H.sub.11ClNO). Observed: 196.0521
##STR00135##
[0804] N-(2-nitrobenzyl)acrylamide (DKM 2-62). Following General Procedure A starting from 2-nitrobenzylamine hydrochloride (406 mg, 2.9 mmol) with an extra equivalent of triethylamine, product was obtained after silica gel chromatography (50% ethyl acetate in hexanes) in 42% yield as a yellow solid (255 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.98 (dd, J=1.1, 8.2 Hz, 1H), 7.58-7.52 (m, 2H), 7.41-7.37 (m, 1H), 7.03 (s, 1H), 6.22 (dd, J=2.0, 17.0 Hz, 1H), 6.14 (dd, J=9.7, 17.0 Hz, 1H), 5.59 (dd, J=2.0, 9.7 Hz, 1H), 4.68 (d, J=6.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 148.2, 134.1, 133.6, 131.9, 130.4, 128.7, 127.1, 125.1, 41.2. HRMS (+ESI): Calculated: 207.0764 (C.sub.10H.sub.11N.sub.2O.sub.3). Observed: 207.0760.
##STR00136##
[0805] N-(2,3-dihydro-1H-inden-4-yl)acrylamide (DKM 2-84). Following General Procedure A starting from 4-aminoindan (402 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% ethyl acetate in hexanes) in 59% yield as a white solid (332 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.72 (d, J=7.5 Hz, 1H), 7.54 (s, 1H), 7.10 (t, J=7.7 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.40-6.26 (m, 2H), 5.69 (dd, J=1.9, 9.7 Hz, 1H), 2.91 (t, J=7.4 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.05 (quint, J=7.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 163.5, 145.3, 134.4, 133.6, 131.2, 127.5, 127.2, 12.0, 19.2, 33.2, 30.1, 24.8. HRMS (+ESI): Calculated: 188.1070 (C.sub.12H.sub.14NO). Observed: 188.1069.
##STR00137##
[0806] Ethyl 4-acrylamidobenzoate (DKM 2-85). Following General Procedure A starting from benzocaine (486 mg, 2.9 mmol), product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 68% yield as a white solid (438 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.39 (s, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 6.43-6.41 (m, 2H), 5.71 (dd, J=4.7, 6.9 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.33 (s, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.5, 164.6, 142.5, 131.0, 130.6, 128.4, 125.7, 119.4, 61.0, 14.2. HRMS (ESI): Calculated: 218.0823 (C.sub.12H.sub.12NO.sub.3). Observed: 218.0822.
##STR00138##
[0807] N-benzyl-N-methylacrylamide (DKM 2-95). Following General Procedure A starting from N-methylbenzylamine (350 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% ethyl acetate in hexanes) in 60% yield as a clear oil (304 mg). .sup.1H NMR (48:52 rotamer ratio, asterisks denote minor peaks, 400 MHz, CDCl.sub.3): 7.34-7.23 (m, 4H), 7.16 (s, 1H), 7.14* (s, 1H), 6.61 (dd, J=10.4, 16.8 Hz, 1H), 6.57* (dd, J=10.4, 16.8 Hz, 1H), 6.38 (dd, J=1.9, 16.8 Hz, 1H), 6.36* (dd, J=1.9, 16.8 Hz, 1H), 5.71 (dd, J=1.9, 10.4 Hz, 1H), 5.64* (dd, J=1.9, 10.4 Hz), 4.63 (s, 2H), 4.56* (s, 2H), 2.98* (s, 3H), 2.96 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 167.0, 166.4, 137.1, 136.5, 128.8, 128.5, 128.2, 128.0, 17.62, 127.59, 127.3, 126.3, 53.3, 51.0, 34.8, 34.0. HRMS (+ESI): Calculated: 176.1070 (C.sub.11H.sub.14NO). Observed: 176.1070.
##STR00139##
[0808] 1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (DKM 2-97). Following General Procedure A starting from 4-phenylpiperidine (331 mg, 2.1 mmol), product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 86% yield as a yellow oil (379 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.32-7.28 (m, 2H), 7.22-7.17 (m, 3H), 6.62 (dd, J=10.6, 16.8 Hz, 1H), 6.30 (dd, J=1.9, 16.8 Hz, 1H), 5.68 (dd, J=1.9, 10.6, Hz, 1H), 4.82 (d, J=12.9 Hz, 1H), 4.11 (d, J=13.2 Hz, 1H), 3.15 (t, J=8.5 Hz, 1H), 2.78-2.67 (m, 2H), 1.90 (d, J=12.9 Hz, 2H), 1.64 (quint, J=12.3 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.3, 145.0, 128.5, 127.8, 127.4, 126.6, 126.4, 46.4, 42.7, 33.9, 32.7. HRMS (+ESI): Calculated: 216.1383 (C.sub.14H.sub.18NO). Observed: 216.1383.
##STR00140##
[0809] N-(2-morpholinoethyl)acrylamide (DKM 2-100). Following General Procedure A starting from 2-morpholinoethylamine (580 mg, 3.0 mmol), product was obtained after silica gel chromatography (2% to 6% methanol in dichloromethane) in 33% yield as a white solid (184 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.39 (s, 1H), 6.21 (dd, J=1.7, 17.0 Hz, 1H), 6.08 (dd, J=10.1, 17.0 Hz, 1H), 5.56 (dd, J=1.7, 10.1 Hz, 1H), 3.63 (t, J=4.6 Hz, 4H), 3.36 (q, J=6.2 Hz, 2H), 2.45 (t, J=6.2 Hz, 2H), 2.40-2.38 (m, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.5, 130.9, 126.2, 66.9, 57.0, 53.3, 35.7. HRMS (+ESI): Calculated: 185.1285 (C.sub.9H.sub.17N.sub.2O.sub.2). Observed: 185.1280.
