CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 62/149,292, filed April 17, 2015, which is incorporated herein by reference in its entirety and for all purposes.

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER

PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE

[0002] The Sequence Listing written in file 48518-501001WO_ST25.TXT, created on April 14, 2016, 8,800 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0003] Centrioles play a role in cytokinesis. Polo-like kinase (PLK4) is one regulator of centriole biogenesis. PLK4 overexpression may trigger centriole overduplication which can lead to cancer. PLK4 shares active site homology with other kinases, including Aurora kinases. Thus, there is a need in art for selective kinase inhibitors for PLK4. Described herein are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

[0004] Provided herein, inter alia, are compounds and methods of using the compounds for inhibiting PLK4 and cancer.

[0005] In one aspect are compounds having the formula:

L ¹ is a bond, -C(O)-, -C(0)0-, -0-, -S-, -NR ¹³ -, -C(0)NR ¹³ -, -NR ¹ C(0)-, -S(0) ₂ -,

-S(0)NR ¹³ -, 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 ¹ is hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , -NR ^1A R ^1B , -C(0)OR ^1A , -C(0) R ^1A R ^1B , -NO ₂ , -SR ^1A , -S(0)„iR ^1A , -S(0)„iOR ^1A , -S(0)„i R ^1A R ^1B ,

- HNR ^1A R ^1B , -O R ^1A R ^1B , - HC(0) HNR ^1A R ^1B , 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 ² is hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A ,

- R ^2A R ^2B , -C(0)OR ^2A , -C(0) R ^2A R ^2B , -N0 ₂ , -SR ^2A , -S(0)„ ₂ R ^2A , -S(0) _I , ₂ OR ^2A ,

-S(0) _I , ₂ R ^2A R ^2B , - HNR ^2A R ^2B , -O R ^2A R ^2B , - HC(0) HNR ^2A R ^2B , 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 ³ is hydrogen, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ , -CN, -COR ^A , - OR ^A , -NR ^A R ^B , -C(0)OR ^A , -C(0)NR ^A R ^B , -N0 ₂ , -SR ^A , -S(0)„ ₃ R ^A ,

-S(0)„ ₃ OR ^A , -S(0)„ ₃ NR ^A R ^B , -NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , 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 ⁴ is hydrogen, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , - CN, -COR ^4A , -OR ^4A , -NR ^4A R ^4B , -C(0)OR ^4A , -C(0)NR ^4A R ^4B , -N0 ₂ , -SR ^4A , -S(0)„ ₄ R ^4A ,

-S(0)„ ₄ OR ^4A , -S(0)„ ₄ NR ^4A R ^4B , -NHNR ^4A R ^4B , -ONR ^4A R ^4B , -NHC(0)NHNR ^4A R ^4B , 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, wherein R ³ and R ⁴ are optionally combined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ⁵ is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^5A , -OR ^5A , -NR ^5A R ^5B ,

-C(0)OR ^5A , -C(0)NR ^5A R ^5B , -NO2, -SR ^5A , -S(0)„ ₅ R ^5A , -S(0)„ ₅ OR ^5A , -S(0)„ ₅ NR ^5A R ^5B ,

-NHNR ^5A R ^5B , -ONR ^5A R ^5B , -NHC(0)NHNR ^5A R ^5B , 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 ⁶ is hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -CHO, -OR ^6A ,

-NR ^6A R ^6B , -C(0)OR ^6A , -C(0)NR ^6A R ^6B , -N0 ₂ , -SR ^6A , -S(0)„ ₆ R ^6A , -S(0)„ ₆ OR ^6A ,

-S(0)„ ₆ NR ^6A R ^6B , -NHNR ^6A R ^6B , -ONR ^6A R ^6B , -NHC(0)NHNR ^6A R ^6B , 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. They symbols nl, n2, n3, n4, n5, and n6 are independently 1 or 2. The symbol zl is 1, 2, 3, or 4. R ^1A , R ^1B , R ^2A , R ^2B , R ^3A , R ^3B , R ^4A , R ^4B , R ^5A , R ^5B , R ^6A , R ^6B , and R ¹³ are independently hydrogen, oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ ,

-COOH, -CO H ₂ , -NO ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , 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.

[0006] Also provided herein are compounds having the formula:

[0007] In a first aspect of formula (II), L ¹ is a bond, -C(O)-, -C(0)0-, -0-, -S-, - R ¹³ -, -C(0) R ¹³ -, - R ¹ C(0)-, -S(0) ₂ -, -S(0) R ¹³ -, 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. L ² is independently a bond, -C(O)-, -C(0)0-, -0-,

-S-, -NR ¹⁴ -, -C(0)NR ¹⁴ -, -NR ¹⁴ C(0)-, -S(O)-, -S(0) ₂ -, -S(0)NR ¹⁴ -, 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 ¹ is hydrogen, halogen, -N , -CF ₃ ,

-CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , -NR ^1A R ^1B , -C(0)OR ^1A , -C(0)NR ^1A R ^1B , -N0 ₂ , -SR ^1A , - S(0)„iR ^1A , -S(0)„iOR ^1A , -S(0)„iNR ^1A R ^1B , -NHNR ^1A R ^1B , -ONR ^1A R ^1B , -NHC(0)NHNR ^1A R ^1B , 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 ² is hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A , -NR ^2A R ^2B , -C(0)OR ^2A , -C(0)NR ^2A R ^2B , -N0 ₂ , -SR ^2A , -S(0)„ ₂ R ^2A , -S(0)„ ₂ 0R ^2A , -S(0) _I , ₂ NR ^2A R ^2B , -NHNR ^2A R ^2B , -ONR ^2A R ^2B ,

-NHC(0)NHNR ^2A R ^2B , 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 ³ is halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^A , -OR ^A , -NR ^A R ^B , -C(0)OR ^A ,

-C(0)NR ^A R ^B , -NO ₂ , -SR ^A , -S(0)„ ₃ R ^A , -S(0)„ ₃ OR ^A , -S(0)„ ₃ NR ^A R ^B , -NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , 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 ⁴ is halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^4A , -OR ^4A , - R ^4A R ^4B , -C(0)OR ^4A ,

-C(0) R ^4A R ^4B , -NO ₂ , -SR ^4A , -S(0)„ ₄ R ^4A , -S(0)„ ₄ OR ^4A , -S(0)„ ₄ R ^4A R ^4B , - HNR ^4A R ^4B , -O R ^4A R ^4B , - HC(0) HNR ^4A R ^4B , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ⁷ is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^7A , -OR ^7A , -NR ^7A R ^7B , -C(0)OR ^7A ,

-C(0)NR ^7A R ^7B , -NO ₂ , -SR ^7A , -S(0)„ ₇ R ^7A , -S(0)„ ₇ OR ^7A , -S(0)„ ₇ NR ^7A R ^7B , -NHNR ^7A R ^7B , -ONR ^7A R ^7B , -NHC(0)NHNR ^7A R ^7B , -I^-R ⁶ , 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 ⁶ is hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -CHO, -OR ^6A , -NR ^6A R ^6B , -C(0)OR ^6A , -C(0)NR ^6A R ^6B , -NO ₂ , -SR ^6A , -S(0)„ ₆ R ^6A , -S(0)„ ₆ OR ^6A , -S(0)„ ₆ NR ^6A R ^6B ,

-NHNR ^6A R ^6B , -ONR ^6A R ^6B , -NHC(0)NHNR ^6A R ^6B , 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. The symbols nl, n2, n3, n4, n6, and n7 are independently 1 or 2. The symbol z2 is 1, 2, 3, 4, or 5.

_R 1A _R m _R 2A _R 2B _R 3A _R3 B _R 4A _R 4B _{; R} 6A _R 6B _{; R} 7A _R 7B _R 1 ₃ ^ _R 14 ^ _{INDEPENDENTLY} hydrogen, oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH,

-S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , - NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , 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.

[0008] In a second aspect of formula (II), compounds are provided in which L ¹ is a bond,

-C(O)-, -C(0)0-, -0-, -S-, -NR ¹³ -, -C(0)NR ¹³ -, -NR ¹ C(0)-, -S(0) ₂ -, -S(0)NR ¹³ -, 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. L ² is independently a bond, -C(O)-, -

C(0)0-, -0-, -S-, -NR ¹⁴ -, -C(0)NR ¹⁴ -, -NR ¹⁴ C(0)-, -S(0) ₂ -, -S(0)NR ¹⁴ -, 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 ¹ is hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , - R ^1A R ^1B , -C(0)OR ^1A , -C(0) R ^1A R ^1B , -NO ₂ , -SR ^1A , -S(0)„iR ^1A , -S(0)„iOR ^1A , -S(0)„i R ^1A R ^1B , - HNR ^1A R ^1B , -O R ^1A R ^1B ,

- HC(0) HNR ^1A R ^1B , 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 ² is hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI3, -CN, -COR ^2A , -OR ^2A , -NR ^2A R ^2B ,

-C(0)OR ^2A , -C(0)NR ^2A R ^2B , -NO ₂ , -SR ^2A , -S(0)„ ₂ R ^2A , -S(0) _I , ₂ OR ^2A , -S(0) _I , ₂ NR ^2A R ^2B ,

-NHNR ^2A R ^2B , -ONR ^2A R ^2B , -NHC(0)NHNR ^2A R ^2B , 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 ³ is -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^A , -OR ^A , -NR ^A R ^B , -C(0)OR ^A ,

-C(0)NR ^A R ^B , -NO ₂ , -SR ^A , -S(0)„ ₃ R ^A , -S(0)„ ₃ OR ^A , -S(0)„ ₃ NR ^A R ^B , -NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ⁴ is hydrogen, halogen, -N ₃ ,

-CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^4A , -OR ^4A , -NR ^4A R ^4B , -C(0)OR ^4A , -C(0)NR ^4A R ^4B , -N0 ₂ , -SR ^4A , -S(0) _n4 R ^4A , -S(0) _n4 OR ^4A , -S(0) _n4 NR ^4A R ^4B , -NHNR ^4A R ^4B , -ONR ^4A R ^4B ,

-NHC(0)NHNR ^4A R ^4B , 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 ⁷ is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^7A ,

-OR ^7A , -NR ^7A R ^7B , -C(0)OR ^7A , -C(0)NR ^7A R ^7B , -N0 ₂ , -SR ^7A , -S(0)„ ₇ R ^7A , -S(0)„ ₇ OR ^7A ,

-S(0)„ ₇ NR ^7A R ^7B , -NHNR ^7A R ^7B , -ONR ^7A R ^7B , -NHC(0)NHNR ^7A R ^7B , -I^-R ⁶ , 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 ⁶ is hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -CHO, -OR ^6A , -NR ^6A R ^6B , -C(0)OR ^6A , -C(0)NR ^6A R ^6B , -N0 ₂ , -SR ^6A , -S(0)„ ₆ R ^6A , -S(0)„ ₆ OR ^6A , -S(0)„ ₆ NR ^6A R ^6B , -NHNR ^6A R ^6B , -ONR ^6A R ^6B , -NHC(0)NHNR ^6A R ^6B , 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. The symbols nl, n2, n3, n4, n6, and n7 are independently 1 or 2. The symbol z2 is 1, 2, 3, 4, or 5. R ^1A , R ^1B , R ^2A , R ^2B , R ^A , R ^B , R ^4A , R ^4B , R ^6A , R ^6B , R ^7A ,

R 7B , R 13 , and R 14 are independently hydrogen, oxo, halogen, -CF ₃ , -CN, -OH,

-NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , 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. [0009] Provided herein are pharmaceutical compositions that include a compound described herein and a pharmaceutically acceptable excipient.

[0010] Methods of inhibiting a PLK4 kinase are provided herein. In one aspect, is a method of inhibiting a PLK4 kinase by contacting the PLK4 kinase with a compound described herein and allowing the compound to bind to the PLK4 kinase, thereby inhibiting the PLK4 kinase. [0011] Methods of treating cancer in a subject in need thereof are also provided. In one aspect is a method of treating cancer in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound described herein. In another aspect is a method of treating basal cell carcinoma, medulloblastoma, pancreatic cancer, small cell lung cancer, gastric cancer, colon cancer, or chondrosarcoma in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound described herein. In another aspect, the method is a method of treating cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound having formula:

L ¹ is a bond, -C(O)-, -C(0)0-, -0-, -S-, - R ¹³ -, -C(0) R ¹³ -, - R ¹ C(0)-, -S(0) ₂ -, -S(0) R ¹³ -, 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. L ² is independently a bond, - C(O)-, -C(0)0-, -0-, -S-, -NR ¹⁴ -, -C(0)NR ¹⁴ -, -NR ¹⁴ C(0)-, -S(0) ₂ -, -S(0)NR ¹⁴ -, 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 ¹ is hydrogen, halogen,

-N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , -NR ^1A R ^1B , -C(0)OR ^1A , -C(0)NR ^1A R ^1B , -NO ₂ , -SR ^1A , -S(0)„iR ^1A , -S(0)„iOR ^1A , -S(0)„iNR ^1A R ^1B , -NHNR ^1A R ^1B , -ONR ^1A R ^1B ,

-NHC(0)NHNR ^1A R ^1B , 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 ² is hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A , - R ^2A R ^2B ,

-C(0)OR ^2A , -C(0) R ^2A R ^2B , -NO ₂ , -SR ^2A , -S(0)„ ₂ R ^2A , -S(0) _I , ₂ OR ^2A , -S(0) _I , ₂ R ^2A R ^2B ,

- HNR ^2A R ^2B , -O R ^2A R ^2B , - HC(0) HNR ^2A R ^2B , 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 ³ is halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^A , -OR ^A , -NR ^A R ^B ,

-C(0)OR ^A , -C(0)NR ^A R ^B , -NO ₂ , -SR ^A , -S(0)„ ₃ R ^A , -S(0)„ ₃ OR ^A , -S(0)„ ₃ NR ^A R ^B ,

-NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , 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 ⁴ is hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^4A , -OR ^4A ,

-NR ^4A R ^4B , -C(0)OR ^4A , -C(0)NR ^4A R ^4B , -N0 ₂ , -SR ^4A , -S(0)„ ₄ R ^4A , -S(0)„ ₄ OR ^4A ,

-S(0)„ ₄ NR ^4A R ^4B , -NHNR ^4A R ^4B , -ONR ^4A R ^4B , -NHC(0)NHNR ^4A R ^4B , 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 ⁷ is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , - CI ₃ , -CN, -COR ^7A , -OR ^7A , -NR ^7A R ^7B , -C(0)OR ^7A , -C(0)NR ^7A R ^7B , -N0 ₂ , -SR ^7A , -S(0)„ ₇ R ^7A , - S(0)„ ₇ OR ^7A , -S(0)„ ₇ NR ^7A R ^7B , -NHNR ^7A R ^7B , -ONR ^7A R ^7B , -NHC(0)NHNR ^7A R ^7B , -I^-R ⁶ , 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 ⁶ is hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -CHO, -OR ^6A , -NR ^6A R ^6B , -C(0)OR ^6A , -C(0)NR ^6A R ^6B , -NO2, -SR ^6A , -S(0)„ ₆ R ^6A , -S(0)„ ₆ OR ^6A , -S(0)„ ₆ NR ^6A R ^6B , -NHNR ^6A R ^6B , -ONR ^6A R ^6B ,

-NHC(0)NHNR ^6A R ^6B , 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. The symbols nl, n2, n3, n4, n6, and n7 are independently 1 or 2. The symbol z2 is 1, 2, 3, 4, or 5.

_R 1A _R m _R2 A _R2 B _R3 A _R3 B _R 4A _R 4B _{; R} 6A _R 6B _{; R} 7A _R 7B _R 13 ^ _R 14 ^ _{independently} hydrogen, oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ ,

-NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIGS. 1 A-1E. Centrinone is a selective Plk4 inhibitor that reversibly depletes centrioles from cells. (FIG. 1 A) Chemical structures, IQ values, and selectivities [Plk4 versus Aurora A/B; Ki(kinase)/Ki(Plk4)] of the centrinones and VX-680. (FIG. IB) Crystal structure of the centrinone-Plk4 kinase domain complex (highlighted aC helix). (FIG. 1C) Close-up of centrinone in the Plk4 active site. The aminopyrazole moiety of centrinone hydrogen bonds (clashes) with the main chain carbonyl of Glu 90 and the carbonyl and amide nitrogen of Cys 92. The 5-methoxy substituent (spheres) packs against the Met 91 side chain ( ^' stick and gray spheres). The benzylsulfone moiety {surface) wraps around Lys 41. (FIG. ID) HeLa cells 7 days after centrinone addition and 10 days after centrinone washout (insets 3.3X magnified). Scale bar, 10 μπι. Schematic shows progressive centrosome depletion following Plk4 inhibition. Bar graph shows the centrosome number distribution after centrinone addition and washout. (FIG. IE) γ-tubulin foci in NIH/3T3 cells induced to overexpress wild-type or centrinone-resistant (G95L) Plk4-GFP. Scale bar, 5 μιη. Data m D-E are mean +/- SD (N=3).

[0013] FIGS. 2A-2G. Transformed cells proliferate indefinitely in the absence of centrosomes. (FIG. 2 A) Proliferation curves of HeLa and NIH/3T3 cells immediately following addition of centrinone or DMSO (control). (FIG. 2B) Proliferation curves after chronic (>2 weeks) centrinone treatment (left), or after chronic centrinone treatment followed by drug washout for >2 weeks (right). (FIG. 2C) Proliferation curves after chronic (>2 weeks) centrinone treatment in cell lines with varying degrees of centrosome amplification. Numbers in parentheses are percent of cells exhibiting centrosome amplification in untreated population. Data in A-C are mean +/- SEM (N=3). (FIG. 2D) Gl+S and G2 durations measured in HeLa and NIH/3T3 cells co- expressing GFP-PCNA and H2B-RFP (see FIG. 10A-10D). Data are mean +/- SD. (FIG. 2E) Percentage of cells exhibiting mitotic defects measured in HeLa and NIH/3T3 cells co- expressing centrin-GFP and H2B-RFP (see FIGS. 11 A-l 1C). (FIG. 2F) Percentage of cells undergoing cell death in HeLa and NIH/3T3 cells, measured using a fluorescent caspase substrate. Data are mean +/- SD (N=2). (FIG. 2G) Graphs showing centrosome number distribution over time after centrinone washout from long-term (>2 weeks) treated HeLa, BT-549 and NlE-115-1 cells. The centrosome number distribution in untreated cells ("Pre" bars) is also shown for each cell line. Data are mean +/- SD (N=3). [0014] FIGS. 3A-3E. Centrosome loss triggers a p53-dependent arrest in normal cells. (FIG. 3 A) Centrosome number distribution {left; data are mean +/- SD; N=3) and proliferation {right, data are mean +/- SEM; N=3) of RPEl cells following centrinone addition. (FIG. 3B) {left) Centrosome number distribution in RPEl cells expressing WT or centrinone-resistant G95L (homozygous knock-in at the endogenous locus) Plk4. {right) Passaging assay on RPEl Plk4 G95L cells. Data are mean +/- SD {N=2). (FIG. 3C) Lineage analysis showing the percentage of RPEl cells with the indicated number of centrosomes arresting in each generation after centrinone addition {N=2). Cells co-expressing centrin-GFP and H2B-RFP were initially filmed in both GFP and RFP channels to count centrosomes and monitor mother cell mitosis. Daughter cell fate was subsequently tracked using RFP only. Arrest was the inability to enter mitosis within 48 hours of cell birth. (FIG. 3D) Western Blot of p53 and p21 in RPEl cells. (FIG. 3E) Western Blot of RPEl cells expressing control or p53 shRNA, and passaging assay of RPEl cells expressing control or p53 shRNA following centrinone addition. Data are mean +/- SD {N=2). [0015] FIGS. 4A-4G. The irreversible Gl arrest following centrosome loss occurs via an unidentified mechanism. (FIG. 4A) Western Blot for p53 phosphoepitopes associated with DNA damage in RPEl cells treated with centrinone or doxorubicin as a positive control. (FIG. 4B) Quantification of γ-Η2Α.Χ foci in RPEl nuclei. Data are mean +/- SD {N=3). (FIG. 4C) Western Blot of activated p38 in RPEl cells. (FIG. 4D) Passaging assay of RPEl cells expressing LATS 1/2 microRNA, following addition of centrinone. (FIG. 4E) Daughter cell fate in RPEl cells co-expressing centrin-GFP and H2B-RFP. Vertical bars represent measurements from individual daughter cells. Bar height is the time their mother spent in mitosis and color indicates arrest or division. Asterisks indicate chromosome mis segregation in the mother cell. Daughter cell fate following nocodazole treatment of mother cells with a normal 2-centrosome

complement {left) confirms existence of a mitotic duration sensor that arrests daughter cells if the mother cell spends more than -84 minutes (black dashed lines on all plots) in mitosis. (FIG. 4F) Western Blot of RPEl cells treated with centrinone or R7112. (FIG. 4G) Passaging assay of RPEl cells following addition (Day 0) and washout (Day 8) of centrinone or R7112. Data in FIG. 4D and FIG. 4G are mean +/- SD (N=2). [0016] FIGS. 5A-5C. CFI-400945 is a non-selective Plk4 inhibitor that does not deplete centrioles from cells. Treatment of HeLa cells with 50 or 100 nM CFI-400945 causes centrosome amplification, likely due to partial blockade of Plk4 autophosphorylation-mediated degradation (52). At these concentrations, CFI-400945-treated cells also become grossly multinuclear (see examples in A) and stop dividing, presumably due to Aurora B inhibition {18, 19). (FIG. 5A) Deconvolved wide-field images of HeLa cells treated for 3 days with DMSO, centrinone, centrinone-B, or CFI-400945. Cells were fixed and stained for γ-tubulin and Cepl92. Images are maximum intensity projections. Cell boundaries are outlined in gray. Insets are 3.4X magnified. Scale bar, 10 μπι. (FIG. 5B) Quantification of y-tubulin/Cepl92 foci from cells in Data are mean +/- SD (N=3). Results similar to those described in _^ 4 and B for HeLa cells were also observed in mouse NIH/3T3 fibroblasts as well as human breast (MDA-MB-231 and MDA- MB-468) and colon (HCT-116) carcinoma cells. (FIG. 5C) Western Blot of DLD-1 cells induced to overexpress full-length mouse Plk4-YFP (53), treated with the indicated centrinone or CFI- 400945 concentrations for 24 hours. In untreated cells, levels of overexpressed Plk4-YFP are limited by autophophorylation-induced degradation. Inhibition of Plk4 kinase activity leads to Plk4-YFP stabilization. At 250 nM CFI-400945, only slight Plk4-YFP stabilization is observed compared to the more substantial stabilization seen in the presence of 25 nM or 100 nM centrinone. [0017] FIGS. 6A-6E. Centrinone is a selective Plk4 inhibitor that depletes centrioles from cells. (FIG. 6A) Selection of VX-680 as the lead compound and selectivity design strategy. Inspection of a previously deposited structure of the Plk4 kinase domain bound to AMP-P P (PDB:3COK) revealed an uncommon residue (Met 91) in the hinge region connecting the two kinase domain lobes. Hinge interactions can account for 40-60% of the binding energy of certain classes of ATP-competitive kinase inhibitors (54), and this region has previously been successfully targeted to generate selective inhibitors (e.g. the Plkl inhibitor BI2356; 55).