##STR00141##
[0810] 1-(indolin-1-yl)prop-2-en-1-one (DKM 2-101). Following General Procedure A starting from indoline (580 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 20% ethyl acetate in hexanes) in 56% yield as a green solid (285 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.30 (d, J=7.7 Hz, 1H), 7.22-7.17 (m, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.60-6.48 (m, 2H), 5.79 (dd, J=2.6, 9.5 Hz, 1H), 4.15 (t, J=8.5 Hz, 2H), 3.20 (t, J=8.1, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 163.6, 142.6, 131.5, 129.0, 128.6, 127.2, 124.4, 123.8, 117.2, 47.8, 27.7. HRMS (+ESI): Calculated: 174.0913 (C.sub.11H.sub.12NO). Observed: 174.0911.
##STR00142##
[0811] N-butylacrylamide (DKM 2-102). Following General Procedure A starting from butylamine (223 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% ethyl acetate in hexanes) in 61% yield as a clear oil (237 mg). .sup.1H NMR (400 MHz, (CDCl.sub.3): 6.81 (s, 1H), 6.21-6.10 (m, 2H), 5.52 (dd, J=3.6, 8.3 Hz, 1H), 3.26-3.21 (m, 2H), 1.48-1.41 (m, 2H), 1.33-1.23 (m, 2H), 0.84 (t, J=7.3 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.0, 131.2, 125.6, 39.3, 31.5, 20.1, 13.7. HRMS (+ESI): Calculated: 128.1070 (C.sub.7H.sub.14NO). Observed: 128.1068.
##STR00143##
[0812] N-(3-methoxypropyl)acrylamide (DKM 2-103). Following General Procedure A starting from 3-methoxypropylamine (274 mg, 3.1 mmol), product was obtained after silica gel chromatography (35% to 60% ethyl acetate in hexanes) in 54% yield as a clear oil (236 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.84 (s, 1H), 6.15 (dd, J=2.0, 17.0 Hz. 1H), 6.07 (dd, J=9.8, 17.0 Hz, 1H), 5.51 (dd, J=2.0, 9.8 Hz, 1H), 3.39 (t, J=5.9 Hz, 2H), 3.33 (q, J=6.3 Hz, 2H), 3.25 (s, 3H), 1.72 (quint, J=6.3 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 131.2, 125.7, 71.3, 58.7, 37.7, 29.0. HRMS (+ESI): Calculated: 144.1019 (C.sub.7H.sub.14NO.sub.2). Observed: 144.1017.
##STR00144##
[0813] N-cyclohexylacrylamide (DKM 2-106). Following General Procedure A starting from cyclohexylamine (292 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 86% yield as a white solid (313 mg). .sup.1H NMR (400 MHz, (CDCl.sub.3): 6.55 (d, J=6.7 Hz, 1H), 6.21-6.09 (m, 2H), 5.51 (dd, J=2.5, 9.1 Hz, 1H), 3.79-3.70 (m, 1H), 1.86-1.82 (m, 2H), 1.67-1.63 (m, 2H), 1.56-1.52 (m, 1H), 1.28-1.21 (m, 2H), 1.16-1.05 (m, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.8, 131.5, 125.7, 48.3, 32.9, 25.5, 24.9. HRMS (+ESI): Calculated: 154.1226 (C.sub.9H.sub.16NO). Observed: 154.1224.
##STR00145##
[0814] N-(4-chlorophenyl)acrylamide (DKM 2-107). Following General Procedure A starting from 4-chloroaniline (386 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) followed by recrystallization from toluene in 31% yield as a white solid (168 mg). .sup.1H NMR (400 MHz, (CD.sub.3).sub.2CO): 9.47 (s, 1H), 7.77-7.74 (m, 2H), 7.35-7.31 (m, 2H), 6.43 (dd, J=9.6, 16.9 Hz, 1H), 6.35 (dd, J=2.5, 16.9 Hz, 1H), 5.73 (dd, J=2.5, 9.6 Hz, 1H). .sup.13C NMR (100 MHz, (CD.sub.3).sub.2CO): 164.1, 139.0, 132.5, 129.5, 128, 127.5, 121.7. HRMS (ESI): Calculated: 180.0222 (C.sub.9H.sub.7NOCl). Observed: 180.0221.
##STR00146##
[0815] N-cyclopentylacrylamide (DKM 2-108). Following General Procedure A starting from cyclopentylamine (257 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 55% yield as a colorless oil (229 mg). .sup.1H NMR (400 MHz, (CDCl.sub.3): 6.70 (s, 1H), 6.21-6.10 (m, 2H), 5.51 (dd, J=3.5, 8.5 Hz, 1H), 5.53-5.50 (sex, J=7.1 Hz, 1H), 1.94-1.86 (m, 2H), 1.65-1.46 (m, 4H), 1.41-1.32 (m, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.4, 131.3, 125.7, 51.1, 32.9, 23.8. HRMS (+ESI): Calculated: 140.1070 (C.sub.81H.sub.14NO). Observed: 140.1067.
##STR00147##
[0816] 1-(4-methoxypiperidin-1-yl)prop-2-en-1-one (DKM 2-109). Following General Procedure A starting from 4-methoxypiperidine (461 mg, 3.0 mmol), product was obtained after silica gel chromatography (40% to 60% ethyl acetate in hexanes) in 75% yield as a pale yellow oil (386 mg). .sup.1H NMR (400 MHz, (CDCl.sub.3): 6.45 (dd, J=10.6, 16.8 Hz, 1H), 6.09 (dd, J=2.0, 16.8 Hz, 1H), 5.51 (dd, J=2.0, 10.6 Hz, 1H), 3.80-3.74 (m, 1H), 3.65-3.58 (m, 1H), 3.33-3.17 (m, 6H), 1.74-1.67 (m, 2H), 1.47-1.39 (m, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.1, 127.6, 127.2, 75.0, 55.5, 42.7, 38.9, 31.1, 29.9. HRMS (+ESI): Calculated: 170.1176 (C.sub.9H.sub.16NO.sub.2). Observed: 170.1176.
##STR00148##
[0817] N-(3,4-dimethoxybenzyl)acrylamide (DKM 2-110). Following General Procedure A starting from 3,4-dimethoxybenzylamine (497 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 65% yield as a white solid (425 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.07 (s, 1H), 6.70-6.64 (m, 3H), 6.18-6.08 (m, 2H), 5.50 (dd, J=3.1, 8.8 Hz, 1H), 4.26 (d, J=5.8 Hz, 2H), 3.70 (d, J=7.8 Hz, 6H). .sup.13C NMR (400 MHz, CDCl.sub.3): 165.5, 148.7, 148.0, 130.73, 130.67, 126.2, 119.9, 110.98, 110.96, 55.64, 55.55, 43.12. HRMS (+ESI): Calculated: 222.1125 (C.sub.12H.sub.16NO.sub.3). Observed: 222.1121.
##STR00149##
[0818] tert-butyl 4-acryloylpiperazine-1-carboxylate (DKM 2-111). Following General Procedure A starting from 1-boc-piperazine (552 mg, 3.0 mmol), product was obtained after silica gel chromatography (50% to 70% ethyl acetate in hexanes) in 75% yield as a pale yellow oil (534 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.48 (dd, J=10.5, 16.8 Hz, 1H), 6.20 (dd, J=1.8, 16.8 Hz, 1H), 5.60 (dd, J=1.8, 10.5 Hz, 1H), 3.55 (s, 2H), 3.44 (s, 2H), 3.36-3.34 (m, 4H), 1.37 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.4, 154.4, 128.2, 127.2, 80.2, 45.5, 41.7, 28.3. HRMS (+ESI): Calculated: 241.1547 (C.sub.12H.sub.21N.sub.2O.sub.3). Observed: 241.1543.
##STR00150##
[0819] N-(2-phenoxyethyl)acrylamide (DKM 2-113). Following General Procedure A starting from 2-phenoxyethylamine (279 mg, 2.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 61% yield as a white solid (239 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.31-7.25 (m, 2H), 6.98-6.94 (m, 1H), 6.90-6.87 (m, 2H), 6.58 (s, 1H), 6.31 (dd, J=1.6, 17.0 Hz, 1H), 6.17 (dd, J=10.2, 17.0 Hz, 1H), 5.64 (dd, J=1.6, 10.2 Hz, 1H), 4.05 (t, J=5.2 Hz, 2H), 3.73 (q, J=5.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 158.4, 130.7, 129.6, 126.7, 121.2, 114.4, 66.5, 39.1. HRMS (+ESI): Calculated: 192.1019 (C.sub.11H.sub.14NO.sub.2). Observed: 192.1016.
##STR00151##
[0820] N,N-dicyclohexylacrylamide (DKM 2-114). Following General Procedure A starting from dicyclohexylamine (537 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 40% ethyl acetate in hexanes) in 55% yield as a white solid (382 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.49 (dd, J=10.6, 16.8 Hz, 1H), 6.11 (dd, J=1.9, 16.8 Hz, 1H), 5.49 (dd, J=2.0, 10.6 Hz, 1H), 3.45 (s, 1H), 3.22 (s, 1H), 2.22 (s, 2H), 1.74-1.49 (m, 12H), 1.22-1.07 (m, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.2, 130.9, 125.5, 57.5, 55.6, 31.6, 30.1, 26.4, 26.0, 25.3. HRMS (+ESI): Calculated: 236.2009 (C.sub.15H.sub.26NO). Observed: 236.2004.
##STR00152##
[0821] N-(4-(trifluoromethyl)benzyl)acrylamide (DKM 2-116). Following General Procedure A starting from 4-(trifluoromethyl)benzylamine (516 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 24% yield as a white solid (165 mg). .sup.1H NMR (600 MHz, CDCl.sub.3): 7.53 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 6.28 (dd, J=1.5, 17.0 Hz, 1H), 6.14 (dd, J=10.1, 17.0 Hz, 1H), 5.64 (dd, J=1.5, 10.1 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H). .sup.13C NMR (150 MHz, CDCl.sub.3): 165.9, 142.3, 130.5, 130.0, 129.7, 128.0, 127.3, 125.73, 125.69, 12566, 125.62, 43.1. HRMS (ESI): Calculated: 228.0642 (C.sub.11H.sub.9NOF.sub.3). Observed: 228.0641.
##STR00153##
[0822] Ethyl 1-acryloylpiperidine-4-carboxylate (DKM 2-120). Following General Procedure A starting from ethyl isonipecotate (459 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 45% ethyl acetate in hexanes) in 71% yield as a pale yellow liquid (440 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.40 (dd, J=10.6, 16.8 Hz, 1H), 6.04 (dd, J=2.0, 16.8 Hz, 1H), 5.47 (dd, J=2.0, 10.6 Hz, 1H), 4.23 (d, J=13.2 1H), 3.93 (q, J=7.1 Hz, 2H), 3.76 (d, J=14.0 Hz, 1H), 2.99 (t, J=11.8 Hz, 1H), 2.70 (t, J=11.5 Hz, 1H), 2.37 (tt, J=4.1, 10.7 Hz, 1H), 1.77-1.73 (m, 2H), 1.51-1.42 (m, 2H), 1.05 (t, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 173.7, 165.0, 127.5, 127.2, 60, 44.7, 41.0, 40.5, 28.2, 27.4, 13.8. HRMS (+ESI): Calculated: 212.1281 (C.sub.11H.sub.18NO.sub.3). Observed: 212.1276.
##STR00154##
[0823] N-benzhydrylacrylamide (DKM 3-4). Following General Procedure A starting from benzhydrylamine (459 mg, 3.0 mmol), product was obtained after silica gel chromatography (0% to 20% ethyl acetate in hexanes) and recrystallization from toluene in 15% yield as a white solid (110 mg). .sup.1H NMR (400 MHz, (CD.sub.3).sub.2CO): 7.35-7.23 (m, 10H), 6.45 (dd, J=10.2, 17.0 Hz, 1H), 6.36-6.34 (m, 1H), 6.25 (dd, J=2.2, 17.0 Hz, 1H), 5.61 (dd, J=2.2, 10.2 Hz, 1H). .sup.13C NMR (100 MHz, (CD.sub.3).sub.2CO): 164.84, 164.76, 143.51, 143.48, 132.51, 132.47, 129.4, 128.5, 1280, 126.3, 57.5, 57.4. HRMS (+ESI): Calculated: 238.1226 (C.sub.16H.sub.16NO). Observed: 238.1222.