Modeling of reported biochemical Plk4 inhibitors predicted that the Aurora kinase inhibitor VX- 680 would bind with its pyrimidine ring adjacent to Met 91. We hypothesized that selectivity for Plk4 could be introduced into this scaffold by adding substituents to the C5 ring position that would be accommodated by the flexible Met 91 of Plk4, but not by the bulkier tyrosine residues at the equivalent positions in human Aurora A/B/C. The image shown here was generated by superimposing the structure of human Aurora A bound to VX-680 (PDB:3E5A) over that of Plk4 bound to AMPP P (PDB:3COK). The C5 position of VX-680 (gray sphere), Tyr 212 of Aurora A (gray sticks and surface), and Met 91 of Plk4 (sticks) are highlighted. (FIG. 6B) Flowchart illustrating the centrinone development process. Using VX-680 as a starting point, inhibitor analogs were iteratively synthesized based on the structure-activity relationship (SAR) results from cellular centrosome depletion and biochemical Plk4 and Aurora A/B kinase inhibition assays. Only one of the 133 compounds that robustly inhibited Plk4 in vitro (LCR-015) depleted centrosomes from both human and mouse cells at <10 μΜ. This result validated our approach of monitoring cellular activity in parallel with biochemical potency. LCR-015 was further optimized for potency and selectivity, resulting in centrinone and centrinone-B. (FIG. 6C) Stereo diagram of centrinone in the Plk4 active site showing a Ca trace of the Plk4 main chain, and residues whose side chains form nonpolar contacts with centrinone. The Ca of Gly 95 (sphere) is packed against centrinone. Mutation of this residue to a bulky leucine preserves in vitro catalytic activity but severely compromises centrinone binding. The benzylsulfone moiety inserts itself between the side chain of the catalytic lysine (Lys 41) and the aspartic acid (Asp 154) of the DFG motif. The side chain of Asp 154 is not visible in the electron density so it has been modeled as an alanine. (FIG. 6D) HeLa cells treated with DMSO, VX-680, or centrinone for 7 hours. Cells were fixed and stained for p-LATS2(S83) and p-H3(S 10), which are reporters of Aurora A and Aurora B activity, respectively. Scale bar, 5 μπι. The mean intensities of p- LATS2 and p-H3 staining were quantified for the three conditions. Values are normalized to DMSO. Data are mean +/- SD (N=3). (FIG. 6E) Quantification of the number of cells with detectable foci in HeLa cells stained for centriolar (centrin, SAS-6, CPAP) and pericentriolar material (γ-tubulin, Cepl92, PCNT) proteins. Centrinone treatment resulted in loss of all markers from cells.

[0018] FIGS. 7A-7C. Centrinone prevents assembly of primary cilia and centrosomal microtubule-organizing centers but Golgi organization is largely normal. (FIG. 7A) Serum- starved DMSO- and centrinone-treated NIH/3T3 cells stained for γ-tubulin and the ciliary marker IFT88. Inset is 3.4X magnified. Scale bar, 10 μπι. The mean percentage of cells with cilia was quantified. Data are mean +/- SD (N=3). (FIG. 7B) Deconvolved wide-field images of DMSO- and centrinone-treated NIH/3T3 cells either untreated, in the presence of 16 μΜ nocodazole or 5 minutes after nocodazole washout. Maximum intensity projections are shown. In the absence of centrosomes, short microtubules form throughout the cytoplasm after nocodazole washout, instead of focused asters. Insets are 3.3X magnified. Scale bar, 10 μπι. The mean percentage of cells with visible asters 5 minutes after nocodazole washout was quantified. Data are mean +/- SD (N=3). (FIG. 7C) Golgi staining in NIH/3T3 cells treated with DMSO or centrinone for 10 days. Nocodazole treatment was used as a positive control for Golgi dispersal. Scale bar, 5 μπι. Similar results were obtained in HeLa cells. [0019] FIGS. 8A-8B. Centrinone inhibits centriole assembly in Xenopus multiciliated cells. Dexamethasone-induced Multicilin expression leads to the formation of ectopic multiciliated cells that cover the entire ectoderm in Xenopus embryos (50). These cells contain numerous centrioles that are primarily generated from structures called deuterosomes that are marked by xCCDC78 and also recruit Plk4 (57). (FIG. 8A) Fluorescence confocal images of multiciliated cells treated with DMSO (control) or 10 μΜ centrinone expressing GFP-xCCDC78 and

Centrin4-RFP and stained with Phalloidin to mark cell boundaries indicate that deuterosomes are present in centrinone-treated cells. Scale bar, 5 μιη. (FIG. 8B) Fluorescence confocal images of DMSO, centrinone, and centrinone-B -treated multiciliated cells expressing Centrin4-GFP and stained with Phalloidin. Boxed regions are 3X magnified. Scale bars, 10 μπι. Graph quantifying centriole density after treatment with DMSO or the indicated concentations of centrinone or centrionone-B. Centrinone-treated cells exhibit dramatically reduced centriole numbers, suggesting that centriole assembly in multiciliated cells is Plk4-dependent. Data are mean +/- SD (N=3).

[0020] FIGS. 9A-9B. HeLa and NIH/3T3 cells proliferate indefinitely without centrosomes. (FIG. 9 A) Centrosome depletion kinetics immediately following centrinone addition to IH/3T3 cells. Data are mean +/- SD (N=3). (FIG. 9B) Passaging assay of HeLa and NIH/3T3 cells beginning immediately after centrinone addition. Cells were passaged at the indicated intervals. Centrinone-treated cells continue proliferating indefinitely, albeit at a slower rate than control cells. Data are mean +/- SD (N=2).

[0021] FIGS. 10A-10D. Centrosome loss does not affect interphase duration but leads to an increase in apoptotic cell death. To determine how centrosome removal led to a reduction in population growth, we first analyzed whether centrosome-less cells exhibit altered progression through interphase. We measured the duration of Gl+S and G2 in control and centrosome-less HeLa and NIH/3T3 cells engineered to co-express GFP-PCNA and H2B-RFP. The H2B-RFP enables monitoring chromosome decondensation and nuclear envelope breakdown (NEBD), which mark the M/Gl and G2/M transitions, respectively. GFP-PCNA localizes to nuclear foci representing sites of active DNA replication that form during S-phase and persist until the S/G2 boundary (56), enabling assessment of the end of S phase. (FIG. 10A) Confocal images

(maximum intensity projections) illustrating how cell cycle intervals (Gl+S and G2) were measured. Times in the bottom left of each panel are in minutes relative to the beginning of Gl (chromosome decondensation). Scale bar, 10 μπι. (FIG. 10B) Plots showing Gl+S and G2 durations in DMSO- and centrinone-treated HeLa and NIH/3T3 cells co-expressing GFP-PCNA and H2B-RFP. Horizontal bars represent measurements from individual cells, ordered by total interphase duration. N=2. (FIG. IOC) Confocal images (maximum intensity projections) of HeLa cells treated with DMSO or centrinone for 8 days, then stained for apoptotic cells using a fluorescent caspase-3/7 activity reporter substrate. Scale bar, 50 μπι. The percentage of dying cells is underestimated by this assay because it does not account for the fragile cells that have detached from the surface (in particular, those that die during or shortly after mitosis while the cell is loosely adherent). (FIG. 10D) Theoretical proliferation curves (black) for HeLa and NIH/3T3 cells with the indicated percentages of cell death, compared to measurements of centrinone-treated cells (squares; data reproduced from FIG. 2B). The equations used to generate the curves are shown above each plot (50,000 = starting cell number; n = generation number). The doubling times were calculated by best-fit exponential regression of proliferation data from DMSO-treated cells adjusted as shown for increased time spent in mitosis. The curves indicate that the reduced proliferation rate of centrosome-less HeLa and NIH/3T3 cells can be explained by 25% and 15% cell death per generation, respectively.

[0022] FIGS. 1 1 A-l 1C. Centrosome loss slows spindle assembly and leads to mitotic errors. (FIG. 1 1 A) Schematic of the staggered treatment regime used to capture pioneer 2-, 1- and 0- centrosome mitoses. (FIG. 1 IB) Representative confocal images (maximum intensity

projections) of 2-, 1- and 0-centrosome mitosis in NIH/3T3 cells co-expressing centrin-GFP and H2B-RFP. Arrowheads indicate centrin foci. Times in the bottom left of each panel are in minutes relative to NEBD. Scale bar, 10 μπι. (FIG. 1 1C) Plots of mitotic duration for NIH/3T3 and HeLa cells expressing centrin-GFP and H2B-RFP. Horizontal bars represent measurements from individual cells, ordered by the duration of NEBD to anaphase onset (N=2). Specific mitotic outcomes and associated percentages are indicated to the right of each box. Times in brackets are mean +/- SD of NEBD to anaphase onset. As centrosomes were lost, NIH/3T3 cells exhibited increases in chromosome mis segregation and cytokinesis failure, and HeLa cells exhibited increases in chromosome mis segregation and mitotic arrest, likely due to cohesion fatigue (57). These errors lead to cell death in mitosis or via apoptosis in the ensuing Gl (see FIG. 2F and FIG. 10D). [0023] FIG. 12. Cells maintain an intact DNA damage response in the absence of

centrosomes. NIH/3T3 and HeLa cells were subjected to the schematized experimental protocol. Double-stranded DNA breaks were induced by treatment of cells with doxorubicin. DNA content analysis was used to measure the proportion of cells in mitosis, based on phospho-H3(S 10) staining. In the presence of an intact G2 DNA damage checkpoint, the mitotic index of the population is reduced because cells that would have entered mitosis are arrested prior to mitotic entry, whereas cells already in mitosis can exit. Treatment of cells with 5 mM caffeine was used as a positive control for bypass of the DNA damage checkpoint. The mitotic index of centrinone- treated HeLa cells does not fall completely to zero after being challenged with doxorubicin because 24% of centrosome-less HeLa cells undergo a persistent mitotic arrest (see FIGS. 1 1 A- 1 1C).

[0024] FIGS. 13A-13D. Centriole number set points arise from a dynamic equilibrium between centriole overduplication and removal of cells with extra centrioles. (FIG. 13 A) Representative confocal images (maximum intensity projections) from a centrinone washout experiment in HeLa cells co-expressing centrin-GFP and H2B-RFP; only the GFP channel is shown. Yellow arrowheads mark centrin foci. Each frame was acquired at NEBD when the centrosomes are optimally distributed for counting. Times in the bottom left of each panel are in minutes relative to NEBD in the mother cell. Scale bar, 10 μιη. (FIG. 13B) Histogram of mitotic outcomes for HeLa cells with <2, 2 or >2 centrosomes. The fates of daughter cells arising from 2-centrosome bipolar mitosis, multi-centrosome bipolar mitosis, and multi-centrosome multipolar mitosis are shown below. Data are mean +/- SD (N=2). (FIG. 13C) Plots of the number of centrin foci in the mother cell (x-axis) versus the sum of the centrin foci in her two daughter cells (y-axis) are shown for 3 different time intervals after centrinone washout (N=2). Intervals are based on the time of NEBD in the mother cells. The diagonal line represents the 2: 1 ratio expected under normal conditions; points above or below this line correspond to over- or under-duplication, respectively. (FIG. 13D) Representative images of HeLa cells that were untreated, treated with 125 nM centrinone for 8 hours, or treated with centrinone for 8 hours followed by a 24-hour washout. Boxed regions are magnified 2.3X in panels below. Scale bar, 5 μηι. The Plk4 intensity at centrosomes was quantified and normalized to the intensity in untreated cells. Data are mean +/- SD (N=3). An 8-hour centrinone treatment was sufficient to double the measured levels of Plk4 at the centrosome.

[0025] FIGS. 14A-14F. Centrosome loss triggers a p53-dependent arrest in normal cells within two to three cell cycles. (FIG. 14 A) DNA content analysis of DMSO- and centrinone- treated RPEl cells. The percentage of cells in Gl is indicated. (FIG. 14B) Passaging assay showing growth of primary fibroblasts immediately following addition of centrinone or DMSO as a control. Data are mean +/- SD (N=2). (FIG. 14C) Western Blot of p53 and p21 in primary fibroblasts after treatment with DMSO or centrinone for 8 days. (FIG. 14D) DNA content analysis of DMSO- and centrinone-treated primary fibroblasts. The percentage of cells in Gl is indicated. (FIG. 14E) Wide-field images of RPEl cells and primary fibroblasts treated with centrinone for 1-3 days. Maximum intensity projections are shown. Nuclear boundaries are outlined in gray. A fraction of 1- and 0-centrosome cells exhibit increased nuclear p53 staining. Scale bar, 10 μιη. (FIG. 14F) Quantification of p53-positive cells following centrinone addition to RPE1 and primary fibroblasts. Data are mean +/- SD (N=3).

[0026] FIG. 15. Generation of RPE1 cells with a centrinone-resistant (G95L) Plk4 knock-in. The codon for residue G95 is located in exon 4 of the Plk4 locus. A Cas9 recognition site within the intronic region between exons 4 and 5 was targeted to generate a double-stranded DNA break. AAV-mediated homology-directed repair was used to introduce the G95L point mutation into exon 4, together with a neomycin resistance cassette in the intron. The resistance cassette, driven by its own promoter on the anti-sense strand, enabled selection of clones positive for the knock-in. Homozygosity of the point mutation was verified by PCR and sequencing of genomic DNA at the locus.

[0027] FIGS. 16A-16F. Arrest after centrosome loss is not related to DNA damage or stress. (FIG. 16A) Western Blot of p53 post-translational modifications from RPE1 cells treated with the indicated compounds. Ser9, Ser33, Ser37, Ser315 and Ser392 have been demonstrated to be phosphorylated in response to DNA damage (58-62), which also triggers acetylation of Lys382 (57). A 16-hour treatment with 0.5 μΜ doxorubicin was used as a positive control for induction of DNA damage. (FIG. 16B) Deconvolved wide-field images of γ-Η2Α.Χ foci in RPE1 cells treated with DMSO or centrinone for 4 days, or 0.5 μΜ doxorubicin as a control. The presence or absence (centrinone) of centrosomes in imaged cells was confirmed by γ-tubulin staining. Scale bar, 5 μπι. (FIG. 16C) Passaging assays of RPE1 cells treated with the indicated inhibitors of the DNA damage response pathway, beginning immediately after centrinone addition. Data are mean +/- SD (N=2). (FIG. 16D) Western Blot of phospho-MAPKAPK-2 after induction of osmotic stress, in the presence or absence of the p38 MAPK inhibitor SB203580. SB203580 blocks phosphorylation of MAPKAPK-2 by p38. (FIG. 16E) Passaging assay of RPE1 cells treated with the p38 inhibitor SB203580, beginning immediately after centrinone addition. Data are mean +/- SD (N=2). (FIG. 16F) Western Blot of p53 and p21 in RPE1 cells treated with DMSO or centrinone for 8 days, or treated with centrinone for 8 days and then washed out for another 8 days. p53 and p21 levels remain elevated after centrinone washout.

[0028] FIGS. 17A-17C. Arrest after centrosome loss is not related to the Hippo signaling pathway. Cytokinesis failure has been shown to trigger activation of the Hippo signaling pathway and subsequent cell cycle arrest (27). A key step in the activation of Hippo signaling is phosphorylation of YAP by LATS2 kinase. (FIG. 17A) Western Blot of LATS2, YAP and phospho-YAP(Serl27) in diploid and tetraploid RPE1 cells. Knockdown of LATS2 results in decreased YAP phosphorylation, even in tetraploid (4n) cells generated by induction of cytokinesis failure. (FIG. 17B) Passaging assay of RPEl cells expressing constitutively- active (S5A) YAP that cannot be phosphorylated by LATS2, following addition of centrinone. Data are mean +/- SD (N=2). (FIG. 17C) Quantification of the percentage of YAP-expressing RPEl Fucci cells in Gl, 12 hours after drug washout. Diploid cells measurements were obtained from cells treated with DMSO for 24 hours before washout, whereas tetraploid cell measurements were obtained from cells treated with 4 μΜ cytochalasin D (to induce cytokinesis failure) for 24 hours before washout. Tetraploid cells expressing wild-type YAP are arrested at Gl, whereas cells expressing constitutively-active (S5A) YAP bypass the arrest. Data are mean +/- SD (N=3).

[0029] FIGS. 18A-18B. Arrest after centrosome loss is not related to the mitotic duration sensor or chromosome missegregation. Analysis of daughter cell fate in RPEl cells expressing centrin-GFP and H2B-RFP. Vertical bars represent measurements from individual daughter cells (N=2). The height of each bar is the time their mother spent in prometaphase. (FIG. 18 A) Cells treated with DMSO or centrinone. Asterisks (*) mark cases in which the mother cell had visible chromosome missegregation. The percentage of daughters not dividing within 48 hours = 3.5% (DMSO) and 1.5% (centrinone). (FIG. 18B) Cells treated with the Mpsl inhibitor MS-P715. Only mitotic events with clear missegregation (lagging chromosomes and subsequent formation of daughter cells with micronuclei) were analyzed. The percentage of daughters not dividing within 48 hours = 1 1.4%.

DETAILED DESCRIPTION OF THE INVENTION

[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 ₂ 0- is equivalent to -OCH 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, having the number of carbon atoms designated (i.e., Ci-Cio 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, (cyclohexyl)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-(l,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 (-0-).

[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 ₂ CH ₂ CH ₂ CH 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. selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized). The heteroatom(s) O, N, P, S, B, As, and 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 ₂ -CH ₂ -0-CH ₃ , -CH ₂ -CH ₂ - H-CH ₃ ,

-CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(0)-CH ₃ , -CH ₂ -CH ₂ -S(0) ₂ -CH ₃ , -CH=CH-0-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ , -0-CH ₃ ,

-0-CH ₂ -CH ₃ , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH ₂ - H-OCH ₃ and -CH ₂ -0-Si(CH ₃ ) ₃ . [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 ₂ -CH ₂ -S-CH ₂ -CH ₂ - and -CH ₂ -S-CH ₂ -CH ₂ - H-CH 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(0) ₂ R'- represents both -C(0) ₂ R'- and -R'C(0) 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(0)R', -C(0) R', -NR'R", -OR, -SR, and/or -S0 ₂ R. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" 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 -NR'R" 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 heteroalkyl 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, l-(l,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 polyhalo alkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyl, difiuoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0038] The term "acyl" means, unless otherwise stated, -C(0)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] A "fused ring aryl-heterocycloalkyl" is an aryl fused to a heterocycloalkyl. A "fused ring heteroaryl-heterocycloalkyl" is a heteroaryl fused to a heterocycloalkyl. A "fused ring heterocycloalkyl-cycloalkyl" is a heterocycloalkyl fused to a cycloalkyl. A "fused ring heterocycloalkyl-heterocycloalkyl" is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring

heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein. Fused ring aryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be named according to the size of each of the fused rings. Thus, for example, 6,5 aryl-heterocycloalkyl fused ring describes a 6 membered aryl moiety fused to a 5 membered heterocycloalkyl. [0041] 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.

[0042] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0043] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0044] 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', =0, = R', =N-OR', - R'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, -C0 ₂ R, -CO R'R", -OC(0) R'R", - R"C(0)R,

- R'-C(0) R"R", - R"C(0) ₂ R, - R-C( R'R"R")= R"", - R-C( R'R")= R"', -S(0)R, -S(0) ₂ R, -S(0) ₂ R'R", - RS0 ₂ R, - R'NR'R", -O R'R", - R'C(0) R" R"'R"", -CN, -N0 ₂ , - R'S0 ₂ R", - R'C(0)R", - R'C(0)-OR", - R'OR", in a number ranging from zero to (2m'+l), 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, - R'R" 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 ₃ and -CH ₂ CF ₃ ) and acyl (e.g., -C(0)CH ₃ ,

-C(0)CF ₃ , -C(0)CH ₂ OCH ₃ , and the like). [0045] 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, -NR'R", -SR, -halogen, - SiRR'R", -OC(0)R, -C(0)R, -C0 ₂ R, -CONR'R", -OC(0)NR'R", -NR"C(0)R,

-NR'-C(0)NR"R", -NR"C(0) ₂ R, -NR-C(NR'R"R")=NR"", -NR-C(NR'R")=NR"', -S(0)R, -S(0) ₂ R, -S(0) ₂ NR'R", -NRS0 ₂ R, -NR'NR'R", -ONR'R", -NR'C(0)NR"NR"'R"", -CN, -N0 ₂ , -R, -N ₃ , -CH(Ph) ₂ , fluoro(Ci-C ₄ )alkoxy, and fluoro(Ci-C ₄ )alkyl, -NR'S0 ₂ R",

-NR'C(0)R", -NR'C(0)-OR", -NR'OR", 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.

[0046] 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 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.

[0047] 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. The ring-forming substituents may be 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. The ring- forming substituents may be 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. The ring-forming substituents may be attached to non-adjacent members of the base structure.

[0048] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') _q -U-, wherein T and U are independently - R-, -0-, - 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 ₂ ) _r -B-, wherein A and B are independently -CRR'-, -0-,

- R-, -S-, -S(O) -, -S(0) ₂ -, -S(0) ₂ R'-, 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') _S -X'- (C"R"R") _d -, where s and d are independently integers of from 0 to 3, and X' is -0-, - R'-, -S-, -S(O)-, -S(0) ₂ -, or

-S(0) ₂ R'-. 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.

[0049] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), Arsenic (As), and silicon (Si). [0050] A "substituent group," as used herein, means a group selected from the following moieties:

(A) oxo, halogen, -CF ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S0 ₂ C1, -S0 ₃ H, -SO ₄ H, -S0 ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS0 ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(i) oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ C1,

-S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ ,

-NHS0 ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(a) oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S0 ₂ C1, -S0 ₃ H, -SO ₄ H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S0 ₂ C1, -S0 ₃ H, -SO4H, -S0 ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS0 ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, - OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. [0051] 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 ₁ -C 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 C3-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or

unsubstituted 3 to 8 membered heterocycloalkyl.

[0052] 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 Ci-C 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 C3-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. [0053] Each substituted group described in the compounds herein may be substituted with at least one substituent group. More specifically, 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 may be substituted with at least one substituent group. At least one or all of these groups may be substituted with at least one size-limited substituent group. At least one or all of these groups may be substituted with at least one lower substituent group.

[0054] Each substituted or unsubstituted alkyl may be a substituted or unsubstituted C ₁ -C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl may be a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl may be a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl may be a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Each substituted or

unsubstituted alkylene may be a substituted or unsubstituted C ₁ -C ₂₀ alkylene, each substituted or unsubstituted heteroalkylene may be a substituted or unsubstituted 2 to 20 membered

heteroalkylene, each substituted or unsubstituted cycloalkylene may be a substituted or unsubstituted C ₃ -C ₈ cycloalkylene, and/or each substituted or unsubstituted heterocycloalkylene may be a substituted or unsubstituted 3 to 8 membered heterocycloalkylene. [0055] Each substituted or unsubstituted alkyl may be a substituted or unsubstituted Ci-C ₈ alkyl, each substituted or unsubstituted heteroalkyl may be a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl may be a substituted or unsubstituted C3-C7 cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl may be a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. Each substituted or

unsubstituted alkylene may be a substituted or unsubstituted Ci-C ₈ alkylene, each substituted or unsubstituted heteroalkylene may be a substituted or unsubstituted 2 to 8 membered

heteroalkylene, each substituted or unsubstituted cycloalkylene may be a substituted or unsubstituted C3-C7 cycloalkylene, and/or each substituted or unsubstituted heterocycloalkylene may be a substituted or unsubstituted 3 to 7 membered heterocycloalkylene.

[0056] Certain compounds herein 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 compounds described herein. The compounds described herein do not include those which are known in art to be too unstable to synthesize and/or isolate. The compounds described herein also are 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.

[0057] 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. [0058] 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.

[0059] It will be apparent to one skilled in the art that certain compounds described herein may exist in tautomeric forms, and that all such tautomeric forms of the compounds may be considered within the scope of the compounds described herein. [0060] 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, generally recognized as stable by those skilled in the art, are within the scope of the compounds described herein.

[0061] 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 ¹ C- or ¹⁴ C-enriched carbon are within the scope of the compounds described herein.

[0062] The compounds described herein 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 ( H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds described herein, whether radioactive or not, are encompassed within the scope of the compounds described herein.

[0063] The symbol " W" denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0064] 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 decimal symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R ¹³

13 13 1 13 2 13 3 13 4 sub stituents are present, each R substituent may be distinguished as R , R , R , R , etc., wherein each of R ¹ R ^{13 2} , R ^{13 C} , R ^{13 4} , etc. is defined within the scope of the definition of R ¹ and optionally differently.

[0065] Description of compounds described herein is 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. [0066] The terms "VX-680," "tozasertib," and "MK-0457" as used herein refer to the compound having the formul

[0067] 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 described herein 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 described herein 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 described herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0068] Thus, the compounds described herein may exist as salts, such as with

pharmaceutically acceptable acids. The compounds described herein include such salts.

Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0069] 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 differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0070] In addition to salt forms, the compounds described herein may be provided in a prodrug form. Prodrugs of the compounds described herein include those compounds that readily undergo chemical or enzymatic changes under physiological conditions to provide the compounds described herein. Additionally, prodrugs can be converted to the compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds described herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0071] Certain compounds described herein 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 compounds described herein. Certain compounds described herein may exist in multiple crystalline or amorphous forms.

[0072] As used herein, the term "salt" refers to acid or base salts of the compounds described herein. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0073] The terms "treating", or "treatment" refer 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 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, include prevention of an injury, pathology, condition, or disease. [0074] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, 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 herein is 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. 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). [0075] 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.

[0076] 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.

[0077] 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 compounds described herein 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.

[0078] 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. [0079] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0080] "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. A control may be the measurement of the activity of a protein in the absence of a compound as described herein.

[0081] "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 which can be produced in the reaction mixture.

[0082] 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. Contacting may include allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0083] As defined herein, the term "inhibition", "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. Inhibition may refer to negatively affecting (e.g. decreasing) the concentration or level of the protein relative to the concentration or level of the protein in the absence of the inhibitor. Inhibition may refer reduction of a disease or symptoms of disease. Inhibition may refer to a reduction in the activity of a particular protein or nucleic acid 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.

[0084] "PLK4" is used according to its common, ordinary meaning and refers to proteins of the same or similar names and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of PLK4 (e.g. Polo-like Kinase 4; GI No: 160113150, SEQ ID NO: 2), or variants thereof that maintain PLK4 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to PLK4).

[0085] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule.

[0086] 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, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.

[0087] "Selective" or "selectivity" or the like of a compound refers to the compound's ability to discriminate between molecular targets. "Specific", "specifically", "specificity", or the like of a compound refers to the compound's ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.

[0088] "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 compounds described herein 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 described herein. One of skill in the art will recognize that other pharmaceutical excipients are useful in combination with the compounds described herein. [0089] 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. [0090] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, 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 compatible with the selected compound preparation, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). 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.

[0091] The compositions disclosed herein can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The pharmaceutical compositions described herein may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;

5,212, 162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). The formulations of the compositions of the compounds described herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the compounds described herein into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13 :293-306, 1996; Chonn,

Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, ^w. J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions can also be delivered as nanoparticles.

[0092] Pharmaceutical compositions may include compositions wherein the active ingredient (e.g. compounds described herein) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms. [0093] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art. [0094] The compounds and complexes described herein can be used in combination with one another, with other active drugs known to be useful in treating a disease (e.g. anti-cancer agents) or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. [0095] By "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, for example an anti-cancer agent as described herein. The compounds described herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. anti-cancer agents).

[0096] Co-administration includes administering one active agent (e.g. a compound described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g. anticancer agents). Co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. The active agents can be formulated separately. The active and/or adjunctive agents may be linked or conjugated to one another. The compounds described herein may be combined with treatments for cancer such as chemotherapy or radiation therapy.

[0097] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease means that the disease is caused by or characterized by (in whole or in part), a symptom of the disease is caused by or characterized by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by or characterized by (in whole or in part) the substance or substance activity or function.

[0098] "Patient," "subject," "patient in need thereof," and "subject in need thereof are herein used interchangeably and refer 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. A patient may be a human.

[0099] "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. Disease as used herein may refer to cancer.

[0100] As used herein, the term "cancer" refers to all types of cancer, neoplasm, malignant or benign tumors found in mammals, including leukemia, carcinomas and sarcomas. Exemplary cancers include acute myeloid leukemia ("AML"), chronic myelogenous leukemia ("CML"), and cancer of the brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and prostate. Additional examples include, cervix cancers, stomach cancers, head & neck cancers, uterus cancers, mesothelioma, metastatic bone cancer, Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, 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, and neoplasms of the endocrine and exocrine pancreas.

[0101] 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). The murine leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity. It is believed that a compound that tests positive in the P388 cell assay will generally exhibit some level of anti-leukemic activity regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, including treating acute myeloid 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,

megakaryocyte 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, and undifferentiated cell leukemia.

[0102] 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 which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent 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, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0103] The term "melanoma" is taken to mean a tumor arising from the melanocyte system of the skin and other organs. Melanomas which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent 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, and superficial spreading melanoma.

[0104] 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 which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent include, for example, 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, hypemephroid 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, and carcinoma villosum.

[0105] "Anti-cancer agent" is used in accordance with its plain and 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. An anti-cancer agent may be an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.

[0106] 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 (VP 16), 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.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,

LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-l, 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; 06-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 Bl ; 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; topsentin; 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 II

(including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b;

interferon alfa-nl ; interferon alfa-n3; interferon beta- la; interferon gamma- lb; 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.TM (i.e. paclitaxel), Taxotere.TM, 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- hydroxy epothilone 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.HC1), 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 Al (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, Inanocine (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-rel easing 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-Guerin (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 ^{U 1} ln, ⁹⁰ Y, or ^{1 1} I, 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. [0107] "Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

[0108] "Cancer model organism", as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.

[0109] "Analog," or "analogue" are used in accordance with plain ordinary meaning within Chemistry and Biology and refer 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 analogue is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

I. Compounds [0110] Provided herein are compounds having the formula:

[0111] L ¹ is a bond, -C(O)-, -C(0)0-, -0-, -S-, - R ¹³ -, -C(0) R ¹³ -, - R ¹ C(0)-, -S(0) ₂ -, -S(0) R ¹³ -, 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 ¹ is hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , - R ^1A R ^1B ,

-C(0)OR ^1A , -C(0) R ^1A R ^1B , -N0 ₂ , -SR ^1A , -S(0)„iR ^1A , -S(0)„iOR ^1A , -S(0)„i R ^1A R ^1B ,

- HNR ^1A R ^1B , -O R ^1A R ^1B , - HC(0) HNR ^1A R ^1B , 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 ² is hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A ,

- R ^2A R ^2B , -C(0)OR ^2A , -C(0) R ^2A R ^2B , -N0 ₂ , -SR ^2A , -S(0)„2R ^2A , -S(0) _I , ₂ OR ^2A ,

-S(0) _I , ₂ R ^2A R ^2B , - HNR ^2A R ^2B , -O R ^2A R ^2B , - HC(0) HNR ^2A R ^2B , 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 ³ is hydrogen, halogen, -N , -CF , -CC1 , -CBr , -CI , -CN, -COR ^A , - OR ^A , -NR ^A R ^B , -C(0)OR ^A , -C(0)NR ^A R ^B , -N0 ₂ , -SR ^A , -S(0)„ ₃ R ^A ,

-S(0)„ ₃ OR ^A , -S(0)„ ₃ NR ^A R ^B , -NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , 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 ⁴ is hydrogen, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , - CN, -COR ^4A , -OR ^4A , -NR ^4A R ^4B , -C(0)OR ^4A , -C(0)NR ^4A R ^4B , -N0 ₂ , -SR ^4A , -S(0)„ ₄ R ^4A ,

-S(0)„ ₄ OR ^4A , -S(0)„ ₄ NR ^4A R ^4B , -NHNR ^4A R ^4B , -ONR ^4A R ^4B , -NHC(0)NHNR ^4A R ^4B , 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, wherein R ³ and R ⁴ are optionally combined to form a

3 C

substituted or unsubstituted cycloalkyl (e.g. R -substituted or unsubstituted cycloalkyl),

3 C

substituted or unsubstituted heterocycloalkyl (e.g. R -substituted or unsubstituted

3 C

heterocycloalkyl), substituted or unsubstituted aryl (e.g. R -substituted or unsubstituted aryl), or

3 C 5 substituted or unsubstituted heteroaryl (e.g. R -substituted or unsubstituted heteroaryl). R is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^5A , -OR ^5A ,

-NR ^5A R ^5B , -C(0)OR ^5A , -C(0)NR ^5A R ^5B , -N0 ₂ , -SR ^5A , -S(0)„ ₅ R ^5A , -S(0)„ ₅ OR ^5A , - S(0)„ ₅ NR ^5A R ^5B , -NHNR ^5A R ^5B , -ONR ^5A R ^5B , -NHC(0)NHNR ^5A R ^5B , 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 ⁶ is hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 , -CBr ₃ ,

-CI ₃ , -CN, -CHO, -OR ^6A , -NR ^6A R ^6B , -C(0)OR ^6A , -C(0)NR ^6A R ^6B , -N0 ₂ , -SR ^6A , -S(0)„ ₆ R ^6A , -S(0)„ ₆ OR ^6A , -S(0)„ ₆ NR ^6A R ^6B , -NHNR ^6A R ^6B , -ONR ^6A R ^6B , -NHC(0)NHNR ^6A R ^6B , 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. The symbols nl, n2, n3, n4, n5, and n6 are independently 1 or 2. The symbol zl is 1, 2, 3, or 4. R ^1A , R ^1B , R ^2A , R ^2B , R ^A , R ^B , R ^4A , R ^4B , R ^5A , R ^5B , R ^6A , R ^6B , and R ¹³ are independently hydrogen, oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , - N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ ,

- HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , 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.

[0112] In embodiments, the compound is not VX-680. In embodiments of formula lb, R ⁴ is not a para-methyl piperidinyl. In embodiments of formula lb, R ⁴ is not a para-ethyl piperidinyl. In embodiments of formula lb, R ⁴ is not a para-propyl piperidinyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a methyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a ethyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a propyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with an unsubstituted alkyl at the para position. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with an unsubstituted alkyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a substituted or unsubstituted alkyl. In embodiments of formula lb, R ⁴ is not a substituted or unsubstituted piperidinyl. In embodiments of formula lb, R ⁴ is not a substituted heterocycloalkyl. In embodiments of formula lb, R ⁴ is not a substituted or unsubstituted heterocycloalkyl. In embodiments of formula la, R ⁴ is not a para-methyl piperidinyl. In embodiments of formula lb, R ⁴ is not a para-ethyl piperidinyl. In embodiments of formula lb, R ⁴ is not a para-propyl piperidinyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a methyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a ethyl. In embodiments of formula lb, R ⁴ is not a piperidinyl substituted with a propyl. In embodiments of formula la, R ⁴ is not a piperidinyl substituted with an unsubstituted alkyl at the para position. In embodiments of formula la, R ⁴ is not a piperidinyl substituted with an unsubstituted alkyl. In embodiments of formula la, R ⁴ is not a piperidinyl substituted with a substituted or unsubstituted alkyl. In embodiments of formula la, R ⁴ is not a substituted or unsubstituted piperidinyl. In embodiments of formula la, R ⁴ is not a substituted

heterocycloalkyl. In embodiments of formula la, R ⁴ is not a substituted or unsubstituted heterocycloalkyl. In embodiments, the provisos set forth in the embodiemtns of the paragraph apply only when -I^-R ⁶ is cyclopropyl. The embodiments in this paragraph are equally applicable to all other appropriate formulae set forth herein.

[0113] In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl. In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl. In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with substituted or unsubstituted alkyl. In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with unsubstituted alkyl. In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with methyl, ethyl or propyl. In embodiments of formula lb, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with para methyl, para ethyl or para propyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with substituted or unsubstituted alkyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with unsubstituted alkyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with methyl, ethyl or propyl. In embodiments of formula la, -I^-R ⁶ is not cyclopropyl when R ⁴ is piperidinyl substituted with para methyl, para ethyl or para propyl. The embodiments in this paragraph are equally applicable to all other appropriate formulae set forth herein.

[0114] The compound may be a compound of formula:

[0115] The compound may be a compound of formula:

[0116] In embodiments, the compound of formula (lb) is not,

(VX-680).

[0117] R ¹ may be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , - R ^1A R ^1B , -C(0)OR ^1A , or -C(0) R ^1A R ^1B . R ¹ may be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ ,

-CBr ₃ , -CI ₃ , -CN, -COR ^1A , -OR ^1A , -NR ^1A R ^1B , -C(0)OR ^1A , or -C(0)NR ^1A R ^1B where R ^1A and R ^1B are independently hydrogen, oxo, halogen, -CF ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. R ¹ may be hydrogen. R ¹ may be hydrogen or substituted or unsubstituted alkyl.

[0118] R ¹ may be 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.

[0119] R ¹ may be substituted or unsubstituted alkyl. R ¹ may be substituted alkyl. R ¹ may be unsubstituted alkyl. R ¹ may be substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ¹ may be substituted C ₁ -C ₂₀ alkyl. R ¹ may be unsubstituted C ₁ -C ₂₀ alkyl. R ¹ may be substituted or unsubstituted C ₁ -C ₁₀ alkyl. R ¹ may be substituted C ₁ -C ₁₀ alkyl. R ¹ may be unsubstituted C ₁ -C ₁₀ alkyl. R ¹ may be substituted or unsubstituted C ₁ -C ₅ alkyl. R ¹ may be unsubstituted C ₁ -C ₅ alkyl. R ¹ may be substituted C ₁ -C ₅ alkyl. R ¹ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R ¹ may be methyl. R ¹ may be ethyl.

l ie 1 1c 1

[0120] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

1 c 1 1c 1 may be R -substituted or unsubstituted C ₁ -C ₂₀ alkyl. R may be R -substituted C ₁ -C ₂₀ alkyl. R

1 c 1 1c 1 may be R -substituted or unsubstituted C ₁ -C ₁₀ alkyl. R may be R -substituted C ₁ -C ₁₀ alkyl. R

1 c 1 1c 1 may be R -substituted or unsubstituted C ₁ -C ₅ alkyl. R may be R -substituted C ₁ -C ₅ alkyl. R

1 c 1 c

may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl.