##STR00155##
[0824] 1-(4-phenylpiperazin-1-yl)prop-2-en-1-one (DKM 3-5). Following General Procedure A starting from 1-phenylpiperazine (479 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 87% yield as a yellow oil (555 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.30-7.25 (m, 2H), 6.92-6.87 (m, 3H), 6.60 (dd, J=10.5, 16.8 Hz 1H), 6.33 (dd, J=2.0, 16.8 Hz, 1H), 5.72 (dd, J=2.0, 10.5 Hz, 1H), 3.81 (s, 2H), 3.66 (s, 2H), 3.14 (t, J=5.2 Hz, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.0, 150.6, 18.9, 127.8, 127.1, 120.2, 116.3, 49.4, 48.9, 45.3, 41.5. HRMS (+ESI): Calculated: 217.1335 (C.sub.13H.sub.17N.sub.2O). Observed: 217.1332.
##STR00156##
[0825] N-(4-acetylphenyl)acrylamide (DKM 3-7). Following General Procedure A starting from 4-aminoacetophenone (398 mg, 2.9 mmol), product was obtained after silica gel chromatography (20% to 50% ethyl acetate in hexanes) in 45% yield as a white solid (253 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.40 (s, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 6.46 (dd, J=1.3, 16.9 Hz, 1H), 6.34 (dd, J=10.1, 16.9 Hz, 1H), 5.79 (dd, J=1.3, 10.1 Hz, 1H), 2.57 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 197.5, 164.1, 142.5, 133.0, 130.9, 129.9, 128.9, 119.4, 26.6. HRMS (+ESI): Calculated: 190.0863 (C.sub.11H.sub.12NO.sub.2). Observed: 190.0858.
##STR00157##
[0826] 1-(4-methylpiperidin-1-yl)prop-2-en-1-one (DKM 3-8). Following General Procedure A starting from 4-methylpiperidine (295 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 84% yield as a yellow oil (385 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.51 (dd, J=10.6, 16.5 Hz, 1H), 6.16 (dd, J=2.0, 16.5 Hz, 1H), 5.57 (dd, J=2.0, 10.6 Hz, 1H), 4.53 (d, J=13.1 Hz, 1H), 3.88 (d, J=13.3 Hz, 1H), 2.99-2.92 (m, 1H), 2.55 (td, J=2.1, 12.8 Hz, 1H), 1.62 (d, J=13.1 Hz, 2H), 1.57-1.49 (m, 1H), 1.10-0.98 (m, 2H), 0.87 (d, J=6.5 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.2, 128.0, 127.0, 46.2, 42.4, 34.7, 33.7, 31.1, 21.7. HRMS (+ESI): Calculated: 154.1226 (C.sub.9H.sub.16NO). Observed: 154.1224.
##STR00158##
[0827] N-(2,2-diethoxyethyl)acrylamide (DKM 3-9). Following General Procedure A starting from aminoacetaldehyde diethyl acetal (402 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 75% yield as a clear oil (313 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.25-6.19 (m, 2H), 6.09 (dd, J=10.1, 17.0 Hz, 1H), 5.56 (dd, J=1.7, 10.1 Hz, 1H), 4.48 (t, J=5.3 Hz, 1H), 3.64 (dq, J=7.1, 9.4 Hz, 2H), 3.47 (dq, J=7.1, 9.4 Hz, 2H), 3.38 (t, J=5.6 Hz, 2H), 1.13 (t, J=7.1 Hz, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.7, 130.6, 126.4, 100.6, 62.8, 42.0, 15.2. HRMS (+ESI): Calculated: 188.1281 (C.sub.9H.sub.18NO.sub.3). Observed: 188.1278.
##STR00159##
[0828] 1-acryloylpiperidine-4-carbonitrile (DKM 3-11). Following General Procedure A starting from piperidine-4-carbonitrile (329 mg, 3.0 mmol), product was obtained after silica gel chromatography (30% to 70% ethyl acetate in hexanes) in 48% yield as a colorless oil (234 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.49 (dd, J=10.6, 16.8 Hz, 1H), 6.19 (d, J=1.9, 16.8 Hz, 1H), 5.64 (dd, J=1.9, 10.6 Hz, 1H), 3.77-3.46 (m, 4H), 2.88-2.82 (sept, J=3.9 Hz, 1H), 1.90-1.73 (m, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.4, 128.3, 127.3, 120.8, 43.8, 39.9, 29.1, 28.1, 26.3. HRMS (+ESI): Calculated: 165.1022 (C.sub.9H.sub.13N.sub.2O). Observed: 165.1020.
##STR00160##
[0829] N-(3-(methylthio)propyl)acrylamide (DKM 3-12). Following General Procedure A starting from 3-(methylthio)propylamine (313 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 60% ethyl acetate in hexanes) in 69% yield as a colorless oil (328 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.79 (s, 1H), 6.19 (dd, J=2.2, 17.0 Hz, 1H), 6.11 (dd, J=9.6, 17.0 Hz, 1H), 5.55 (dd, J=2.2, 9.6 Hz, 1H), 3.35 (q, J=6.5 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.02 (s, 3H), 1.78 (quint, J=7.0 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 131.0, 126.1, 38.6, 31.6, 28.6, 15.4. HRMS (+ESI): Calculated: 160.0791 (C.sub.7H.sub.14NOS). Observed: 160.0788.