[0121] R ¹ may be substituted or unsubstituted heteroalkyl. R ¹ may be substituted heteroalkyl. R ¹ may be unsubstituted heteroalkyl. R ¹ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ¹ may be substituted 2 to 20 membered heteroalkyl. R ¹ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ¹ may be substituted 2 to 10 membered

heteroalkyl. R ¹ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ¹ may be substituted 2 to 6 membered heteroalkyl.

l ie 1 1c

[0122] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted

l ie 1 heteroalkyl. R may be R -substituted or unsubstituted 2 to 20 membered heteroalkyl. R may

1 c 1 1c

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 l ie 1 to 10 membered heteroalkyl. R may be R -substituted 2 to 10 membered heteroalkyl. R may

1 c 1 1c

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to

6 membered heteroalkyl. [0123] R ¹ may be substituted or unsubstituted cycloalkyl. R ¹ may be substituted cycloalkyl. R ¹ may be unsubstituted cycloalkyl. R ¹ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ¹ may be substituted 3 to 20 membered cycloalkyl. R ¹ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ¹ may be substituted 3 to 10 membered cycloalkyl. R ¹ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R ¹ may be substituted 3 to 6 membered cycloalkyl.

l ie l ie

[0124] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted

l lC 1 cycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered cycloalkyl. R may be

1 C l lC

R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10 l ie l ie membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R -

1 1 c

substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl. [0125] R ¹ may be substituted or unsubstituted heterocycloalkyl. R ¹ may be substituted heterocycloalkyl. R ¹ may be unsubstituted heterocycloalkyl. R ¹ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ¹ may be substituted 3 to 20 membered heterocycloalkyl. R ¹ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ¹ may be substituted 3 to 10 membered heterocycloalkyl. R ¹ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ¹ may be substituted 3 to 6 membered heterocycloalkyl.

l ie l ie

[0126] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted

1 1 c

heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R l may be Rie -substituted 3 to 20 membered heterocycloalkyl. R l may be Rie -

1 1 c

substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to

1 1 c

10 membered heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R 1 may be R 1 c -substituted 3 to 6 membered heterocycloalkyl.

[0127] R ¹ may be substituted or unsubstituted aryl. R ¹ may be substituted aryl. R ¹ may be unsubstituted aryl. R ¹ may be substituted or unsubstituted 5 to 20 membered aryl. R ¹ may be substituted 5 to 20 membered aryl. R ¹ may be substituted or unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ¹ may be substituted 5 to 8 membered aryl. R ¹ may be substituted or

unsubstituted 5 or 6 membered aryl. R ¹ may be substituted 5 or 6 membered aryl.

l lC l lC 1

[0128] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R l c l ie

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to l ie l 20 membered aryl. R may be R -substituted or unsubstituted 5 to 8 membered aryl. R may be

1 C l lC

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6

1 1 c

membered aryl. R may be R -substituted 5 or 6 membered aryl (e.g. phenyl). [0129] R ¹ may be substituted or unsubstituted heteroaryl. R ¹ may be substituted heteroaryl. R ¹ may be unsubstituted heteroaryl. R ¹ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ¹ may be substituted 5 to 20 membered heteroaryl. R ¹ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ¹ may be substituted 5 to 8 membered heteroaryl. R ¹ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ¹ may be substituted 5 or 6 membered heteroaryl.

l ie l ie

[0130] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted

l lC 1 heteroaryl. R may be R -substituted or unsubstituted 5 to 20 membered heteroaryl. R may be

1 C l lC

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8 l ie l ie membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R -

1 1 c

substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

[0131] R ^1A may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CCI ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ^1D , -COR ^1D , - R ^1D R ^1E , -COOR ^1D , -CO R ^1D R ^1E , -N0 ₂ , -SR ^1D , -S(0) ₂ R ^1D , -S(0) ₃ R ^1D , - S(0) ₄ R ^1D , -S(0) ₂ R ^1D R ^1E , - HNR ^1D R ^1E , -O R ^1D R ^1E , - HC(0) HNR ^1D R ^1E ,

- HC(0) R ^1D R ^1E , - HS(0) ₂ R ^1D , - HC(0)R ^1D , - HC(0)-OR ^1D , - HOR ^1D , -OCF ₃ , -OCHF ₂ ,

1 c 1 c

R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl,

1 c 1 c

R -substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl,

1 c 1 c

R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl. [0132] R ^1C is independently halogen, oxo, N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN,

-OH, -COR ^1D ,-NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF ₃ , -OCFIF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0133] R ^1C may independently be halogen, oxo, N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -OH, -

COH,-NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, - OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0134] R ^1B may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -

OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ ,

-ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCFIF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0135] R ^1D and R ^1E are independently hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , - CN, -OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0136] R ² may be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A , -NR ^2A R ^2B , -C(0)OR ^2A , or -C(0)NR ^2A R ^2B . R ² may be hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ^2A , -OR ^2A , -NR ^2A R ^2B , -C(0)OR ^2A , or -C(0)NR ^2A R ^2B where R ^2A and R ^2B are independently hydrogen, oxo, halogen, -CF ₃ , -OH, -NH ₂ , -COOH, -CONH ₂ , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0137] R ² may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² may be R ^2A - substituted or unsubstituted cycloalkyl, R ^2A - substituted or unsubstituted heterocycloalkyl, R ^2A - substituted or unsubstituted aryl, or R ^2A - substituted or unsubstituted heteroaryl. R ² may be substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ² may be R ^2A - substituted or unsubstituted heterocycloalkyl, R ^2A - substituted or unsubstituted aryl, or R ^2A - substituted or unsubstituted heteroaryl.

2 2C 2C

[0138] R may be R -substituted or unsubstituted alkyl, R -substituted or unsubstituted

9 ¹ 9 ¹

heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted

9 ¹ 9 ¹

heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl. In embodiments, R ² is substituted with an alkyl, heteroalkyl, cycloalkyl,

heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl,

heterocycloalkyl, aryl or heteroaryl is substituted with a substituent selected from -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl. [0139] R ² may be substituted or unsubstituted alkyl. R ² may be substituted alkyl. R ² may be unsubstituted alkyl. R ² may be substituted or unsubstituted Ci-C ₂₀ alkyl. R ² may be substituted Ci-C ₂ o alkyl. R ² may be unsubstituted Ci-C ₂₀ alkyl. R ² may be substituted or unsubstituted Ci- Cio alkyl. R ² may be substituted Ci-Cio alkyl. R ² may be unsubstituted Ci-Cio alkyl. R ² may be substituted or unsubstituted C1-C5 alkyl. R ² may be unsubstituted C1-C5 alkyl. R ² may be substituted C1-C5 alkyl. R ² may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R ² may be methyl. R ² may be ethyl.

2 2C 2 2C 2

[0140] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

2C 2 2C 2 may be R -substituted or unsubstituted C1-C20 alkyl. R may be R -substituted C1-C20 alkyl. R

2C 2 2C 2 may be R -substituted or unsubstituted C1-C10 alkyl. R may be R -substituted C1-C10 alkyl. R

2C 2 2C 2 may be R -substituted or unsubstituted C1-C5 alkyl. R may be R -substituted C1-C5 alkyl. R

9 ¹ 9 ¹

may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl. [0141] R ² may be substituted or unsubstituted heteroalkyl. R ² may be substituted heteroalkyl. R ² may be unsubstituted heteroalkyl. R ² may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ² may be substituted 2 to 20 membered heteroalkyl. R ² may be unsubstituted 2 to 20 membered heteroalkyl. R ² may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ² may be substituted 2 to 10 membered heteroalkyl. R ² may be unsubstituted 2 to 10 membered heteroalkyl. R ² may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ² may be substituted 2 to 6 membered heteroalkyl. R ² may be unsubstituted 2 to 6 membered heteroalkyl.

2 2C 2 2C

[0142] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted heteroalkyl. R ² may be R ^2C -substituted or unsubstituted 2 to 20 membered heteroalkyl. R ² may

2C 2 2C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R ² may be R ^2C -substituted 2 to 10 membered heteroalkyl. R ² may

2C 2 2C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0143] R ² may be substituted or unsubstituted cycloalkyl. R ² may be substituted cycloalkyl. R ² may be unsubstituted cycloalkyl. R ² may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ² may be substituted 3 to 20 membered cycloalkyl. R ² may be unsubstituted 3 to 20 membered cycloalkyl. R ² may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ² may be substituted 3 to 10 membered cycloalkyl. R ² may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ² may be unsubstituted 3 to 6 membered cycloalkyl. R ² may be substituted 3 to 6 membered cycloalkyl. [0144] 2 2C -substituted or unsubstituted cycloalkyl. 2 2C

R may be R R may be R -substituted cycloalkyl. R ² may be R ^2C -substituted or unsubstituted 3 to 20 membered cycloalkyl. R ² may be

2C 2 2C

R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10 2 2C 2 2C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R -

2 2C

substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0145] R ² may be substituted or unsubstituted heterocycloalkyl. R ² may be substituted heterocycloalkyl. R ² may be unsubstituted heterocycloalkyl. R ² may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ² may be substituted 3 to 20 membered heterocycloalkyl. R ² may be unsubstituted 3 to 20 membered heterocycloalkyl. R ² may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ² may be substituted 3 to 10 membered heterocycloalkyl. R ² may be unsubstituted 3 to 10 membered heterocycloalkyl. R ² may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ² may be substituted 3 to 6 membered heterocycloalkyl. R ² may be unsubstituted 3 to 6 membered heterocycloalkyl.

2 2C 2 2C

[0146] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted

2 2C

heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R 2 may be R 2C -substituted 3 to 20 membered heterocycloalkyl. R 2 may be R 2C -

2 2C

substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to

2 2C

10 membered heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R 2 may be R 2C -substituted 3 to 6 membered heterocycloalkyl.

[0147] R ² may be substituted or unsubstituted aryl. R ² may be substituted aryl. R ² may be unsubstituted aryl. R ² may be substituted or unsubstituted 5 to 20 membered aryl. R ² may be substituted 5 to 20 membered aryl. R ² may be unsubstituted 5 to 20 membered aryl. R ² may be substituted or unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ² may be substituted 5 to 8 membered aryl. R ² may be substituted or unsubstituted 5 or 6 membered aryl. R ² may be unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ² may be substituted 5 or 6 membered aryl. R ² may be unsubstituted 5 or 6 membered aryl.

2 2C 2 2C 2

[0148] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R

2C 2 2C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R ² may be R ^2C -substituted or unsubstituted 5 to 8 membered aryl. R ² may be

2C 2 2C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6

2 2C

membered aryl. R may be R -substituted 5 or 6 membered aryl (e.g. phenyl). [0149] R ² may be substituted or unsubstituted heteroaryl. R ² may be substituted heteroaryl. R ² may be unsubstituted heteroaryl. R ² may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ² may be substituted 5 to 20 membered heteroaryl. R ² may be unsubstituted 5 to 20 membered heteroaryl. R ² may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ² may be substituted 5 to 8 membered heteroaryl. R ² may be unsubstituted 5 to 8 membered heteroaryl. R ² may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ² may be substituted 5 or 6 membered heteroaryl. R ² may be unsubstituted 5 or 6 membered heteroaryl.

2 2C 2 2C

[0150] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted heteroaryl. R ² may be R ^2C -substituted or unsubstituted 5 to 20 membered heteroaryl. R ² may be

2C 2 2C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8

2 2C 2 2C membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R -

2 2C

substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

2 A

[0151] R may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CCI ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -COR ^2C , - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^2C -substituted or unsubstituted alkyl, R ^2C -substituted

9 ¹ 9 ¹

or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or

9 ¹ 9 ¹

unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl. R ^2A may independently be substituted or unsubstituted C1-C5 alkyl. R ^2A may independently be methyl.

[0152] R ^2C is independently hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ^2D , -COR ^2D ,-NR ^2D R ^2E , -COOR ^2D , -CONR ^2D R ^2E , -N0 ₂ , -SH, -S(0) ₂ R ^2D , -S(0) ₃ R ^2D ,

-S(0) ₄ R ^2D , -S(0) ₂ NR ^2D R ^2E , -NHNR ^2D R ^2E , -ONR ^2D R ^2E , -NHC(0)NHNR ^2D R ^2E ,

-NHC(0)NR ^2D R ^2E , -NHS(0) ₂ R ^2D , -NHC(0)R ^2D , -NHC(0)-OR ^2D , -NHOR ^2D , -OCF ₃ , -OCHF ₂ ,

2D 2D 2D

R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R - substituted or unsubstituted cycloalkyl, R ^2D -substituted or unsubstituted heterocycloalkyl, R ^2D - substituted or unsubstituted aryl, or R ^2D -substituted or unsubstituted heteroaryl.

[0153] R ^2C may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, - OH, -COR ^2D ,-NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF ₃ , -OCHF ₂ , R ^2D - substituted or unsubstituted alkyl, R ^2D -substituted or unsubstituted heteroalkyl, R ^2D -substituted or unsubstituted cycloalkyl, R ^2D -substituted or unsubstituted heterocycloalkyl, R ^2D -substituted or unsubstituted aryl, or R ^2D -substituted or unsubstituted heteroaryl. [0154] R ^2C may independently be hydrogen, halogen, oxo, N ₃ , -CF , -CC1 , -CBr , -CI , -CN, -

OH, -COH,- H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^2D - substituted or unsubstituted alkyl, R ^2D -substituted or unsubstituted heteroalkyl, R ^2D -substituted or unsubstituted cycloalkyl, R ^2D -substituted or unsubstituted heterocycloalkyl, R ^2D -substituted or unsubstituted aryl, or R ^2D -substituted or unsubstituted heteroaryl.

[0155] R ^2B may independently be hydrogen, halogen, oxo, N , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ , -CN, - OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , - ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, - OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0156] R ^2D and R ^2E are independently hydrogen, halogen, oxo, N , -CF ₃ , -CC1 , -CBr ₃ , -CI , - CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, - S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF , -OCHF ₂ , unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0157] R ² may be R ^2A -substituted or unsubstituted heteroaryl where R ^2A is -N , -CF , -CC1 , - CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. R ² may be R ^2A - substituted or unsubstituted heteroaryl where R ^2A is -CF ₃ , -CN, -OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , or substituted or unsubstituted alkyl. R ^2A may be substituted or unsubstituted C1-C5 alkyl. R ^2A may be methyl.

[0158] R ² may be substituted or unsubstituted furanyl, substituted or unsubstituted pyrroyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazoyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazoyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. R ² may be substituted or unsubstituted furanyl. R ² may be substituted or unsubstituted pyrroyl. R ² may be substituted or unsubstituted thiophenyl. R ² may be substituted or unsubstituted imidazoyl. R ² may be substituted or unsubstituted pyrazolyl. R ² may be substituted or unsubstituted oxazoyl. R ² may be substituted or unsubstituted isoxazolyl. R ² may be substituted or unsubstituted thiazolyl. R ² may be substituted or unsubstituted pyridinyl. R ² may be substituted or unsubstituted pyrazinyl. R ² may be substituted or unsubstituted pyrimidinyl. R ² may be substituted or unsubstituted pyridazinyl.

[0159] R ² may be R ^2A -substituted or unsubstituted furanyl, substituted or unsubstituted pyrroyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazoyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazoyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. R ² may be R ^2A - substituted or unsubstituted furanyl. R ²

2 A 2 2 A

may be R -substituted or unsubstituted pyrrolyl. R may be R -substituted or unsubstituted

2 2A 2 2A thiophenyl. R may be R -substituted or unsubstituted imidazoyl. R may be R -substituted or

2 2 A 2 A unsubstituted pyrazolyl. R may be R -substituted or unsubstituted pyrazolyl where R is -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, - H ₂ , -C(0)OH, -C(0) H ₂ , -N0 ₂ , -SH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R ² may be R ^2A -substituted or

2 2A 2 2A unsubstituted oxazoyl. R may be R -substituted or unsubstituted isoxazolyl. R may be R - substituted or unsubstituted thiazolyl. R ² may be R ^2A - substituted or unsubstituted pyridinyl. R ²

2 A 2 2 A

may be R -substituted or unsubstituted pyrazinyl. R may be R -substituted or unsubstituted pyrimidinyl. R ² may be R ^2A -substituted or unsubstituted pyridazinyl. R ² may be 5-methyl-lH- pyrazolyl.

[0160] R ³ may be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^A , -OR ^A , -NR ^A R ^B , -C(0)OR ^A , -C(0)NR ^A R ^B , -N0 ₂ , -SR ^A , -S(0)„ ₃ R ^A , -S(0)„ ₃ OR ^A ,

-S(0)„ ₃ NR ^A R ^B , -NHNR ^A R ^B , -ONR ^A R ^B , -NHC(0)NHNR ^A R ^B , substituted or unsubstituted alkyl, or optionally combined with R ⁴ to form a substituted or unsubstituted cycloalkyl where R ^A and R ^B are independently hydrogen, oxo, halogen, -CF ₃ , -OH, -NH ₂ ,

-COOH, -CONH ₂ , substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [0161] R ³ may be hydrogen, halogen, -OR ^A , or substituted or unsubstituted alkyl, where R ^A is as defined herein. R ³ may be hydrogen, halogen, -OR ^A , or R ^C - substituted or unsubstituted alkyl, where R 3 A and R 3 C are as defined herein. R 3 may be hydrogen, halogen, -OR 3 A , or substituted or unsubstituted alkyl where R ^A is substituted or unsubstituted alkyl. R ³ may be

3 A 3 C 3 A

hydrogen, halogen, -OR , or R -substituted or unsubstituted alkyl where R is substituted or unsubstituted alkyl and R ^C is as defined herein. R ³ may be hydrogen, halogen, -OR ^A , or substituted or unsubstituted alkyl where R ^A is R ^C -substituted or unsubstituted alkyl. R ³ may be

3A 3C 3A 3C hydrogen, halogen, -OR , or R -substituted or unsubstituted alkyl where R is R -substituted

3 C

or unsubstituted alkyl and R is as defined herein. [0162] R ³ may be -CI, -I, or -Br. R ³ may be -CI. R ³ may be -Br. R ³ may be - 1. R ³ may be -F. R ³ may be -OR ^A , where R ^A is as defined herein. R ³ may be -OR ^A where R ^A is substituted or

3 3 A 3 A 3 unsubstituted alkyl. R may be -OR where R is substituted or unsubstituted C ₁ -C ₅ alkyl. R may be -OR ^A where R ^A is R ^C - substituted or unsubstituted C ₁ -C ₅ alkyl. R ³ may be -OCH ₃ . R ³ may be -OCH ₂ CH ₃ . R ³ may be -OR ^A where R ^A is substituted or unsubstituted C ₅ -C6 aryl.

[0163] R ³ may be substituted or unsubstituted alkyl. R ³ may be substituted alkyl. R ³ may be unsubstituted alkyl. R ³ may be substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ³ may be substituted C ₁ -C ₂₀ alkyl. R ³ may be unsubstituted C ₁ -C ₂₀ alkyl. R ³ may be substituted or unsubstituted Ci- C ₁₀ alkyl. R ³ may be substituted C ₁ -C ₁₀ alkyl. R ³ may be unsubstituted C ₁ -C ₁₀ alkyl. R ³ may be substituted or unsubstituted C ₁ -C ₅ alkyl. R ³ may be unsubstituted C ₁ -C ₅ alkyl. R ³ may be substituted C ₁ -C5 alkyl. R ³ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R ³ may be methyl. R ³ may be ethyl.

3 3 C 3 3 C 3

[0164] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

3 C 3 3 C 3 may be R -substituted or unsubstituted C ₁ -C ₂₀ alkyl. R may be R -substituted C ₁ -C ₂₀ alkyl. R

3 C 3 3 C 3 may be R -substituted or unsubstituted C ₁ -C ₁₀ alkyl. R may be R -substituted C ₁ -C ₁₀ alkyl. R

3 C 3 3 C 3 may be R -substituted or unsubstituted C ₁ -C ₅ alkyl. R may be R -substituted C ₁ -C ₅ alkyl. R

3 C 3 C

may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl.

[0165] R ³ may be substituted or unsubstituted heteroalkyl. R ³ may be substituted heteroalkyl. R ³ may be unsubstituted heteroalkyl. R ³ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ³ may be substituted 2 to 20 membered heteroalkyl. R ³ may be unsubstituted 2 to 20 membered heteroalkyl. R ³ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ³ may be substituted 2 to 10 membered heteroalkyl. R ³ may be unsubstituted 2 to 10 membered heteroalkyl. R ³ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ³ may be substituted 2 to 6 membered heteroalkyl. R ³ may be unsubstituted 2 to 6 membered heteroalkyl.