##STR00161##
[0830] N-(cyclohexylmethyl)acrylamide (DKM 3-13). Following General Procedure A starting from cyclohexanemethylamine (331 mg, 2.9 mmol), product was obtained after silica gel chromatography (10% to 50% ethyl acetate in hexanes) in 67% yield as a pale yellow solid (330 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.51 (s, 1H), 6.22 (dd, J=2.5, 17.0 Hz, 1H) 6.15 (dd, J=9.3, 17.0 Hz, 1H), 5.55 (dd, J=2.5, 9.3 Hz, 1H), 3.11 (t, J=6.5 Hz, 2H), 1.70-1.58 (m, 5H), 1.51-1.40 (m, 1H), 1.22-1.04 (m, 3H), 0.93-0.83 (m, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 131.2, 125.9, 45.9, 38.0, 30.9, 26.4, 25.8. HRMS (+ESI): Calculated: 168.1383 (C.sub.10H.sub.18NO). Observed: 168.1380.
##STR00162##
[0831] 1-(4-(4-acetylphenyl)piperazin-1-yl)prop-2-en-1-one (DKM 3-29). Following General Procedure A starting from 4-piperazinoacetophenone (607 mg, 3.0 mmol), product was obtained after silica gel chromatography (50% to 85% ethyl acetate in hexanes) in 65% yield as a yellow solid (496 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.79 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.54 (dd, J=10.5, 16.8 Hz, 1H), 6.25 (dd, J=1.9, 16.8 Hz, 1H), 5.66 (dd, J=1.9, 10.5 Hz, 1H), 3.75 (s, 2H), 3.66 (s, 2H), 3.31-3.29 (m, 4H), 2.42 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 196.3, 165.2, 153.4, 130.2, 128.3, 127.9, 127.0, 113.5, 47.3, 47.0, 45.0, 41.2, 26.0. HRMS (+ESI): Calculated: 259.1441 (C.sub.15H.sub.19N.sub.2O.sub.2). Observed: 259.1436.
##STR00163##
[0832] N-(4-(4-chlorophenoxy)phenyl)acrylamide (DKM 3-30). Following General Procedure A starting from 4-(4-chlorophenoxy)aniline (440 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 30% ethyl acetate in hexanes) in 33% yield as a white solid (180 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.00 (s, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.29-7.25 (m, 2H), 6.96-6.88 (m, 4H), 6.43 (dd, J=1.4, 16.9 Hz, 1H), 6.30 (dd, J=10.1, 16.9 Hz, 1H), 5.75 (dd, J=1.4, 10.1 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3): 163.9, 156.2, 153.4, 133.7, 131.2, 129.8, 128.2, 128.0, 122.1, 119.8, 119.7. HRMS (+ESI): Calculated: 272.0484 (C.sub.15H.sub.11NO.sub.2Cl). Observed: 272.0479.
##STR00164##
[0833] N-(4-fluorophenyl)acrylamide (DKM 3-31). Following General Procedure A starting from 4-fluoroaniline (239 mg, 2.2 mmol), product was obtained after silica gel chromatography (20% to 30% ethyl acetate in hexanes) in 16% yield as a white solid (56 mg). .sup.1H NMR (600 MHz, MeOD): 7.64-7.60 (m, 2H), 7.07-7.03 (m, 2H), 6.41 (dd, J=9.8, 17.0 Hz, 1H), 6.35 (dd, J=2.1, 17.0 Hz, 1H), 5.76 (dd, J=2.1, 9.8 Hz, 1H). .sup.13C NMR (150 MHz, MeOD): 166.0, 161.56, 160.0, 135.93, 135.91, 132.3, 127.8, 123.2, 123.1, 116.4, 116.2. HRMS (ESI): Calculated: 164.0517 (C.sub.9H.sub.7NOC). Observed: 164.0517.
##STR00165##
[0834] N-(sec-butyl)acrylamide (DKM 3-32). Following General Procedure A starting from sec-butylamine (222 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 74% yield as a yellow oil (287 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.56 (d, J=5.6 Hz, 1H), 6.17 (s, 1H), 6.16 (d, J=3.5 Hz, 1H), 5.51 (dd, J=4.3, 7.6 Hz, 1H), 3.93-3.83 (m, 1H), 1.47-1.36 (m, 2H), 1.06 (d, J=6.6 Hz, 3H), 0.82 (t, J=7.5 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.2, 131.4, 125.6, 46.6, 29.5, 20.2, 10.4. HRMS (+ESI): Calculated: 128.1070 (C.sub.7H.sub.14NO). Observed: 128.1069.
##STR00166##
[0835] 1-(4-(4-methoxyphenyl)piperazin-1-yl)prop-2-en-1-one (DKM 3-36). Following General Procedure A starting from 1-(4-methoxyphenyl)piperazine (388 mg, 2.0 mmol), product was obtained after silica gel chromatography (20% to 80% ethyl acetate in hexanes) in 29% yield as a white solid (143 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.87-6.79 (m, 4H), 6.57 (dd, J=10.5, 16.8 Hz, 1H), 6.28 (dd, J=1.9, 16.8 Hz, 1H), 5.68 (dd, J=1.9, 10.5 Hz, 1H), 3.79 (s, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 3.01 (t, J=5.1 Hz, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.2, 154.3, 145.1, 128.0, 127.3, 118.8, 114.4, 55.4, 51.3, 50.7, 45.8, 41.9. HRMS (+ESI): Calculated: 247.1441 (C.sub.14H.sub.19N.sub.2O.sub.2). Observed: 247.1443.
##STR00167##
[0836] N-tritylacrylamide (DKM 3-41). Following General Procedure A starting from triphenylmethylamine (386 mg, 1.5 mmol), product was obtained after silica gel chromatography (5% to 30% ethyl acetate in hexanes) in 74% yield as a white solid (346 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.38-7.27 (m, 15H), 6.83 (s, 1H), 6.28-6.26 (m, 2H), 5.66 (dd, J=3.9, 7.2 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.6, 144.6, 131.5, 128.8, 128.1, 127.2, 127.1, 70.7. HRMS (+ESI): Calculated: 314.1539 (C.sub.22H.sub.20NO). Observed: 314.1542.
##STR00168##
[0837] (E)-N-(3,7-dimethylocta-2,6-dien-1-yl)acrylamide (DKM 3-42). Following General Procedure A starting from geranylamine (462 mg, 3.0 mmol), product was obtained after silica gel chromatography (10% to 40% ethyl acetate in hexanes) in 23% yield as a colorless oil (141 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.25 (dd, J=1.5, 17.0 Hz, 1H), 6.09 (dd, J=10.2, 17.0 Hz, 1H), 5.83 (s, 1H), 5.59 (dd, J=1.5, 10.2 Hz), 5.22-5.18 (m, 1H), 5.07-5.03 (m, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.09-2.03 (m, 2H), 2.00-1.97 (m, 2H), 1.65 (s, 6H), 1.57 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.5, 140.2, 131.8, 131.0, 126.2, 123.9, 119.7, 39.6, 37.6, 265, 25.8, 17.8, 16.4. HRMS (+ESI): Calculated: 208.1696 (C.sub.13H.sub.22NO). Observed: 208.1697.
##STR00169##
[0838] N-(benzo[d][1,3]dioxol-5-ylmethyl)acrylamide (DKM 3-43). Following General Procedure A starting from piperonylamine (312 mg, 2.1 mmol), product was obtained after silica gel chromatography (20% to 50% ethyl acetate in hexanes) in 74% yield as a white solid (315 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.78 (s, 1H), 6.71 (s, 1H), 6.68 (s, 2H), 6.22 (dd, J=1.9, 17.0 Hz, 1H), 6.13 (dd, J=9.9, 17.0 Hz, 1H), 5.87 (s, 2H), 5.58 (dd, J=1.9, 9.9 Hz, 1H), 4.30 (d, J=5.8 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.7, 147.8, 146.9, 132.0, 130.8, 126.6, 121.1, 108.4, 108.2, 101.0, 43.4. HRMS (+ESI): Calculated: 206.0812 (C.sub.11H.sub.12NO.sub.3). Observed: 206.0808.
##STR00170##
[0839] N-decylacrylamide (TRH 1-12). Following General Procedure A starting from decylamine (479 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 40% ethyl acetate in hexanes) in 26% yield as a white solid (163 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.54 (s, 1H), 6.21 (dd, J=2.0, 16.9 Hz, 1H) 6.13 (dd, J=9.7, 16.9 Hz, 1H), 5.55 (dd, J=2.0, 9.7 Hz, 1H), 3.25 (q, J=6.7 Hz, 2H), 1.50-1.45 (m, 2H), 1.29-1.20 (m, 14H), 0.83 (t, J=6.7 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 131.2, 125.9, 71.9, 39.7, 31.9, 29.6, 29.6, 29.38, 29.35, 27.0, 22.7, 14.1. HRMS (+ESI): Calculated: 212.2009 (C.sub.13H.sub.26NO). Observed: 212.2009.
##STR00171##
[0840] N-(2,4-dimethoxybenzyl)acrylamide (TRH 1-13). Following General Procedure A starting from 2,4-dimethoxybenzylamine (514 mg, 3.0 mmol), product was obtained after silica gel chromatography (20% to 60% ethyl acetate in hexanes) in 11% yield as a white solid (73 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.17 (d, J=8.1 Hz, 1H), 6.43-6.39 (m, 2H), 6.26-6.22 (m, 2H), 6.07 (dd, J=10.7, 17.0 Hz, 1H), 5.57 (dd, J=1.4, 10.7 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.2, 160.6, 158.6, 131.1, 130.7, 126.2, 118.7, 104.0, 98.6, 55.5, 55.4, 39.0. HRMS (+ESI): Calculated: 222.1125 (C.sub.12H.sub.16NO.sub.3). Observed: 222.1124.
##STR00172##
[0841] N-Phenylacrylamide (TRH 1-19). Following General Procedure A starting from aniline (277 mg, 3.0 mmol), product was obtained after recrystallization from a 1:20 ethyl acetate:hexanes mixture in 46% yield as a white solid (200 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.59 (s, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.30 (t, J=7.9 Hz, 2H), 7.11 (t, J=7.4 Hz, 1H), 6.44-6.33 (m, 2H), 5.70 (dd, J=2.8, 8.9 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.3, 138.0, 131.4, 129.0, 127.7, 124.6, 120.5. HRMS (+ESI): Calculated: 148.0757 (C.sub.9H.sub.10NO). Observed: 148.0754.
##STR00173##
[0842] N-(1-phenylethyl)acrylamide (TRH 1-20). Following General Procedure A starting from 1-phenylethan-1-amine (387 mg, 3.0 mmol), product was obtained after silica gel chromatography (5% to 20% ethyl acetate in hexanes) in 46% yield as a white solid (315 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.61 (d, J=7.8 Hz, 1H) 7.37-7.24 (m, 5H), 6.33-6.24 (m, 2H), 5.57 (dd, J=4.8, 7.9 Hz, 1H), 5.20 (quint, J=7.2 Hz, 1H), 1.49 (d, J=7.0 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.0, 143.4, 131.1, 128.4, 126.9, 126.0, 126.0, 48.7, 21.8. HRMS (+ESI): Calculated: 176.1070 (C.sub.11H.sub.14NO). Observed: 176.1067.
##STR00174##
[0843] 1-(2-ethylpiperidin-1-yl)prop-2-en-1-one (TRH 1-27). Following General Procedure A starting from 2-ethylpiperidine (238 mg, 2.0 mmol), product was obtained after silica gel chromatography (5% to 30% ethyl acetate in hexanes) in 72% yield as a white solid (253 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.41 (dd, J=10.6, 16.7 Hz, 1H), 6.03 (d, J=16.4 Hz, 1H), 5.43 (dd, J=2.0, 10.6 Hz, 1H), 4.54-4.34 (m, 1H), 3.77-3.58 (m, 1H), 2.93-2.42 (m, 1H), 1.61-1.06 (m, 8H), 0.66 (t, J=7.5 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 130.0, 129.1, 128.4, 126.6, 54.4, 49.6, 41.1, 36.5, 28.8, 27.5, 26.2, 25.2, 23.0, 22.1, 18.8, 10.4. HRMS (+ESI): Calculated: 168.1383 (C.sub.10H.sub.18NO). Observed: 168.1380.