3 3 C 3 3 C

[0166] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted heteroalkyl. R ³ may be R ^C - substituted or unsubstituted 2 to 20 membered heteroalkyl. R ³ may

3 C 3 3 C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2 to 10 membered heteroalkyl. R ³ may be R ^C - substituted 2 to 10 membered heteroalkyl. R ³ may

3 C 3 3 C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl.

[0167] R ³ may be substituted or unsubstituted cycloalkyl. R ³ may be substituted cycloalkyl. R ³ may be unsubstituted cycloalkyl. R ³ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ³ may be substituted 3 to 20 membered cycloalkyl. R ³ may be unsubstituted 3 to 20 membered cycloalkyl. R ³ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ³ may be substituted 3 to 10 membered cycloalkyl. R ³ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ³ may be unsubstituted 3 to 6 membered cycloalkyl. R ³ may be substituted 3 to 6 membered cycloalkyl.

3 3 C 3 3 C

[0168] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted cycloalkyl. R ³ may be R ^C - substituted or unsubstituted 3 to 20 membered cycloalkyl. R ³ may be

3 C 3 3 C

R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10

3 3 C 3 3 C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R -

3 3 C

substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0169] R ³ may be substituted or unsubstituted heterocycloalkyl. R ³ may be substituted heterocycloalkyl. R ³ may be unsubstituted heterocycloalkyl. R ³ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ³ may be substituted 3 to 20 membered heterocycloalkyl. R ³ may be unsubstituted 3 to 20 membered heterocycloalkyl. R ³ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ³ may be substituted 3 to 10 membered heterocycloalkyl. R ³ may be unsubstituted 3 to 10 membered heterocycloalkyl. R ³ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ³ may be substituted 3 to 6 membered heterocycloalkyl. R ³ may be unsubstituted 3 to 6 membered heterocycloalkyl.

3 3 C 3 3 C

[0170] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted

3 3 C

heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R 3 may be R 3 C -substituted 3 to 20 membered heterocycloalkyl. R 3 may be R 3 C -

3 3 C

substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to

3 3 C

10 membered heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R 3 may be R 3 C -substituted 3 to 6 membered heterocycloalkyl.

[0171] R ³ may be substituted or unsubstituted aryl. R ³ may be substituted aryl. R ³ may be unsubstituted aryl. R ³ may be substituted or unsubstituted 5 to 20 membered aryl. R ³ may be substituted 5 to 20 membered aryl. R ³ may be unsubstituted 5 to 20 membered aryl. R ³ may be substituted or unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ³ may be substituted 5 to 8 membered aryl. R ³ may be substituted or unsubstituted 5 or 6 membered aryl. R ³ may be unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ³ may be substituted 5 or 6 membered aryl. R ³ may be unsubstituted 5 or 6 membered aryl. 3 3 C 3 3 C 3

[0172] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R

3 C 3 3 C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to 20 membered aryl. R ³ may be R ^C - substituted or unsubstituted 5 to 8 membered aryl. R ³ may be

3 C 3 3 C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6

3 3 C

membered aryl. R may be R -substituted 5 or 6 membered aryl (e.g. phenyl).

[0173] R ³ may be substituted or unsubstituted heteroaryl. R ³ may be substituted heteroaryl. R ³ may be unsubstituted heteroaryl. R ³ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ³ may be substituted 5 to 20 membered heteroaryl. R ³ may be unsubstituted 5 to 20 membered heteroaryl. R ³ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ³ may be substituted 5 to 8 membered heteroaryl. R ³ may be unsubstituted 5 to 8 membered heteroaryl. R ³ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ³ may be substituted 5 or 6 membered heteroaryl. R ³ may be unsubstituted 5 or 6 membered heteroaryl.

3 3 C 3 3 C

[0174] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted heteroaryl. R ³ may be R ^C - substituted or unsubstituted 5 to 20 membered heteroaryl. R ³ may be

3 C 3 3 C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8

3 3 C 3 3 C membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R -

3 3 C

substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

[0175] R ^A may independently be hydrogen, halogen, oxo, N ₃ , -CF , -CC1 , -CBr , -CI , -CN, -COR ^C , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^C - substituted or unsubstituted alkyl, R ^C - substituted

3 C 3 C

or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or

3 C 3 C

unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl.

[0176] R ^C is independently hydrogen, halogen, oxo, N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -COR ^D , -OR ^D , -NR ^D R ^E , -COOR ^D , -CONR ^D R ^E , -N0 ₂ , -SR ^D , -S(0) ₂ R ^D , -S(0) ₃ R ^D , -S(0) ₄ R ^D , -S(0) ₂ NR ^D R ^E , -NHNR ^D R ^E , -ONR ^D R ^E , -NHC(0)NHNR ^D R ^E ,

-NHC(0)NR ^D R ^E , -NHS(0) ₂ R ^D , -NHC(0)R ^D , -NHC(0)-OR ^D , -NHOR ^D , -OCF ₃ , -OCHF ₂ ,

3D 3D 3D

R -substituted or unsubstituted alkyl, R -substituted or unsubstituted heteroalkyl, R - substituted or unsubstituted cycloalkyl, R ^D -substituted or unsubstituted heterocycloalkyl, R ^D - substituted or unsubstituted aryl, or R ^D -substituted or unsubstituted heteroaryl. [0177] R ^C may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -

COR ^D , -OH, - H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCFIF ₂ , R ^D -substituted or unsubstituted alkyl, R ^D -substituted or unsubstituted heteroalkyl, R ^D -substituted or unsubstituted cycloalkyl, R ^D -substituted or unsubstituted heterocycloalkyl, R ^D -substituted or unsubstituted aryl, or R ^D -substituted or unsubstituted heteroaryl.

[0178] R ^B may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, - OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0179] R ^D is independently hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -COR ^F ,-NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^F -substituted or unsubstituted heteroalkyl, R ^F -substituted or unsubstituted cycloalkyl, R ^F - substituted or unsubstituted heterocycloalkyl, R ^F -substituted or unsubstituted aryl, or R ^F -substituted or unsubstituted heteroaryl.

[0180] R ^D may independently be hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -COH,-NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0181] R ^E and R ^F are independently hydrogen, halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, - S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0182] R ³ and R ⁴ may together form a substituted or unsubstituted cycloalkyl. R ³ and R ⁴ may together form a R ^C - substituted or unsubstituted cycloalkyl. R ³ and R ⁴ may together form an unsubstituted cycloalkyl. R ³ and R ⁴ may together form an unsubstituted C3-C ₆ cycloalkyl. R ³ and R ⁴ may together form an unsubstituted saturated C3-C ₆ cycloalkyl. R ³ and R ⁴ may together form an C3-C ₆ unsubstituted unsaturated cycloalkyl. R ³ and R ⁴ may together form an R ^C - substituted

3 C 3 C

saturated C3-C ₆ cycloalkyl where R is as defined herein. R may be halogen,

-COR ^D , unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted cycloalkyl, or substituted or

3 C

unsubstituted heterocycloalkyl. R may be methyl, unsubstituted ethyl, or unsubstituted propyl.

3 C 3 C

R may be substituted or unsubstituted C3-C ₆ cycloalkyl. R may be unsubstituted C3-C ₆ cycloalkyl. 3 C may be substituted 3 C 3D

R C3-C ₆ cycloalkyl. R may be R -substituted cycloalkyl, where R ^D is as defined herein. R ^C may be substituted or unsubstituted C3-C ₆ heterocycloalkyl.

3 C 3 C

R may be unsubstituted C3-C ₆ heterocycloalkyl. R may be substituted C3-C ₆

heterocycloalkyl. 3 C 3D ere 3D

R may be R -substituted heterocycloalkyl, wh R is as defined herein. R ^D may be -COR ^E , substituted or unsubstituted alkyl or substituted or unsubstituted

heterocycloalkyl.

[0183] R ⁴ may be 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 ⁴ may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0184] R ⁴ may be substituted or unsubstituted alkyl. R ⁴ may be substituted alkyl. R ⁴ may be unsubstituted alkyl. R ⁴ may be substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ⁴ may be substituted C ₁ -C ₂₀ alkyl. R ⁴ may be unsubstituted C ₁ -C ₂₀ alkyl. R ⁴ may be substituted or unsubstituted C ₁ -C ₁₀ alkyl. R ⁴ may be substituted C ₁ -C ₁₀ alkyl. R ⁴ may be unsubstituted C ₁ -C ₁₀ alkyl. R ⁴ may be substituted or unsubstituted C ₁ -C ₅ alkyl. R ⁴ may be substituted C ₁ -C ₅ alkyl. R ⁴ may be unsubstituted C ₁ -C ₅ alkyl. R ⁴ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0185] R ⁴ may be R ⁴⁰ -substituted or unsubstituted alkyl. R ⁴ may be R ⁴⁰ -substituted alkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ⁴ may be R ⁴⁰ -substituted C ₁ -C ₂₀ alkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted C ₁ -C ₁₀ alkyl. R ⁴ may be R ⁴⁰ -substituted C ₁ -C ₁₀ alkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted C ₁ -C ₅ alkyl. R ⁴ may be R ⁴⁰ -substituted C ₁ -C ₅ alkyl. R ⁴ may be methyl, R ⁴⁰ -substituted or unsubstituted ethyl, or R ⁴⁰ - substituted or unsubstituted propyl. [0186] R ⁴ may be substituted or unsubstituted heteroalkyl. R ⁴ may be substituted heteroalkyl. R ⁴ may be unsubstituted heteroalkyl. R ⁴ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ⁴ may be substituted 2 to 20 membered heteroalkyl. R ⁴ may be unsubstituted 2 to 20 membered heteroalkyl. R ⁴ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ⁴ may be substituted 2 to 10 membered heteroalkyl. R ⁴ may be unsubstituted 2 to 10 membered heteroalkyl. R ⁴ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ⁴ may be substituted 2 to 6 membered heteroalkyl. R ⁴ may be unsubstituted 2 to 6 membered heteroalkyl.

[0187] R ⁴ may be R ⁴⁰ -substituted or unsubstituted heteroalkyl. R ⁴ may be R ⁴⁰ -substituted heteroalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 2 to 20 membered heteroalkyl. R ⁴ may be R ⁴⁰ -substituted 2 to 20 membered heteroalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 2 to 10 membered heteroalkyl. R ⁴ may be R ⁴⁰ -substituted 2 to 10 membered heteroalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 2 to 6 membered heteroalkyl. R ⁴ may be R ⁴⁰ -substituted 2 to 6 membered heteroalkyl.

[0188] R ⁴ may be substituted or unsubstituted cycloalkyl. R ⁴ may be substituted cycloalkyl. R ⁴ may be unsubstituted cycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ⁴ may be substituted 3 to 20 membered cycloalkyl. R ⁴ may be unsubstituted 3 to 20 membered cycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ⁴ may be substituted 3 to 10 membered cycloalkyl. R ⁴ may be unsubstituted 3 to 10 membered cycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R ⁴ may be substituted 3 to 6 membered cycloalkyl. R ⁴ may be unsubstituted 3 to 6 membered cycloalkyl.

[0189] R ⁴ may be R ⁴⁰ -substituted or unsubstituted cycloalkyl. R ⁴ may be R ⁴⁰ -substituted cycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 3 to 20 membered cycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 20 membered cycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 3 to 10 membered cycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 10 membered cycloalkyl. R ⁴ may be R ⁴⁰ - substituted or unsubstituted 3 to 6 membered cycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 6 membered cycloalkyl.

[0190] R ⁴ may be substituted or unsubstituted heterocycloalkyl. R ⁴ may be substituted heterocycloalkyl. R ⁴ may be unsubstituted heterocycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ⁴ may be substituted 3 to 20 membered heterocycloalkyl. R ⁴ may be unsubstituted 3 to 20 membered heterocycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ⁴ may be substituted 3 to 10 membered heterocycloalkyl. R ⁴ may be unsubstituted 3 to 10 membered heterocycloalkyl. R ⁴ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ⁴ may be substituted 3 to 6 membered heterocycloalkyl. R ⁴ may be unsubstituted 3 to 6 membered heterocycloalkyl.

[0191] R ⁴ may be R ⁴⁰ -substituted or unsubstituted heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 20 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 10 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted 3 to 6 membered heterocycloalkyl.

[0192] R ⁴ may be substituted or unsubstituted aryl. R ⁴ may be substituted aryl. R ⁴ may be unsubstituted aryl. R ⁴ may be substituted or unsubstituted 5 to 20 membered aryl. R ⁴ may be substituted 5 to 20 membered aryl. R ⁴ may be unsubstituted 5 to 20 membered aryl. R ⁴ may be substituted or unsubstituted 5 to 8 membered aryl. R ⁴ may be substituted 5 to 8 membered aryl. R ⁴ may be unsubstituted 5 to 8 membered aryl. R ⁴ may be substituted or unsubstituted 5 or 6 membered aryl. R ⁴ may be substituted 5 or 6 membered aryl (e.g. phenyl). R ⁴ may be

unsubstituted 5 or 6 membered aryl.

[0193] R ⁴ may be R ⁴⁰ -substituted or unsubstituted aryl. R ⁴ may be R ⁴⁰ -substituted aryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 20 membered aryl. R ⁴ may be R ⁴⁰ -substituted 5 to 20 membered aryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 8 membered aryl. R ⁴ may be R ⁴⁰ -substituted 5 to 8 membered aryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 or 6 membered aryl. R ⁴ may be R ⁴⁰ -substituted 5 or 6 membered aryl (e.g. phenyl).

[0194] R ⁴ may be substituted or unsubstituted aryl. R ⁴ may be substituted heteroaryl. R ⁴ may be unsubstituted heteroaryl. R ⁴ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ⁴ may be substituted 5 to 20 membered aryl. R ⁴ may be unsubstituted 5 to 20 membered heteroaryl. R ⁴ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ⁴ may be substituted 5 to 8 membered heteroaryl. R ⁴ may be unsubstituted 5 to 8 membered heteroaryl. R ⁴ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ⁴ may be substituted 5 or 6 membered heteroaryl. R ⁴ may be unsubstituted 5 or 6 membered heteroaryl.

[0195] R ⁴ may be R ⁴⁰ -substituted or unsubstituted heteroaryl. R ⁴ may be R ⁴⁰ -substituted heteroaryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 20 membered heteroaryl. R ⁴ may be R ⁴⁰ -substituted 5 to 20 membered heteroaryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 8 membered heteroaryl. R ⁴ may be R ⁴⁰ -substituted 5 to 8 membered heteroaryl. R ⁴ may be R ⁴⁰ - substituted or unsubstituted 5 or 6 membered heteroaryl. R ⁴ may be R ⁴⁰ -substituted 5 or 6 membered heteroaryl.

[0196] R ⁴ may be R ⁴⁰ -substituted or unsubstituted cycloalkyl, R ⁴⁰ -substituted or unsubstituted heterocycloalkyl, R ⁴⁰ -substituted or unsubstituted aryl, or R ⁴⁰ - substituted or unsubstituted heteroaryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted cycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted aryl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted heteroaryl.

[0197] R ⁴ may be R ⁴⁰ -substituted or unsubstituted heterocycloalkyl. R ⁴ may be substituted or unsubstituted 5 to 8 membered heterocycloalkyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 8 membered heterocycloalkyl. R ⁴ may be substituted or unsubstituted 5 to 8 membered heterocycloalkyl having at least one ring nitrogen. R ⁴ may be R ⁴⁰ -substituted or unsubstituted 5 to 8 membered heterocycloalkyl having at least one ring nitrogen.

[0198] R ⁴ may be substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholino, or substituted or unsubstituted pyrrolidinyl. R ⁴ may be substituted or unsubstituted piperidinyl. R ⁴ may be substituted or unsubstituted piperazinyl. R ⁴ may be substituted or unsubstituted morpholino. R ⁴ may be substituted or unsubstituted pyrrolidinyl.

[0199] R ⁴ may be R ⁴⁰ -substituted or unsubstituted piperidinyl, R ⁴⁰ -substituted or unsubstituted piperazinyl, R ⁴⁰ -substituted or unsubstituted morpholino, or R ⁴⁰ - substituted or unsubstituted pyrrolidinyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted piperidinyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted piperazinyl. R ⁴ may be R ⁴⁰ -substituted or unsubstituted morpholino. R ⁴ may be R ⁴⁰ -substituted or unsubstituted pyrrolidinyl.

[0200] R ⁴⁰ is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-COR ^40A , -OR ^40A , - R ^40A R ^40B , -C(O)OR ^40A , -C(O) R ^40A R ^40B , -N0 ₂ , -SR ^40A , -S(O) ₂ R ^40A , -S(O) ₂ OR ^40A , -S(O) ₂ R ^40A R ^40B , - HNR ^40A R ^40B , -O R ^40A R ^40B , - HC(O) HNR ^40A R ^40B , R ^40A - substituted or unsubstituted alkyl, R ^40A - substituted or unsubstituted heteroalkyl, R ^40A - substituted or unsubstituted cycloalkyl, R ^40A - substituted or unsubstituted heterocycloalkyl, R ^40A - substituted or unsubstituted aryl, or R ^40A - substituted or unsubstituted heteroaryl.

[0201] R ⁴⁰ may independently be oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ ,

-CN, -COR ^40A , -OR ^40A , -NR ^40A R ^40B , -C(O)OR ^40A , -C(O)NR ^40A R ^40B , -N0 ₂ , -SR ^40A , -S(O) ₂ R ^40A , -S(O) ₂ OR ^40A , -S(O) ₂ NR ^40A R ^40B , -NHNR ^40A R ^40B , -ONR ^40A R ^40B , -NHC(O)NHNR ^40A R ^40B , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0202] R ⁴⁰ may independently be oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH,

- H ₂ , -C(0)OH, -C(0) H ₂ , -COH, -COC¾, -N0 ₂ , -SH, -S(0) ₂ H, -S(0) ₂ OH, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0203] R ^40A is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁴¹ , -NR ⁴¹ R ^40C , -COR ⁴¹ , -COOR ⁴¹ , -CONR ⁴¹ R ^40C , -N0 ₂ , -SR ⁴¹ , -S(0) ₂ R ⁴¹ , -S(0) ₃ R ⁴¹ , - S(O) ₂ NR ⁴¹ R ^40C , S(0) ₄ R ⁴¹ , -NHNR ⁴¹ R ^40C , -ONR ⁴¹ R ^40C , -NHC(O)NHNR ⁴¹ R ^40C ,

-NHC(O)NR ⁴¹ R ^40C , -NHS(0) ₂ R ⁴¹ , -NHC(0)R ⁴¹ , -NHC(0)-OR ⁴¹ , -NHOR ⁴¹ , -OCF ₃ , -OCHF ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ - substituted or unsubstituted cycloalkyl, R ⁴¹ - substituted or unsubstituted heterocycloalkyl, R ⁴¹ - substituted or unsubstituted aryl, or R ⁴¹ - substituted or unsubstituted heteroaryl.

[0204] R ^40A may independently be hydrogen, oxo, halogen, -N , -CF , -CC1 , -CBr , -CI , -CN, -OH, -NH ₂ , -COR ⁴¹ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ - substituted or unsubstituted cycloalkyl, R ⁴¹ - substituted or unsubstituted heterocycloalkyl, R ⁴¹ - substituted or unsubstituted aryl, or R ⁴¹ - substituted or unsubstituted heteroaryl.

[0205] R ^40A may independently be hydrogen, oxo, halogen, -N , -CF , -CC1 , -CBr , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0206] R ⁴¹ is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^41A , - OR ^41A , -NR ^41A R ^41B , -C(0)OR ^41A , -C(0)NR ^41A R ^41B , -N0 ₂ , -SR ^41A , -S(0) ₂ R ^41A , -S(0) ₂ OR ^41A , -S(0) ₂ NR ^41A R ^41B , -NHNR ^41A R ^41B , -ONR ^41A R ^41B , -NHC(0)NHNR ^41A R ^41B , R ⁴² -substituted or unsubstituted alkyl, R ⁴² -substituted or unsubstituted heteroalkyl, R ⁴² -substituted or unsubstituted cycloalkyl, R ⁴² -substituted or unsubstituted heterocycloalkyl, R ⁴² -substituted or unsubstituted aryl, or R ⁴² - substituted or unsubstituted heteroaryl.