##STR00175##
[0844] N-(4-methoxyphenyl)acrylamide (TRH 1-32). Following General Procedure A starting from p-anisidine (258 mg, 2.0 mmol), product was obtained after silica gel chromatography (10% to 50% ethyl acetate in hexanes) in 58% yield as a white solid (216 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.94 (s, 1H), 7.48 (d, J=9.1 Hz, 2H), 6.78 (d, J=9.1 Hz, 2H), 6.34 (d, J=5.6 Hz, 2H), 5.61 (t, J=5.9 Hz, 1H), 3.73 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.3, 156.4, 131.4, 131.1, 127, 122.3, 114.0, 55.4. HRMS (+ESI): Calculated: 178.0863 (C.sub.10H.sub.12O.sub.2N). Observed: 178.0859.
##STR00176##
[0845] N-(2-methylbenzyl)acrylamide (TRH 1-54). Following General Procedure A starting from 2-methylbenzylamine (240 mg, 2.0 mmol), product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 73% yield as a white solid (257 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.26-7.12 (m, 4H), 6.66 (s, 1H), 6.24-6.12 (m, 2H), 5.57 (dd, J=9.5, 2.2 Hz, 1H), 4.39 (d, J=5.4 Hz, 2H), 2.27 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.6, 136.3, 135.7, 130.7, 130.4, 128.4, 127.6, 126.4, 126.1, 41.6, 19.0. HRMS (+ESI): Calculated: 176.1070 (C.sub.11H.sub.14NO). Observed: 176.1067.
##STR00177##
[0846] Ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (DKM 2-52). Following General Procedure B starting from ethyl 1-piperazinecarboxylate (477 mg, 3.0 mmol) product was obtained after silica gel chromatography (0% to 80% ethyl acetate in hexanes) in 80% yield as a pale yellow oil (569 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 4.04-3.99 (m, 4H), 3.48-3.34 (m, 8H), 1.14 (t, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.1, 155.0, 61.5, 45.8, 43.3, 43.0, 41.7, 40.7, 14.4. HRMS (+SI): Calculated: 235.0844 (C.sub.9H.sub.16ClN.sub.2O.sub.3). Observed: 235.0842.
##STR00178##
[0847] N-benzyl-2-chloroacetamide (DKM 2-67). Following General Procedure B starting from benzylamine (430 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 70% yield as a white solid (416 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.40-7.31 (m, 5H), 7.08 (s, 1s), 4.50 (d, J=5.8 Hz, 2H), 4.09 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 166.0, 137.4, 128.8, 127.8, 43.8, 42.6. HRMS (ESI): Calculated: 182.0378 (C.sub.9H.sub.9NOCl). Observed: 182.0378.
##STR00179##
[0848] 2-Chloro-1-(pyrrolidin-1-yl)ethan-1-one (DKM 2-71). Following General Procedure B starting from pyrrolidine (511 mg, 3.0 mmol) product was obtained after silica gel chromatography (0% to 30% ethyl acetate in hexanes) in 83% yield as a clear oil (368 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 3.94 (s, 2H), 3.41 (quint, J=7.2 Hz, 4H), 1.91 (quint, J=6.3 Hz, 2H), 1.80 (quint, J=6.6 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): 164.7, 46.5, 46.3, 42.1, 26.1, 24.1. HRMS (+ESI): Calculated: 170.0343 (C.sub.6H.sub.10ClNNaO). Observed: 170.0343.
##STR00180##
[0849] 2-Chloro-N-decylacetamide (DKM 2-72). Following General Procedure B starting from decylamine (472 mg, 3.0 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 81% yield as a white solid (555 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.71 (s, 1H), 3.97 (s, 2H), 3.22 (q, J=6.8 Hz, 2H), 1.51-1.44 (m, 2H), 1.24-1.19 (m, 14H), 0.81 (t, J=6.8 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 42.7, 39.9, 31.9, 29.5, 29.29, 29.27, 29.22, 26.8, 22.6, 14.1. HRMS (+ESI): Calculated: 234.1619 (C.sub.12H.sub.25ClNO). Observed: 234.1618.
##STR00181##
[0850] 2-chloro-N-(4-methoxybenzyl)acetamide (DKM 2-83). Following General Procedure B starting from 4-methoxybenzylamine (430 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 40% ethyl acetate in hexanes) in 55% yield as an off-white solid (369 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 6.91 (s, 1H), 6.86 (d, J=8.6 Hz, 2H), 4.40 (d, J=5.7 Hz, 2H), 4.05 (s, 2H), 3.78 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.9, 159.2, 129.4, 129.2, 114.2, 55.3, 43.4, 42.7. HRMS (+ESI): Calculated: 214.0629 (C.sub.10H.sub.13ClNO.sub.2). Observed: 214.0627.
##STR00182##
[0851] 2-chloro-N-(3,4-dimethoxybenzyl)acetamide (DKM 2-93). Following General Procedure B starting from 3,4-dimethoxybenzylamine (517 mg, 3.1 mmol) product was obtained after silica gel chromatography (0% to 50% ethyl acetate in hexanes) in 55% yield as an off-white solid (416 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.97 (s, 1H), 6.77 (m, 3H), 4.35 (d, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 165.8, 149.0, 148.5, 129.8, 120.1, 111.13, 111.07, 55.83, 55.79, 43.6, 42.5. HRMS (+ESI): Calculated: 266.0554 (C.sub.11H.sub.14NO.sub.3ClNa). Observed: 266.0553.