[0207] R ⁴¹ may independently be hydrogen, oxo, halogen, -N ₃ , -CF , -CC1 ₃ , -CBr , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, - S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0208] R ⁴² is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COC¾, -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - NHOH, -OCF ₃ , -OCHF ₂ , R ⁴³ - substituted or unsubstituted alkyl, R ⁴ -substituted or unsubstituted heteroalkyl, R ⁴ -substituted or unsubstituted cycloalkyl, R ⁴ -substituted or unsubstituted heterocycloalkyl, R ⁴ -substituted or unsubstituted aryl, or R ⁴ -substituted or unsubstituted heteroaryl.

[0209] R ⁴² may independently be oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ ,

-CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0210] R ⁴³ is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴⁴ -substituted or unsubstituted alkyl, R ⁴⁴ -substituted or unsubstituted heteroalkyl, R ⁴⁴ -substituted or unsubstituted cycloalkyl, R ⁴⁴ -substituted or unsubstituted heterocycloalkyl, R ⁴⁴ -substituted or unsubstituted aryl, or R ⁴⁴ - substituted or unsubstituted heteroaryl. [0211] R ^41A is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^41C - substituted or unsubstituted heteroalkyl, R ^41C -

41 C 41 C substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R -

41 C

substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl.

[0212] R ^41C is independently hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^41D -substituted or unsubstituted alkyl, R ^41D - substituted or unsubstituted heteroalkyl, R ^41D -substituted or unsubstituted cycloalkyl, R ^41D - substituted or unsubstituted heterocycloalkyl, R ^41D -substituted or unsubstituted aryl, or R ^41D - substituted or unsubstituted heteroaryl.

[0213] R ^41B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COC¾, -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^41E -substituted or unsubstituted alkyl, R ^41E -

4 IE 4 IE substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -

4 IE 4 IE substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R - substituted or unsubstituted heteroaryl.

[0214] R ^41E is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^41F -substituted or unsubstituted alkyl, R ^41F -substituted

4 IF 4 IF

or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or

4 IF 4 IF

unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl. [0215] R ^40B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁴⁵ , -NR ⁴⁵ R ^40D , -COR ⁴⁵ , -COOR ⁴⁵ , -CONR ⁴⁵ R ^40D , -N0 ₂ , -SR ⁴⁵ , -S(0) ₂ R ⁴⁵ , -S(0) ₃ R ⁴⁵ , -S(0) ₄ R ⁴⁵ , -S(O) ₂ NR ⁴⁵ R ^40D , -NHNR ⁴⁵ R ^40D , -ONR ⁴⁵ R ^40D , -NHC(O)NHNR ⁴⁵ R ^40D ,

-NHC(O)NR ⁴⁵ R ^40D , -NHS(0) ₂ R ⁴⁵ , -NHC(0)R ⁴⁵ , -NHC(0)-OR ⁴⁵ , -NHOR ⁴⁵ , -OCF ₃ , -OCHF ₂ , R ⁴⁵ -substituted or unsubstituted heteroalkyl, R ⁴⁵ -substituted or unsubstituted cycloalkyl, R ⁴⁵ - substituted or unsubstituted heterocycloalkyl, R ⁴⁵ -substituted or unsubstituted aryl, or R ⁴⁵ - substituted or unsubstituted heteroaryl.

[0216] R ^40B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COR ⁴⁵ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴⁵ - substituted or unsubstituted heteroalkyl, R ⁴⁵ - substituted or unsubstituted cycloalkyl, R ⁴⁵ -substituted or unsubstituted heterocycloalkyl, R ⁴⁵ - substituted or unsubstituted aryl, or R ⁴⁵ -substituted or unsubstituted heteroaryl. [0217] R ^40B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ ,

-CN, -OH, - H ₂ , -COOH, -COH, -COC¾, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, - S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0218] R ⁴⁵ is independently hydrogen, halogen, oxo, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^45A , -OR ^45A , -NR ^45A R ^45B , -C(0)OR ^45A , -C(0)NR ^45A R ^45B , -N0 ₂ , -SR ^45A , -S(0) ₂ R ^45A , -S(0) ₂ OR ^45A , -S(0) ₂ NR ^45A R ^45B , -NHNR ^45A R ^45B , -ONR ^45A R ^45B , -NHC(0)NHNR ^45A R ^45B , R ⁴⁶ - substituted or unsubstituted alkyl, R ⁴⁶ -substituted or unsubstituted heteroalkyl, R ⁴⁶ -substituted or unsubstituted cycloalkyl, R ⁴⁶ -substituted or unsubstituted heterocycloalkyl, R ⁴⁶ -substituted or unsubstituted aryl, or R ⁴⁶ - substituted or unsubstituted heteroaryl.

[0219] R ^45A is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^45C - substituted or unsubstituted heteroalkyl, R ^45C - substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R - substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl.

[0220] R ^45C is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^45D -substituted or unsubstituted alkyl, R ^45D - substituted or unsubstituted heteroalkyl, R ^45D -substituted or unsubstituted cycloalkyl, R ^45D - substituted or unsubstituted heterocycloalkyl, R ^45D -substituted or unsubstituted aryl, or R ^45D - substituted or unsubstituted heteroaryl.

[0221] R ^45B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^45E - substituted or unsubstituted alkyl, R ^45E - substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R - substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R - substituted or unsubstituted heteroaryl. [0222] R ^45E is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COC¾, -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^45F - substituted or unsubstituted alkyl, R ^45F -substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl.

[0223] R ⁴⁶ is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴⁷ -substituted or unsubstituted alkyl, R ⁴⁷ -substituted or unsubstituted heteroalkyl, R ⁴⁷ -substituted or unsubstituted cycloalkyl, R ⁴⁷ -substituted or unsubstituted heterocycloalkyl, R ⁴⁷ -substituted or unsubstituted aryl, or R ⁴⁷ - substituted or unsubstituted heteroaryl. [0224] R ^40C , R ^40D , R ^41D , R ^41F , and R ^45D are independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , - CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,

-NO ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0225] R ^45F , R ⁴⁴ , and R ⁴⁷ are independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, - OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, - S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, - NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl

[0226] R ⁴ may be -NR ^4A R ^4B . R ^4A and R ^4B are as defined herein. R ^4A may be hydrogen, R ⁴¹ - substituted or unsubstituted alkyl, or R ⁴¹ - substituted or unsubstituted heteroalkyl, where R ⁴¹ is as defined herein. R ^4A may be hydrogen, R ⁴¹ - substituted or unsubstituted alkyl, or R ⁴¹ - substituted or unsubstituted heteroalkyl, where R ⁴¹ is hydrogen, halogen, -CF ₃ , -OR ^41A ,

-NR ^41A R ^41B , R ⁴² -substituted or unsubstituted alkyl, R ⁴² -substituted or unsubstituted heteroalkyl, or R ⁴² - substituted or unsubstituted aryl. R ^4A may be hydrogen, R ⁴¹ - substituted or unsubstituted alkyl, or R ⁴¹ - substituted or unsubstituted heteroalkyl, where R ⁴¹ is hydrogen, halogen, -CF ₃ , -

OR ^41A , - R ^41A R ^41B , R ⁴² -substituted or unsubstituted alkyl, R ⁴² -substituted or unsubstituted heteroalkyl, or R ⁴² - substituted or unsubstituted aryl, R ^41A and R ^41B are independently hydrogen or unsubstituted C1-C5 alkyl, and R ⁴² is as described herein. [0227] R ^4B may be hydrogen, R ⁴⁵ -substituted or unsubstituted alkyl, or R ⁴⁵ - substituted or unsubstituted heteroalkyl, where R ⁴⁵ is as defined herein. R ^4B may be hydrogen, R ⁴⁵ -substituted or unsubstituted alkyl, or R ⁴⁵ -substituted or unsubstituted heteroalkyl, where R ⁴⁵ is hydrogen, halogen, CF ₃ , -OR ^45A , - R ^45A R ^45B , R ⁴⁶ - substituted or unsubstituted alkyl, R ⁴⁶ -substituted or unsubstituted heteroalkyl, or R ⁴⁶ - substituted or unsubstituted aryl. R ^4B may be hydrogen, R ⁴⁵ - substituted or unsubstituted alkyl, or R ⁴⁵ - substituted or unsubstituted heteroalkyl, where R ⁴⁵ is hydrogen, halogen, CF ₃ , -OR ^45A , - R ^45A R ^45B , R ⁴⁶ -substituted or unsubstituted alkyl, R ⁴⁶ - substituted or unsubstituted heteroalkyl, or R ⁴⁶ -substituted or unsubstituted aryl, R ^45A and R ^45B are independently hydrogen or unsubstituted C1-C5 alkyl and R ⁴⁶ is as defined herein.

[0228] R ^4A may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁴¹ , - R ⁴¹ R ^40C , -COR ⁴¹ , -COOR ⁴¹ , -CO R ⁴¹ R ^40C , -N0 ₂ , -SR ⁴¹ , -S(0) ₂ R ⁴¹ , -S(0) ₃ R ⁴¹ , -S(0) ₄ R ⁴¹ , - HNR ⁴¹ R ^40C , -O R ⁴¹ R ^40C , - HC(O) HNR ⁴¹ R ^40C , - HC(O) R ⁴¹ R ^40C ,

- HS(0) ₂ R ⁴¹ , - HC(0)R ⁴¹ , - HC(0)-OR ⁴¹ , - HOR ⁴¹ , -OCF ₃ , -OCHF ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ - substituted or unsubstituted cycloalkyl, R ⁴¹ - substituted or unsubstituted heterocycloalkyl, R ⁴¹ - substituted or unsubstituted aryl, or R ⁴¹ - substituted or unsubstituted heteroaryl.

[0229] R ^4A may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COR ⁴¹ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ - substituted or unsubstituted cycloalkyl, R ⁴¹ - substituted or unsubstituted heterocycloalkyl, R ⁴¹ - substituted or unsubstituted aryl, or R ⁴¹ - substituted or unsubstituted heteroaryl.

[0230] R ^4A may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴¹ - substituted or unsubstituted alkyl, R ⁴¹ - substituted or unsubstituted heteroalkyl, R ⁴¹ - substituted or unsubstituted cycloalkyl, R ⁴¹ - substituted or unsubstituted heterocycloalkyl, R ⁴¹ - substituted or unsubstituted aryl, or R ⁴¹ - substituted or unsubstituted heteroaryl.

[0231] R ^4B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CCI ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁴⁵ , - R ⁴⁵ R ^40D , -COR ⁴⁵ , -COOR ⁴⁵ , -CO R ⁴⁵ R ^40D , -N0 ₂ , -SR ⁴⁵ , -S(0) ₂ R ⁴⁵ , -S(0) ₃ R ⁴⁵ , -S(0) ₄ R ⁴⁵ , -S(O) ₂ R ⁴⁵ R ^40D , - HNR ⁴⁵ R ^40D , -O R ⁴⁵ R ^40D , - HC(O) HNR ⁴⁵ R ^40D ,

- HC(O) R ⁴⁵ R ^40D , - HS(0) ₂ R ⁴⁵ , - HC(0)R ⁴⁵ , - HC(0)-OR ⁴⁵ , - HOR ⁴⁵ , -OCF ₃ , -OCHF ₂ , R ⁴⁵ -substituted or unsubstituted heteroalkyl, R ⁴⁵ -substituted or unsubstituted cycloalkyl, R ⁴⁵ - substituted or unsubstituted heterocycloalkyl, R ⁴⁵ -substituted or unsubstituted aryl, or R ⁴⁵ - substituted or unsubstituted heteroaryl. [0232] R ^4B may independently be oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁴⁵ -substituted or unsubstituted alkyl, R ⁴⁵ -substituted or unsubstituted heteroalkyl, R ⁴⁵ - substituted or unsubstituted cycloalkyl, R ⁴⁵ -substituted or unsubstituted heterocycloalkyl, R ⁴⁵ - substituted or unsubstituted aryl, or R ⁴⁵ -substituted or unsubstituted heteroaryl.

[0233] The compound of formula (la) may have the formula:

(Ial),

where L ¹ , zl, R ³ , R ⁵ , R ⁶ , R ^40A , and R ^40B are as described herein.

[0234] The compound of formula (lb) may have the formula:

where L ¹ , zl, R ³ , R ⁵ , R ⁶ , R ^40A , and R ^40B are as described herein.

[0235] R ⁵ may independently be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^5A , -OR ^5A , -NR ^5A R ^5B , -C(0)OR ^5A , -C(0)NR ^5A R ^5B , -N0 ₂ , -SR ^5A , -S(0)„ ₅ R ^5A , -S(0)„ ₅ OR ^5A , -S(0)„ ₅ R ^5A R ^5B , - HNR ^5A R ^5B , -O R ^5A R ^5B , or - HC(0) HNR ^5A R ^5B . R ⁵ may independently be 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. [0236] R ⁵ may be hydrogen or halogen. R ⁵ may be hydrogen or -CI, -I, or -Br. R ⁵ may be hydrogen or -CI or -F. R ⁵ may be hydrogen. R ⁵ may be -CI. R ⁵ may be -I. R ⁵ may be -Br. R ⁵ may be -F. The symbol zl may be 1, 2, or 3. The symbol zl may be 1 or 2. R ⁵ may be hydrogen or - CI or -F where the symbol zl is 1 or 2.

[0237] R ⁵ may be substituted or unsubstituted alkyl. R ⁵ may be substituted alkyl. R ⁵ may be unsubstituted alkyl. R ⁵ may be substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ⁵ may be substituted C ₁ -C ₂₀ alkyl. R ⁵ may be unsubstituted C ₁ -C ₂₀ alkyl. R ⁵ may be substituted or unsubstituted Ci- C ₁₀ alkyl. R ⁵ may be substituted C ₁ -C ₁₀ alkyl. R ⁵ may be unsubstituted C ₁ -C ₁₀ alkyl. R ⁵ may be substituted or unsubstituted C ₁ -C ₅ alkyl. R ⁵ may be unsubstituted C ₁ -C ₅ alkyl. R ⁵ may be substituted C ₁ -C ₅ alkyl. R ⁵ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R ⁵ may be methyl. R ⁵ may be ethyl.

5 5C 5 5C 5

[0238] R may be R -substituted or unsubstituted alkyl. R may be R -substituted alkyl. R

5C 5 5C 5 may be R -substituted or unsubstituted C ₁ -C ₂₀ alkyl. R may be R -substituted C ₁ -C ₂₀ alkyl. R

5C 5 5C 5 may be R -substituted or unsubstituted C ₁ -C ₁₀ alkyl. R may be R -substituted C ₁ -C ₁₀ alkyl. R

5C 5 5C 5 may be R -substituted or unsubstituted C ₁ -C ₅ alkyl. R may be R -substituted C ₁ -C ₅ alkyl. R may be methyl, R -substituted or unsubstituted ethyl, or R -substituted or unsubstituted propyl.

[0239] R ⁵ may be substituted or unsubstituted heteroalkyl. R ⁵ may be substituted heteroalkyl. R ⁵ may be unsubstituted heteroalkyl. R ⁵ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ⁵ may be substituted 2 to 20 membered heteroalkyl. R ⁵ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ⁵ may be substituted 2 to 10 membered

heteroalkyl. R ⁵ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ⁵ may be substituted 2 to 6 membered heteroalkyl.

5 5C 5 5C

[0240] R may be R -substituted or unsubstituted heteroalkyl. R may be R -substituted

5 5C 5 heteroalkyl. R may be R -substituted or unsubstituted 2 to 20 membered heteroalkyl. R may

5C 5 5C

be R -substituted 2 to 20 membered heteroalkyl. R may be R -substituted or unsubstituted 2

5 5C 5 to 10 membered heteroalkyl. R may be R -substituted 2 to 10 membered heteroalkyl. R may

5C 5 5C

be R -substituted or unsubstituted 2 to 6 membered heteroalkyl. R may be R -substituted 2 to 6 membered heteroalkyl. [0241] R ⁵ may be substituted or unsubstituted cycloalkyl. R ⁵ may be substituted cycloalkyl. R ⁵ may be unsubstituted cycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ⁵ may be substituted 3 to 20 membered cycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ⁵ may be substituted 3 to 10 membered cycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R ⁵ may be substituted 3 to 6 membered cycloalkyl.

5 5C 5 5C

[0242] R may be R -substituted or unsubstituted cycloalkyl. R may be R -substituted

5 5C 5 cycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered cycloalkyl. R may be

5C 5 5C

R -substituted 3 to 20 membered cycloalkyl. R may be R -substituted or unsubstituted 3 to 10

5 5C 5 5C membered cycloalkyl. R may be R -substituted 3 to 10 membered cycloalkyl. R may be R -

5 5C

substituted or unsubstituted 3 to 6 membered cycloalkyl. R may be R -substituted 3 to 6 membered cycloalkyl.

[0243] R ⁵ may be substituted or unsubstituted heterocycloalkyl. R ⁵ may be substituted heterocycloalkyl. R ⁵ may be unsubstituted heterocycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ⁵ may be substituted 3 to 20 membered heterocycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ⁵ may be substituted 3 to 10 membered heterocycloalkyl. R ⁵ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ⁵ may be substituted 3 to 6 membered heterocycloalkyl.

5 5C 5 5C

[0244] R may be R -substituted or unsubstituted heterocycloalkyl. R may be R -substituted

5 5C

heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 20 membered

heterocycloalkyl. R 5 may be R 5C -substituted 3 to 20 membered heterocycloalkyl. R 5 may be R 5C -

5 5C

substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R may be R -substituted 3 to

5 5C

10 membered heterocycloalkyl. R may be R -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R 5 may be R 5C -substituted 3 to 6 membered heterocycloalkyl. [0245] R ⁵ may be substituted or unsubstituted aryl. R ⁵ may be substituted aryl. R ⁵ may be unsubstituted aryl. R ⁵ may be substituted or unsubstituted 5 to 20 membered aryl. R ⁵ may be substituted 5 to 20 membered aryl. R ⁵ may be substituted or unsubstituted 5 to 8 membered aryl (e.g. phenyl). R ⁵ may be substituted 5 to 8 membered aryl. R ⁵ may be substituted or

unsubstituted 5 or 6 membered aryl. R ⁵ may be substituted 5 or 6 membered aryl.

5 5C 5 5C 5

[0246] R may be R -substituted or unsubstituted aryl. R may be R -substituted aryl. R

5C 5 5C

may be R -substituted or unsubstituted 5 to 20 membered aryl. R may be R -substituted 5 to

5 5C 5

20 membered aryl. R may be R -substituted or unsubstituted 5 to 8 membered aryl. R may be 5C 5 5C

R -substituted 5 to 8 membered aryl. R may be R -substituted or unsubstituted 5 or 6

5 5C

membered aryl. R may be R -substituted 5 or 6 membered aryl (e.g. phenyl).

[0247] R ⁵ may be substituted or unsubstituted heteroaryl. R ⁵ may be substituted heteroaryl. R ⁵ may be unsubstituted heteroaryl. R ⁵ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ⁵ may be substituted 5 to 20 membered heteroaryl. R ⁵ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ⁵ may be substituted 5 to 8 membered heteroaryl. R ⁵ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ⁵ may be substituted 5 or 6 membered heteroaryl.

5 5C 5 5C

[0248] R may be R -substituted or unsubstituted heteroaryl. R may be R -substituted

5 5C 5 heteroaryl. R may be R -substituted or unsubstituted 5 to 20 membered heteroaryl. R may be

5C 5 5C

R -substituted 5 to 20 membered heteroaryl. R may be R -substituted or unsubstituted 5 to 8

5 5C 5 5C membered heteroaryl. R may be R -substituted 5 to 8 membered heteroaryl. R may be R -

5 5C

substituted or unsubstituted 5 or 6 membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl. [0249] R ^5A may independently be hydrogen, halogen, oxo, N ₃ , -CF , -CC1 , -CBr , -CI ,

-CN, -OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^5C - substituted or unsubstituted alkyl, R ^5C - substituted or unsubstituted heteroalkyl, R -substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R -substituted or unsubstituted aryl, or R -substituted or unsubstituted heteroaryl.

[0250] R ^5C is independently halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -COR ^5D ,-NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H,

-S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^5D -substituted or unsubstituted alkyl, R ^5D -substituted or unsubstituted heteroalkyl, R ^5D -substituted or unsubstituted cycloalkyl, R ^5D - substituted or unsubstituted heterocycloalkyl, R ^5D -substituted or unsubstituted aryl, or R ^5D - substituted or unsubstituted heteroaryl.

[0251] R ^5B may independently be hydrogen, halogen, oxo, N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, - OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0252] R ^5D is independently halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -COR ^5E , - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^5E - substituted or unsubstituted heteroalkyl, R ^5E - substituted or unsubstituted cycloalkyl, R ^5E - substituted or unsubstituted heterocycloalkyl, R ^5E - substituted or unsubstituted aryl, or R ^5E - substituted or unsubstituted heteroaryl. [0253] R ^5E is independently halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , - COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0254] R ⁶ may be hydrogen, -NH ₂ , -CF ₃ , -NR ^6A R ^6B , 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 ⁶ may be hydrogen, -CF ₃ , -NR ^6A R ^6B , R ⁶⁰ -substituted or unsubstituted alkyl, R ⁶⁰ - substituted or unsubstituted heteroalkyl, R ⁶⁰ -substituted or unsubstituted cycloalkyl, R ⁶⁰ - substituted or unsubstituted heterocycloalkyl, R ⁶⁰ -substituted or unsubstituted aryl, or R ⁶⁰ - substituted or unsubstituted heteroaryl.

[0255] R ⁶ may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0256] R ⁶ may be substituted or unsubstituted alkyl. R ⁶ may be substituted alkyl. R ⁶ may be unsubstituted alkyl. R ⁶ may be substituted or unsubstituted Ci-C ₂₀ alkyl. R ⁶ may be substituted Ci-C ₂ o alkyl. R ⁶ may be unsubstituted Ci-C ₂₀ alkyl. R ⁶ may be substituted or unsubstituted Ci- Cio alkyl. R ⁶ may be substituted Ci-Cio alkyl. R ⁶ may be unsubstituted Ci-Cio alkyl. R ⁶ may be substituted or unsubstituted C1-C5 alkyl. R ⁶ may be substituted C1-C5 alkyl. R ⁶ may be unsubstituted C1-C5 alkyl. R ⁶ may be methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl. R ⁶ may be hydrogen, methyl, ethyl or propyl. R ⁶ may be hydrogen. R ⁶ may be methyl. [0257] R ⁶ may be R ⁶⁰ -substituted or unsubstituted alkyl. R ⁶ may be R ⁶⁰ -substituted alkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted C ₁ -C ₂₀ alkyl. R ⁶ may be R ⁶⁰ -substituted C ₁ -C ₂₀ alkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted C ₁ -C ₁₀ alkyl. R ⁶ may be R ⁶⁰ -substituted C ₁ -C ₁₀ alkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted C ₁ -C ₅ alkyl. R ⁶ may be R ⁶⁰ -substituted C ₁ -C ₅ alkyl. R ⁶ may be methyl, R ⁶⁰ -substituted or unsubstituted ethyl, or R ⁶⁰ - substituted or unsubstituted propyl.

[0258] R ⁶ may be substituted or unsubstituted heteroalkyl. R ⁶ may be substituted heteroalkyl. R ⁶ may be unsubstituted heteroalkyl. R ⁶ may be substituted or unsubstituted 2 to 20 membered heteroalkyl. R ⁶ may be substituted 2 to 20 membered heteroalkyl. R ⁶ may be unsubstituted 2 to 20 membered heteroalkyl. R ⁶ may be substituted or unsubstituted 2 to 10 membered heteroalkyl. R ⁶ may be substituted 2 to 10 membered heteroalkyl. R ⁶ may be unsubstituted 2 to 10 membered heteroalkyl. R ⁶ may be substituted or unsubstituted 2 to 6 membered heteroalkyl. R ⁶ may be substituted 2 to 6 membered heteroalkyl. R ⁶ may be unsubstituted 2 to 6 membered heteroalkyl.

[0259] R ⁶ may be R ⁶⁰ -substituted or unsubstituted heteroalkyl. R ⁶ may be R ⁶⁰ -substituted heteroalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 2 to 20 membered heteroalkyl. R ⁶ may be R ⁶⁰ -substituted 2 to 20 membered heteroalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 2 to 10 membered heteroalkyl. R ⁶ may be R ⁶⁰ -substituted 2 to 10 membered heteroalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 2 to 6 membered heteroalkyl. R ⁶ may be R ⁶⁰ -substituted 2 to 6 membered heteroalkyl.

[0260] R ⁶ may be substituted or unsubstituted cycloalkyl. R ⁶ may be substituted cycloalkyl. R ⁶ may be unsubstituted cycloalkyl. R ⁶ may be substituted or unsubstituted 3 to 20 membered cycloalkyl. R ⁶ may be substituted 3 to 20 membered cycloalkyl. R ⁶ may be unsubstituted 3 to 20 membered cycloalkyl. R ⁶ may be substituted or unsubstituted 3 to 10 membered cycloalkyl. R ⁶ may be substituted 3 to 10 membered cycloalkyl. R ⁶ may be unsubstituted 3 to 10 membered cycloalkyl. R ⁶ may be substituted or unsubstituted 3 to 6 membered cycloalkyl. R ⁶ may be substituted 3 to 6 membered cycloalkyl. R ⁶ may be unsubstituted 3 to 6 membered cycloalkyl.

[0261] R ⁶ may be R ⁶⁰ -substituted or unsubstituted cycloalkyl. R ⁶ may be R ⁶⁰ -substituted cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 3 to 20 membered cycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 20 membered cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 3 to 10 membered cycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 10 membered cycloalkyl. R ⁶ may be R ⁶⁰ - substituted or unsubstituted 3 to 6 membered cycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 6 membered cycloalkyl. [0262] R ⁶ may be substituted or unsubstituted heterocycloalkyl. R ⁶ may be substituted heterocycloalkyl. R ⁶ may be unsubstituted heterocycloalkyl. R ⁶ may be substituted or

unsubstituted 3 to 20 membered heterocycloalkyl. R ⁶ may be substituted 3 to 20 membered heterocycloalkyl. R ⁶ may be unsubstituted 3 to 20 membered heterocycloalkyl. R ⁶ may be substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ⁶ may be substituted 3 to 10 membered heterocycloalkyl. R ⁶ may be unsubstituted 3 to 10 membered heterocycloalkyl. R ⁶ may be substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ⁶ may be substituted 3 to 6 membered heterocycloalkyl. R ⁶ may be unsubstituted 3 to 6 membered heterocycloalkyl.

[0263] R ⁶ may be R ⁶⁰ -substituted or unsubstituted heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 3 to 20 membered heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 20 membered heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 3 to 10 membered heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 10 membered heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. R ⁶ may be R ⁶⁰ -substituted 3 to 6 membered heterocycloalkyl. [0264] R ⁶ may be substituted or unsubstituted aryl. R ⁶ may be substituted aryl. R ⁶ may be unsubstituted aryl. R ⁶ may be substituted or unsubstituted 5 to 20 membered aryl. R ⁶ may be substituted 5 to 20 membered aryl. R ⁶ may be unsubstituted 5 to 20 membered aryl. R ⁶ may be substituted or unsubstituted 5 to 8 membered aryl. R ⁶ may be substituted 5 to 8 membered aryl. R ⁶ may be unsubstituted 5 to 8 membered aryl. R ⁶ may be substituted or unsubstituted 5 or 6 membered aryl. R ⁶ may be substituted 5 or 6 membered aryl (e.g. phenyl). R ⁶ may be

unsubstituted 5 or 6 membered aryl (e.g. phenyl).

[0265] R ⁶ may be R ⁶⁰ -substituted or unsubstituted aryl. R ⁶ may be R ⁶⁰ -substituted aryl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 5 to 20 membered aryl. R ⁶ may be R ⁶⁰ -substituted 5 to 20 membered aryl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 5 to 8 membered aryl. R ⁶ may be R ⁶⁰ -substituted 5 to 8 membered aryl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 5 or 6 membered aryl. R ⁶ may be R ⁶⁰ -substituted 5 or 6 membered aryl (e.g. phenyl).

[0266] R ⁶ may be substituted or unsubstituted heteroaryl. R ⁶ may be substituted heteroaryl. R ⁶ may be unsubstituted heteroaryl. R ⁶ may be substituted or unsubstituted 5 to 20 membered heteroaryl. R ⁶ may be substituted 5 to 20 membered heteroaryl. R ⁶ may be unsubstituted 5 to 20 membered heteroaryl. R ⁶ may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ⁶ may be substituted 5 to 8 membered heteroaryl. R ⁶ may be unsubstituted 5 to 8 membered heteroaryl. R ⁶ may be substituted or unsubstituted 5 or 6 membered heteroaryl. R ⁶ may be substituted 5 or 6 membered heteroaryl. R ⁶ may be unsubstituted 5 or 6 membered heteroaryl.

[0267] R ⁶ may be R ⁶⁰ -substituted or unsubstituted heteroaryl. R ⁶ may be R ⁶⁰ -substituted heteroaryl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 5 to 20 membered heteroaryl. R ⁶ may be R ⁶⁰ -substituted 5 to 20 membered heteroaryl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted 5 to 8 membered heteroaryl. R ⁶ may be R ⁶⁰ -substituted 5 to 8 membered heteroaryl. R ⁶ may be R ⁶⁰ - substituted or unsubstituted 5 or 6 membered heteroaryl. R ⁶ may be R ⁶⁰ -substituted 5 or 6 membered heteroaryl.

[0268] R ⁶ may be R ⁶⁰ -substituted or unsubstituted cycloalkyl, R ⁶⁰ -substituted or unsubstituted heterocycloalkyl, R ⁶⁰ -substituted or unsubstituted aryl, or R ⁶⁰ - substituted or unsubstituted heteroaryl.

[0269] R ⁶ may be R ⁶⁰ -substituted or unsubstituted C cycloalkyl. R ⁶ may be unsubstituted C cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted C ₄ cycloalkyl. R ⁶ may be unsubstituted C ₄ cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted C ₅ cycloalkyl. R ⁶ may be unsubstituted C ₅ cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted saturated C cycloalkyl. R ⁶ may be unsubstituted saturated C cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted saturated C ₄ cycloalkyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted saturated C ₅ cycloalkyl. R ⁶ may be unsubstituted saturated C ₅ cycloalkyl.

[0270] R ⁶ may R ⁶⁰ -substituted or unsubstituted aryl where R ⁶⁰ is as defined herein, R ^60A is hydrogen, halogen, -N0 ₂ , -CF ₃ , -CN, -COR ⁶¹ , R ⁶¹ -substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, or R ⁶¹ - substituted or unsubstituted aryl, where R ⁶¹ is as defined herein and R ^60B is hydrogen, halogen, or unsubstituted alkyl.

[0271] R ⁶ may be R ⁶⁰ -substituted or unsubstituted heteroaryl where R ⁶⁰ is halogen, -CF ₃ , - R ^60A R ^60B , -N0 ₂ , -OR ^60A , -COOR ^60A , -COR ⁶¹ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, or R ⁶¹ - substituted or unsubstituted aryl, where R ⁶¹ is - R ^61A R ^61B , and R ^60A , R ^60B , R ^61A , and R ^61B are independently hydrogen or unsubstituted C1-C5 unsubstituted alkyl.

[0272] R ⁶ may be substituted or unsubstituted thiophenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted oxazolyl. R ⁶ may be substituted or unsubstituted thiophenyl. R ⁶ may be substituted or unsubstituted thiazolyl. R ⁶ may be substituted or unsubstituted imidazolyl. R ⁶ may be substituted or unsubstituted oxazolyl. [0273] R ⁶ may be R ⁶⁰ -substituted or unsubstituted thiophenyl, R ⁶⁰ -substituted or unsubstituted thiazolyl, R ⁶⁰ -substituted or unsubstituted imidazolyl, or R ⁶⁰ - substituted or unsubstituted oxazolyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted thiophenyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted thiazolyl. R ⁶ may be R ⁶⁰ -substituted or unsubstituted imidazolyl. R ⁶ may be R ⁶⁰ - substituted or unsubstituted oxazolyl.

[0274] R ⁶⁰ is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ⁶¹ , - OR ^60A , - R ^60A R ^60B , -C(O)OR ^60A , -C(O) R ^60A R ^60B , -N0 ₂ , -SR ^60A , -S(0) ₂ H, -S(0) ₂ OH, - S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(O) HNR ^60A R ^60B , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl.

[0275] R ⁶⁰ may independently be oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COH, -COCH ₃ ,-OH, -NH ₂ , -C(0)OH, -C(0)NH ₂ , -N0 ₂ , -SH, -S(0) ₂ H, -S(0) ₂ OH, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0276] R ^60A is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁶¹ , -NR ⁶¹ R ^60C , -COOR ⁶¹ , -CONR ⁶¹ R ^60C , -COR ⁶¹ ,-N0 ₂ , -SR ⁶¹ , -S(0) ₂ R ⁶¹ , -S(0) ₃ R ⁶¹ , -S(0) ₄ R ⁶¹ , -S(O) ₂ NR ⁶¹ R ^60C , -NHNR ⁶¹ R ^60C , -ONR ⁶¹ R ^60C , -NHC(O)NHNR ⁶¹ R ^60C ,

-NHC(O)NR ⁶¹ R ^60C , -NHS(0) ₂ R ⁶¹ , -NHC(0)R ⁶¹ , -NHC(0)-OR ⁶¹ , -NHOR ⁶¹ , -OCF ₃ , -OCHF ₂ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl.

[0277] R ^60A may independently be hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COR ⁶¹ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl. [0278] R ^60A may independently be hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R ^60A may independently be hydrogen or unsubstituted C1-C5 alkyl. R ^60A may independently be hydrogen. R ^60A may independently be methyl or unsubstituted ethyl. R ^60A may independently be methyl.

[0279] R ⁶¹ is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^61A , - OR ^61A , - R ^61A R ^61B , -C(0)OR ^61A , -C(0) R ^61A R ^61B , -N0 ₂ , -SR ^61A , -S(0) ₂ R ^61A , -S(0) ₂ OR ^61A , -S(0) ₂ R ^61A R ^61B , - HNR ^61A R ^61B , -O R ^61A R ^61B , - HC(0) HNR ^61A R ^61B , R ⁶² -substituted or unsubstituted alkyl, R ⁶² -substituted or unsubstituted heteroalkyl, R ⁶² -substituted or unsubstituted cycloalkyl, R ⁶² -substituted or unsubstituted heterocycloalkyl, R ⁶² -substituted or unsubstituted aryl, or R ⁶² - substituted or unsubstituted heteroaryl.

[0280] R ⁶¹ is independently hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^61A , - OR ^61A , -NR ^61A R ^61B , -C(0)OR ^61A , -C(0)NR ^61A R ^61B , -N0 ₂ , -SR ^61A , -S(0) ₂ H, -S(0) ₂ OH,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNR ^61A R ^61B , R ⁶² - substituted or unsubstituted alkyl, R ⁶² -substituted or unsubstituted heteroalkyl, R ⁶² -substituted or unsubstituted cycloalkyl, R ⁶² - substituted or unsubstituted heterocycloalkyl, R ⁶² -substituted or unsubstituted aryl, or R ⁶² - substituted or unsubstituted heteroaryl.

[0281] R ⁶¹ may independently be hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0282] R ⁶² is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ ,

-NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, - NHOH, -OCF ₃ , -OCHF ₂ , R ⁶³ - substituted or unsubstituted alkyl, R ⁶ -substituted or unsubstituted heteroalkyl, R ⁶ -substituted or unsubstituted cycloalkyl, R ⁶ -substituted or unsubstituted heterocycloalkyl, R ⁶ -substituted or unsubstituted aryl, or R ⁶ -substituted or unsubstituted heteroaryl.

[0283] R ⁶² may independently be oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI ,

-CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. [0284] R ⁶³ is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶⁴ -substituted or unsubstituted alkyl, R ⁶⁴ -substituted or unsubstituted heteroalkyl, R ⁶⁴ -substituted or unsubstituted cycloalkyl, R ⁶⁴ -substituted or unsubstituted heterocycloalkyl, R ⁶⁴ -substituted or unsubstituted aryl, or R ⁶⁴ - substituted or unsubstituted heteroaryl.

[0285] R ^61A is independently hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^61C - substituted or unsubstituted heteroalkyl, R ^61C -

61 C 61 C substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R - substituted or unsubstituted aryl, or R ^61C - substituted or unsubstituted heteroaryl. R ^61A may independently be hydrogen or unsubstituted C1-C5 alkyl. R ^61A may independently be hydrogen.

_R 61A may independently be methyl or unsubstituted ethyl. R ^61A may independently be methyl. [0286] R ^61C is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COC¾,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^61D -substituted or unsubstituted alkyl, R ^61D - substituted or unsubstituted heteroalkyl, R ^61D -substituted or unsubstituted cycloalkyl, R ^61D - substituted or unsubstituted heterocycloalkyl, R ^61D -substituted or unsubstituted aryl, or R ^61D - substituted or unsubstituted heteroaryl.

[0287] R ^61B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^61E -substituted or unsubstituted alkyl, R ^61E - substituted or unsubstituted heteroalkyl, R ^61E -substituted or unsubstituted cycloalkyl, R ^61E - substituted or unsubstituted heterocycloalkyl, R ^61E -substituted or unsubstituted aryl, or R ^61E - substituted or unsubstituted heteroaryl. R ^61B may independently be hydrogen or unsubstituted Ci- C ₅ alkyl. R ^61B may independently be hydrogen. R ^61B may independently be methyl or

unsubstituted ethyl. R ^61B may independently be methyl.

[0288] R ^61E is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^61F -substituted or unsubstituted alkyl, R ^61F -substituted or unsubstituted heteroalkyl, R ^61F -substituted or unsubstituted cycloalkyl, R ^61F -substituted or unsubstituted heterocycloalkyl, R ^61F -substituted or unsubstituted aryl, or R ^61F -substituted or unsubstituted heteroaryl.

[0289] R ^60B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁶⁵ , -NR ⁶⁵ R ^60D , -COOR ⁶⁵ , -CONR ⁶⁵ R ^60D , -COR ⁶⁵ , -N0 ₂ , -SH, -S(0) ₂ R ⁶⁵ , -S(0) ₃ R ⁶⁵ ,

-S(0) ₄ R ⁶⁵ , -S(O) ₂ NR ⁶⁵ R ^60D , -NHNR ⁶⁵ R ^60D , -ONR ⁶⁵ R ^60D , -NHC(O)NHNR ⁶⁵ R ^60D ,

-NHC(O)NR ⁶⁵ R ^60D , -NHS(0) ₂ R ⁶⁵ , -NHC(0)R ⁶⁵ , -NHC(0)-OR ⁶⁵ , -NHOR ⁶⁵ , -OCF ₃ , -OCHF ₂ , R ⁶⁵ -substituted or unsubstituted heteroalkyl, R ⁶⁵ -substituted or unsubstituted cycloalkyl, R ⁶⁵ - substituted or unsubstituted heterocycloalkyl, R ⁶⁵ -substituted or unsubstituted aryl, or R ⁶⁵ - substituted or unsubstituted heteroaryl. R ^60B may independently be hydrogen or unsubstituted Ci-

C ₅ alkyl. R 60B may independently be hydrogen. R 60B may independently be methyl or

unsubstituted ethyl. R ^60B may independently be methyl. [0290] R ^60B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COR ⁶⁵ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶⁵ - substituted or unsubstituted heteroalkyl, R ⁶⁵ - substituted or unsubstituted cycloalkyl, R ⁶⁵ -substituted or unsubstituted heterocycloalkyl, R ⁶⁵ - substituted or unsubstituted aryl, or R ⁶⁵ -substituted or unsubstituted heteroaryl. R ^60B may independently be hydrogen or unsubstituted C ₁ -C5 alkyl. R ^60B may independently be hydrogen.

R 60B may independently be methyl or unsubstituted ethyl. R 60B may independently be methyl.

[0291] R ^60B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0292] R ⁶⁵ is independently hydrogen, halogen, oxo, -N ₃ , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ , -CN, -COR ^65A , -OR ^65A , - R ^65A R ^65B , -C(0)OR ^65A , -C(0) R ^65A R ^65B , -N0 ₂ , -SR ^65A , -S(0) ₂ H,

-S(0) ₂ OH, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNR ^65A R ^65B , R ⁶⁶ -substituted or

unsubstituted alkyl, R ⁶⁶ -substituted or unsubstituted heteroalkyl, R ⁶⁶ -substituted or unsubstituted cycloalkyl, R ⁶⁶ -substituted or unsubstituted heterocycloalkyl, R ⁶⁶ -substituted or unsubstituted aryl, or R ⁶⁶ - substituted or unsubstituted heteroaryl.

[0293] R ^65A is independently hydrogen, oxo, halogen, -N , -CF ₃ , -CC1 , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^65C - substituted or unsubstituted heteroalkyl, R ^65C - substituted or unsubstituted cycloalkyl, R -substituted or unsubstituted heterocycloalkyl, R - substituted or unsubstituted aryl, or R ^65C -substituted or unsubstituted heteroaryl. R ^65A may independently be hydrogen or unsubstituted C ₁ -C5 alkyl. R ^65A may independently be hydrogen.