##STR00183##
[0852] 2-Chloro-N-methyl-N-propylacetamide (TRH 1-53). Following General Procedure B starting from N-methylpropylamine (147 mg, 2.0 mmol) product was obtained after silica gel chromatography (30% to 40% ethyl acetate in hexanes) in 64% yield as a white solid (191 mg). .sup.1H NMR (46:54 rotamer ratio, asterisks denote minor peaks, 400 MHz, CDCl.sub.3): 4.03* (s, 2H), 4.02 (s, 2H), 3.28* (t, J=7.4 Hz, 2H), 3.23 (t, J=7.5 Hz, 2H), 3.00 (s, 3H), 2.88* (s, 3H), 1.64-1.56* (m, 2H), 1.53-1.46 (m, 2H), 0.87* (t, J=7.5 Hz, 3H), 0.83 (t, J=7.5 Hz, 3H). .sup.13C NMR (asterisks denote minor rotamer peaks, 100 MHz, CDCl.sub.3): 166.4, 166.3*, 51.9*, 49.8, 41.5, 40.9*, 35.6, 33.6*, 21.6*, 20.1, 11.1, 11.0*. HRMS (+ESI): Calculated: 150.0680 (C.sub.6H.sub.13NOCl). Observed: 150.0678.
[0853] Synthesis and Characterization of YP 1-46
##STR00184##
[0854] N-(4-(4-methoxyphenoxy)phenyl)acrylamide (YP-1-46). To a solution of 4-methoxyphenol (622 mg, 5 mmol) in DMF (2 mL) was added potassium carbonate (1.38 g, 10 mmol). After 10 minutes of stirring, 1-fluoro-4-nitrobenzene (0.43 mL, 4 mmol) was added and the reaction was stirred overnight. As the reaction was not complete by TLC after 21 hours, the reaction was heated to 90 degrees for 1 hour at which point the reaction was found to be complete. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried with magnesium sulfate and concentrated to give 1.07 g of crude 1-methox-4-(nitrophenoxy)benzene as a yellow solid that was used without further purification.
[0855] To a stirring solution of the resulting crude (490 mg, 2 mmol) and 10% palladium on activated charcoal (49 mg) in methanol (4 mL) was added triethylsilane (2.33 g, 20 mmol) dropwise through an addition funnel under a nitrogen-filled balloon. After 30 min, the mixture was filtered through celite and the solvent was removed in vacuo. Without further purification, the obtained crude product was dissolved in DCM (10 mL) and the resultant solution was cooled to 0 C. To the solution was added acryloyl chloride (217 mg, 2.4 mmol) followed by triethylamine (243 mg, 2.4 mmol). The solution was allowed to warm to room temperature after 20 min and stirred overnight. The solution was washed two times with brine and the crude product was purified via silica gel chromatography (30% to 70% ethyl acetate in hexanes) to afford 161 mg of the product as a white solid (33% yield over 3 steps). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.94 (s, 1H), 7.50-7.48 (m, 2H), 6.96-6.92 (m, 2H), 6.90-6.84 (m, 4H), 6.40 (dd, J=1.6, 16.8 Hz, 1H), 6.27 (dd, J=10.1, 16.8 Hz, 1H), (dd, J=1.6, 10.1 Hz, 1H), 3.79 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): 163.8, 155.8, 155.1, 150.4, 132.6, 131.1, 127.6, 121.9, 120.5, 118.2, 114.9, 55.7. HRMS (+ESI): Calculated: 270.1125 (C.sub.16H.sub.16NO.sub.3). Observed: 270.1125.
[0856] Synthesis and Characterization of AMR 1-125
##STR00185##
N-(4-(4-(tert-butyl)phenoxy)phenyl)acrylamide (AMR 1-125)
[0857] ##STR00186##
[0858] An oven dried round bottom flask was charged with a magnetic stir bar, copper (I) iodide (38 mg, 0.2 mmol), N-Boc-4-hydroxyaniline (502 mg, 2.4 mmol), potassium carbonate (552.8 mg, 2 mmol), and crushed 4 angstrom sieves (200 mg). The flask was evacuated and filled with nitrogen twice. Under nitrogen, 1-Bromo-4-tert-butylbenzene (346 uL, 2 mmol) and N,N-Dimethyl-1,2-cyclohexanediamine (62 uL, 0.2 mmol) were added along with 2 mL of butyronitrile. The flask was allowed to react at 70 C for 24 hours. At the end of the reaction, the mixture was diluted with CH.sub.2Cl.sub.2 and rinsed through Celite to remove inorganic salts and other solids. The crude reaction mixture was purified using column chromatograph (10% ethyl acetate in hexanes). The product was a yellow oil (yield 31%).
##STR00187##
[0859] An oven dried round bottom flask was charged with the amine starting material (154.2 mg, 0.6 mmol) along with dry CH.sub.2C.sub.2 and allowed to cool to OC. Acryloyl chloride (69.4 mg, 0.8 mmol) was then added to the flask, followed by triethylamine (196 uL, 1.4 mmol), and the reaction was allowed to come to room temperature overnight. At the end of the reaction, the mixture was washed with brine and then purified using column chromatography (10% ethyl acetate in hexanes). The product was a waxy, white solid (yield <10%). .sup.1H NMR (900 MHz, CDCl.sub.3): 7.51 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 6.97 (m, 2H), 6.90 (m, 2H), 6.42 (d, 1H, J=16.8 Hz), 6.22 (dd, 1H, J=16.8, 10.3 Hz), 5.75 (m, 1H), 1.3 (s, 9H). .sup.13C NMR (900 MHz, CDCl.sub.3): 163.4, 155.1, 154.2, 146.3, 133.0, 131.2, 127.9, 126.7, 121.7, 119.5, 118.3, 34.5, 31.7, 29.9. HRMS (+ESI): Calculated: 296.1645 (C.sub.19H.sub.21NO.sub.2) Observed: 296.1643.
[0860] General Procedure Synthetic Scheme for Derivatives
##STR00188##
[0861] Derivatives being Synthesized
##STR00189##
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[0863] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.