_R 65A may independently be methyl or unsubstituted ethyl. R ^65A may independently be methyl.

[0294] R ^65C is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^65D -substituted or unsubstituted alkyl, R ^65D - substituted or unsubstituted heteroalkyl, R ^65D -substituted or unsubstituted cycloalkyl, R ^65D - substituted or unsubstituted heterocycloalkyl, R ^65D -substituted or unsubstituted aryl, or R ^65D - substituted or unsubstituted heteroaryl.

[0295] R ^65B is independently hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H,

-S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ^65E - substituted or unsubstituted alkyl, R ^65E - substituted or unsubstituted heteroalkyl, R ^65E -substituted or unsubstituted cycloalkyl, R ^65E - substituted or unsubstituted heterocycloalkyl, R ^65E -substituted or unsubstituted aryl, or R ^65E - substituted or unsubstituted heteroaryl. R ^65B may independently be hydrogen or unsubstituted Ci- C ₅ alkyl. R ^65B may independently be hydrogen. R ^65B may independently be methyl or

unsubstituted ethyl. R ^65B may independently be methyl. [0296] R ^65E is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, - H ₂ , -COOH, -CO H ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , R ^65F - substituted or unsubstituted alkyl, R ^65F -substituted or unsubstituted heteroalkyl, R ^65F -substituted or unsubstituted cycloalkyl, R ^65F -substituted or unsubstituted heterocycloalkyl, R ^65F -substituted or unsubstituted aryl, or R ^65F -substituted or unsubstituted heteroaryl.

[0297] R ⁶⁶ is independently oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶⁷ -substituted or unsubstituted alkyl, R ⁶⁷ -substituted or unsubstituted heteroalkyl, R ⁶⁷ -substituted or unsubstituted cycloalkyl, R ⁶⁷ -substituted or unsubstituted heterocycloalkyl, R ⁶⁷ -substituted or unsubstituted aryl, or R ⁶⁷ - substituted or unsubstituted heteroaryl. [0298] R ^60C , R ^60D , R ^61D , R ^61F , R ^65D , R ^65F , R ⁶⁴ , and R ⁶⁷ are independently oxo, halogen, -N ₃ , - CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,

-NO ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0299] R ^6A may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁶¹ , -NR ⁶¹ R ^60C , -COOR ⁶¹ , -CONR ⁶¹ R ^60C , -COR ⁶¹ ,-N0 ₂ , -SR ⁶¹ , -S(0) ₂ R ⁶¹ , -S(0) ₃ R ⁶¹ , -S(0) ₄ R ⁶¹ , -S(O) ₂ NR ⁶¹ R ^60C , -NHNR ⁶¹ R ^60C , -ONR ⁶¹ R ^60C , -NHC(O)NHNR ⁶¹ R ^60C ,

-NHC(O)NR ⁶¹ R ^60C , -NHS(0) ₂ R ⁶¹ , -NHC(0)R ⁶¹ , -NHC(0)-OR ⁶¹ , -NHOR ⁶¹ , -OCF ₃ , -OCHF ₂ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl.

[0300] R ^6A may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H,

-NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl.

[0301] R ^6B may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CCI ₃ , -CBr ₃ , -CI ₃ , -CN, -OR ⁶⁵ , - R ⁶⁵ R ^60D , -COOR ⁶⁵ , -CO R ⁶⁵ R ^60D , -COR ⁶⁵ , -N0 ₂ , -SH, -S(0) ₂ R ⁶⁵ , -S(0) ₃ R ⁶⁵ , -S(0) ₄ R ⁶⁵ , -S(O) ₂ R ⁶⁵ R ^60D , - HNR ⁶⁵ R ^60D , -O R ⁶⁵ R ^60D , - HC(O) HNR ⁶⁵ R ^60D ,

- HC(O) R ⁶⁵ R ^60D , - HS(0) ₂ R ⁶⁵ , - HC(0)R ⁶⁵ , - HC(0)-OR ⁶⁵ , - HOR ⁶⁵ , -OCF ₃ , -OCHF ₂ , R ⁶⁵ -substituted or unsubstituted heteroalkyl, R ⁶⁵ -substituted or unsubstituted cycloalkyl, R ⁶⁵ - substituted or unsubstituted heterocycloalkyl, R ⁶⁵ -substituted or unsubstituted aryl, or R ⁶⁵ - substituted or unsubstituted heteroaryl. [0302] R ^6B may independently be oxo, halogen, -CF ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -NO ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -COH, -COCH ₃ ,-S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , R ⁶⁵ -substituted or unsubstituted alkyl, R ⁶⁵ -substituted or unsubstituted heteroalkyl, R ⁶⁵ - substituted or unsubstituted cycloalkyl, R ⁶⁵ -substituted or unsubstituted heterocycloalkyl, R ⁶⁵ - substituted or unsubstituted aryl, or R ⁶⁵ -substituted or unsubstituted heteroaryl.

[0303] The compound of formula (la) may have the formula:

[0304] R ³ , R ⁴ , R ⁵ , zl, R ¹³ , and R ⁶⁰ are as described herein. The symbol z3 is an integer of 0, 1, 2, 3, 4, or 5. The symbol z3 may be 1, 2, or 3. The symbol z3 may be 1. The symbol z3 may be 2. The symbol z3 may be 3.

[0305] R ⁶⁰ may independently be hydrogen, halogen, -N ₃ , -CF ₃ , -CCI3, -CBr ₃ , -CI ₃ , -CN, -COR ⁶¹ , -OR ^60A , -NR ^60A R ^60B , -C(O)OR ^60A , -C(O)NR ^60A R ^60B , -N0 ₂ , -SR ^60A , -S(0) ₂ H,

-S(0) ₂ OH, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNR ^60A R ^60B , R ⁶¹ - substituted or

unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl. R ^60A may independently be hydrogen, halogen, -N0 ₂ , -CF ₃ , -CN, -COR ⁶¹ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, or R ⁶¹ - substituted or unsubstituted aryl. R ⁶¹ may independently be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ^61A , -OR ^61A ,

- R ^61A R ^61B , -C(0)OR ^61A , -C(0) R ^61A R ^61B , -N0 ₂ , -SR ^61A , -S(0) ₂ H, -S(0) ₂ OH, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNR ^61A R ^61B , R ⁶² - substituted or unsubstituted alkyl, R ⁶² -substituted or unsubstituted heteroalkyl, R ⁶² -substituted or unsubstituted cycloalkyl, R ⁶² -substituted or unsubstituted heterocycloalkyl, R ⁶² -substituted or unsubstituted aryl, or R ⁶² - substituted or unsubstituted heteroaryl. R ⁶² may independently be hydrogen, oxo, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , - CBr ₃ , -CI ₃ , -CN, -OH, -NH ₂ , -COOH, -CONH ₂ , -COH, -COCH ₃ ,-N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(0)NHNH ₂ , -NHC(0)NH ₂ ,

-NHS(0) ₂ H, -NHC(0)H, -NHC(0)-OH, -NHOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. R ^60B may independently be hydrogen halogen, or unsubstituted alkyl.

[0306] The compound of formula (la) may have the formula:

[0307] R ³ , R ⁴ , R ⁵ , zl, z3, and R ⁶⁰ are as described herein. R ⁶⁰ may independently be hydrogen, halogen, -N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN, -COR ⁶¹ , -OR ^60A , -NR ^60A R ^60B ,

-C(O)OR ^60A , -C(O)NR ^60A R ^60B , -N0 ₂ , -SR ^60A , -S(0) ₂ H, -S(0) ₂ OH, -S(0) ₂ NH ₂ , -NHNH ₂ , -ONH ₂ , -NHC(O)NHNR ^60A R ^60B , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, R ⁶¹ - substituted or unsubstituted cycloalkyl, R ⁶¹ - substituted or unsubstituted heterocycloalkyl, R ⁶¹ - substituted or unsubstituted aryl, or R ⁶¹ - substituted or unsubstituted heteroaryl. R ^60A may independently be hydrogen, halogen, -N0 ₂ , -CF ₃ , -CN, -COR ⁶¹ , R ⁶¹ - substituted or unsubstituted alkyl, R ⁶¹ - substituted or unsubstituted heteroalkyl, or R ⁶¹ - substituted or unsubstituted aryl; R ⁶¹ is independently hydrogen, halogen, or unsubstituted alkyl. R ^60B may independently be hydrogen halogen, or unsubstituted alkyl.

[0308] The compound of formula (la) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein. The symbol z4 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7. Ring A is cycloalkyl or heterocycloalkyl. The compound of formula (Ia2) may have formula:

[0309] The compound of formula (la) may have the formula:

(Ia3),

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein. The compound of formula (Ia3) may have formula

[0310] The compound of formula (la) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the symbol z4 is an integer of 0, 1, 2, 3, or 4. The compound of formula have the formula

[0311] The compound of formula (la) may have the formula:

where L ¹ , zl, z4, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein. The compound of formula (Ia5) may have the formula

[0312] The compound of formula (la) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the symbol z4 is an integer of 0, 1, 2, 3, or 4. The compound of formula (Ia6) may have the formula

[0313] The compound of formula (lb) may have the formula:

where L ¹ , zl, z4, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the compound is not VX- 680. Ring A is cycloalkyl or heterocycloalkyl. The compound of formula (Ib2) may have the formula:

where the compound is not VX-680.

[0314] The compound of formula (lb) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the compound is not VX-680. The compound of formula (Ib3) may have the formula:

where the compound is not VX-680.

[0315] The compound of formula (lb) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the symbol z4 is an integer of 0, 1, 2, 3, or 4. The compound of formula (Ib4) may have the formula

[0316] The compound of formula (lb) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the symbol z4 is an integer of 0, 1, 2, 3, 4, or 5. The compound of formula (Ib5) may have the formula

[0317] The compound of formula (lb) may have the formula:

where L ¹ , zl, R ¹ , R ² , R ⁵ , R ⁶ , and R ⁴⁰ are as described herein and the symbol z4 is an integer of 0, 1, 2, 3, or 4. The compound of formula (Ib2) may have the formula

[0318] Further to any of Formulae (la) or (lb), or embodiments thereof, L ¹ may be a bond, -C(O)-, -C(0)0-, -0-, -S-, - R ¹³ -, -C(0) R ¹³ -, - R ¹ C(0)-, -S(0) ₂ -, -S(0) R ¹³ -. L ¹ may be a bond, 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. L ¹ may be a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L ¹ may be a bond, -C(O)-, -C(0)0-, -0-, -S-, -NR ¹³ -, -C(0)NR ¹³ -, -NR ¹ C(0)-, -S(0) ₂ -,

-S(0)NR ¹³ -, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L ¹ may be a bond, -C(O)-, -C(0)0-, -0-, -S-, -NR ¹³ -, -C(0)NR ¹³ -,

-NR ¹ C(0)-, -S(0) ₂ -, -S(0)NR ¹³ -, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene where R ¹³ is hydrogen or substituted or unsubstituted alkyl. L ¹ may be a bond, -C(O)-, -C(0)0-, -0-, -S-, -NR ¹³ -, -C(0)NR ¹³ -, -NR ¹ C(0)-, -S(0) ₂ -, -S(0) R ¹³ -, R ¹ -substituted or unsubstituted alkylene, or R ¹ -substituted or unsubstituted heteroalkylene where R ¹³ is hydrogen or substituted or unsubstituted alkyl. R ¹³ may be unsubstituted alkyl.

[0319] L ¹ may be a bond or substituted or unsubstituted alkylene. L ¹ may be a bond or R ¹³ - substituted or unsubstituted alkylene. L ¹ may be a bond or R ¹ -substituted or unsubstituted alkylene where R ¹³ is hydrogen or substituted or unsubstituted alkyl. L ¹ may be a bond or substituted or unsubstituted C ₁ -C ₅ alkylene. L ¹ may be a bond or R ¹ -substituted or unsubstituted C ₁ -C ₅ alkylene. L ¹ may be a bond or R ¹ -substituted or unsubstituted C ₁ -C ₅ alkylene where R ¹³ is hydrogen or substituted or unsubstituted C ₁ -C ₅ alkyl. L ¹ may be R ¹ -substituted or unsubstituted alkylene where R ¹³ is hydrogen, halogen, or substituted or unsubstituted alkyl. In embodiments, L ¹ may be unsubstituted alkylene. In embodiments, L ¹ may be unsubstituted methylene. In embodiments, L ¹ may be R ¹ -substituted methylene. In embodiments, L ¹ may be methylene substituted with one R ¹ -substituent. In embodiments, the R ¹ -substituent may be halogen. In embodiments, L ¹ may be methylene substituted with one fluoro substituent. In embodiments, L ¹ may be methylene independently substituted with two R ¹ -substituents. In embodiments, L ¹ may be methylene independently substituted with halogen substituents. In embodiments, the R ¹³ - substituent may be alkyl. In embodiments, L ¹ may be methylene mono substituted with substituted or unsubstituted alkyl. In embodiments, L ¹ may be methylene disubstituted with substituted or unsubstituted alkyl. In embodiments, the two independent R ¹ -substitutents combine to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl. In embodiments, L ¹ may be methylene singly substituted with halogen or unsubstituted alkyl. In embodiments, L ¹ may be methylene independently disubstituted with halogen or unsubstituted alkyl. In embodiments, L ¹ may be methylene singly substituted with halogen or substituted alkyl. In embodiments, L ¹ may be methylene independently disubstituted with halogen or substituted alkyl.

[0320] R ¹³ may independently be hydrogen, halogen, oxo, N ₃ , -CF , -CC1 , -CBr , -CI , -CN, - OH, -COH,- H ₂ , -COOH, -CO H ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ H ₂ , - HNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF , -OCHF ₂ , R ^{1 A} - substituted or unsubstituted heteroalkyl, R ^{1 A} - substituted or unsubstituted cycloalkyl, R ^{1 A} - substituted or unsubstituted heterocycloalkyl, R ^{1 A} - substituted or unsubstituted aryl, or R ^{1 A} - substituted or unsubstituted heteroaryl.

[0321] R ^{1 A} is independently halogen, oxo, N ₃ , -CF ₃ , -CC1 ₃ , -CBr ₃ , -CI ₃ , -CN,

-OH, -NH ₂ , -COOH, -CONH ₂ , -N0 ₂ , -SH, -S(0) ₂ C1, -S(0) ₃ H, -S(0) ₄ H, -S(0) ₂ NH ₂ , -NHNH ₂ , -O H ₂ , - HC(0) HNH ₂ , - HC(0) H ₂ , - HS(0) ₂ H, - HC(0)H, - HC(0)-OH, - HOH, -OCF ₃ , -OCHF ₂ , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0322] In embodiments, where L ¹ is a substituted or unsubstituted cycloalkylene or heterocycloalkylene, a single carbon of the cycloalkylene or heterocycloalkylene is connected (bonded) to both the sulfonyl moiety and R ⁶ . For example, in some embodiments, L ¹ is: , wherein the symbol "WV ¹ "denotes the point of attachment to the sulfonyl moiety and R ⁶ .

[0323] In embodiments, L ¹ may be substituted or unsubstituted C ₁ -C5 cycloalkylene. In embodiments, L ¹ may be substituted or unsubstituted cyclopropylene. In embodiments, L ¹ may be substituted or unsubstituted cyclobutylene. In embodiments, L ¹ may be substituted or unsubstituted cyclopentylene. In embodiments, L ¹ may be unsubstituted cyclopropylene. In embodiments, L ¹ may be unsubstituted cyclobutylene. In embodiments, L ¹ may be unsubstituted cyclopentylene. In embodiments, L ¹ may be C ₁ -C5 cycloalkylene substituted with halogen, or substituted or unsubstituted alkyl.

[0324] The compound of formula (la) may have the formula:

where zl, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are as described herein. The compound of formula (Ia7) may have the formula:

[0325] The compound of formula (la) may have the formula:

where zl, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are as described herein. The compound of formula (Ia8) may have the formula:

[0326] In embodiments, the compound of Formula (la) may have the structure of Formula (Ia9a) following:

wherein R ^A is substituted or unsubstituted alkyl, and R ^4C is substituted or unsubstituted heterocycloalkyl.

[0327] In embodiments, R ² is substituted or unsubstituted heteroaryl. In embodiments, R ² is unsubstituted heteroaryl. In embodiments, R ² is substituted heteroaryl. In embodiments, R ² is

2C 2C 2 2C

R -substituted heteroaryl, wherein R is as defined herein. R may be R -substituted or

2 2C

unsubstituted 5 to 20 membered heteroaryl. R may be R -substituted 5 to 20 membered heteroaryl. R ² may be R ^2C -substituted or unsubstituted 5 to 8 membered heteroaryl. R ² may be

2C 2 2C

R -substituted 5 to 8 membered heteroaryl. R may be R -substituted or unsubstituted 5 or 6

2 2C

membered heteroaryl. R may be R -substituted 5 or 6 membered heteroaryl.

[0328] In embodiments, R ² is substituted or unsubstituted pyrazolyl. In embodiments, R ² is unsubstituted pyrazolyl. In embodiments, R ² is substituted pyrazolyl. In embodiments, R ² is pyrazolyl substituted with substituted or unsubstituted alkyl. In embodiments, R ² is pyrazolyl substituted with unsubstituted alkyl. In embodiments, R ² is pyrazolyl substituted with unsubstituted lower alkyl. In embodiments, R ² is pyrazolyl substituted methyl, ethyl or propyl. In embodiments, R ² is methyl substituted pyrazolyl.

2 2C 2 2C

[0329] In embodiments, R is R -substituted pyrazolyl. In embodiments, R is R -

2C 2 substituted pyrazolyl, wherein R is substituted or unsubstituted alkyl. In embodiments, R is

2C 2C 2 2C

R -substituted pyrazolyl, wherein R is unsubstituted alkyl. In embodiments, R is R -

2C 2 2C substituted pyrazolyl, wherein R is unsubstituted lower alkyl. In embodiments, R is R -

2C 2 substituted pyrazolyl, wherein R is unsubstituted methyl, ethyl or propyl. In embodiments, R

9 ¹ 9 ¹

is R -substituted pyrazolyl, wherein R is unsubstituted methyl.

[0330] In embodiments, the compound of Formula (Ia9a) may have a formula with structure of Formula (Ia9b):

[0331] Further to any of Formulae (Ia9a)-(Ia9b), in embodiments R is substituted or unsubstituted alkyl. In embodiments R ^A is unsubstituted alkyl. In embodiments, R ^A is unsubstituted lower alkyl. In embodiments, R ^A is methyl, ethyl or propyl. In embodiments, R

3 A. 3 C 3 C is methyl. In embodiments, R is R -substituted or unsubstituted alkyl, wherein R is as defined herein.

[0332] In embodiments, the compound of Formulae (Ia9a)-(Ia9b) may have the structure of Formula (Ia9c):

[0333] In embodiments, R is substituted or unsubstituted heterocycloalkyl. In embodiments, R is unsubstituted heterocycloalkyl. In embodiments, R is substituted heterocycloalkyl. In

40

embodiments, R ^C is R ⁴⁰ -substituted heterocycloalkyl, wherein R ^4U is as defined herein [0334] In embodiments, the compound of Formulae (Ia9a)-(Ia9c) has the structure of Formula (Ia9d) following:

[0335] In formula (Ia9d), R may be substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl (e.g. -CH ₂ C(0)N(CH ₃ )2).

[0336] Further to any of Formulae (Ia9a)-(Ia9d), in embodiments R ⁵ and zl are as defined herein. In embodiments, R ⁵ is halogen, and zl is 1. In embodiments, R ⁵ is fluoro.

[0337] Further to any of Formulae (Ia9a)-(Ia9d), in embodiments R ⁶ is substituted or unsubstituted aryl. In embodiments, R ⁶ is unsubstituted aryl. R ⁶ is aryl independently substituted one or more times with halogen or -N0 ₂ .

[0338] In embodiments the compound may have the structure of Formula (Ia9e):

wherein R and z5 are as defined herein. In embodim neennttss,, RR ⁶⁰ iiss hhaallooggen or -N0 ₂ , and z5 is 1 or

2. In embodiments, z5 is 1. In embodiments, z5 is 2.

[0339] The compound of formula (lb) may have the formula:

wherein zl, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are as described herein and the compound is not VX-680.

[0340] The compound of formula (Ib7) may have the formula:

wherein the compound is not VX-680.

[0341] In embodiments, the com ound provided herein has the formula: