SUMO INHIBITOR COMPOUNDS AND USES THEREOF - ONCOVALENT THERAPEUTICS INC

Title:

SUMO INHIBITOR COMPOUNDS AND USES THEREOF

Document Type and Number:

WIPO Patent Application WO/2020/191151

Kind Code:

A1

Abstract:

The present invention relates to compounds and compositions capable of acting as inhibitors of small ubiquitin-like modifier (SUMO) family of proteins. The compounds and compositions may be used in the treatment of cancer. There are disclosed, inter alia, methods of inhibiting an E1 enzyme, and compounds useful for inhibiting an E1 enzyme.

Inventors:

OUYANG XIAOHU (US)
KUBOTA MILES DOUGLAS (US)
JUDD TED CHARLES (US)
TASKER ANDREW STEWART (US)

Application Number:

PCT/US2020/023550

Publication Date:

September 24, 2020

Filing Date:

March 19, 2020

Export Citation:

Click for automatic bibliography generation Help

Assignee:

ONCOVALENT THERAPEUTICS INC (US)

International Classes:

C07D209/44; A61K31/4365; A61K31/472; A61P35/00; C07D217/06; C07D223/16; C07D495/04

Domestic Patent References:

WO1998040385A1	1998-09-17
WO2007029106A1	2007-03-15
WO2013080222A1	2013-06-06
WO2013021051A1	2013-02-14
WO2009033581A1	2009-03-19
WO2007109279A2	2007-09-27
WO2016002994A1	2016-01-07

Foreign References:

US20160272572A1	2016-09-22
CN104910174A	2015-09-16
CN107793413A	2018-03-13
EP3111960A1	2017-01-04

Other References:

BERGE ET AL.: "Journal of Pharmaceutical Science", vol. 66, 1977, article "Pharmaceutical Salts", pages: 1 - 19
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
PICKAR, DOSAGE CALCULATIONS, 1999
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT, WILLIAMS & WILKINS
CHENNAMANENIA, N. K.ARIFB, J.FREDERICK, S. B.GELB, M. H., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, 2009, pages 6582 - 6584
CELL CHEMICAL BIOLOGY, vol. 26, 2019, pages 1 - 11

Attorney, Agent or Firm:

DANEK, Shelley, C. et al. (US)

Download PDF:

View/Download PDF PDF Help

Claims:

What is claimed is:

1. A compound of formula I or an isomer or a pharmaceutically acceptable salt thereof:

wherein

is selected from a single bond or double bond;

1, m, and n are independently an integer from 0 to 2;

M is selected from CR³R⁴, NR⁵, C=0, O, S=0, 0=S=0, and S;

Y is selected from CR⁶R⁷, NR⁸, C=0, O, S=0, 0=S=0, and S;

Z is CR⁹, or N;

ring A is selected from

a) 5- or 6-membered partially saturated heterocyclyl,

b) 5- or 6-membered aryl or heteroaryl,

c) 9-, 10- or 11-membered fused partially saturated heterocyclyl, d) 9- or 10-membered fused heteroaryl,

e) naphthyl, and

f) 4-, 5- or 6-membered cycloalkenyl;

wherein ring A is optionally substituted with one or more substituent groups;

E is an electrophilic moiety, selected from

R¹ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, -CX , -CHX^, -CH2X¹, -OCX ¹ ,. -OCH2X¹, -OCHX '2. -SO„iR^1A, -SO_viNR^1AR^1B, -NHC(0)NR^1AR^1B,

-N(0)_mi, -NR^1AR^1B, -NHNR^1AR^1B, -C(0)R^1A, -C(0)-0R^1A, -C(0)NR^1AR^1B, -C(0)NHNR^1AR^1B, -OR^1A, -NR^1AS0₂R^1B, -NR^1AC(0)R^1B, -NR^1AC(0)0R^1B, -NR^1AOR^1B, azido, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R² is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, -CX²₃, -CHX²2, -CH2X², -OCX²₃, -OCH2X², -OCHX²2, -SO„2R^2A, -SO_V2NR^2AR^2B, -NHC(0)NR^2AR^2B,

-N(0)_m2, -NR^2AR^2B, -NHNR^2AR^2B, -C(0)R^2A, -C(0)-0R^2A, -C(0)NR^2AR^2B, -C(0)NHNR^2AR^2B, -OR^2A, -NR^2AS0₂R^2B, -NR^2AC(0)R^2B, -NR^2AC(0)0R^2B, -NR^2AOR^2B, azido, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R¹ and R² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R³ is selected from hydrogen, halogen, -CX³₃, -CHX³2, -CH2X³, -OCX³₃, -OCH2X³, -OCHX³2, -CN, -SO_I13R^3A, -SO_V3NR^3AR^3B, -NHC(0)NR^3AR^3B, -N(0)_m3, -NR^3AR^3B, -NHNR^3AR^3B, -C(0)R^3A, -C(0)-0R^3A, -C(0)NR^3AR^3B, -OR^3A, -NR^3AS0₂R^3B, -NR^3AC(0)R^3B, -NR^3AC(0)0R^3B,

-NR^3AOR^3B, -N3, 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;

R⁴ is selected from hydrogen, halogen, -CX⁴₃, -CHX⁴2, -CH2X⁴, -OCX'S, -OCH2X⁴, -OCHXS, -CN, -SO„₄R^4A, -SO_V4NR^4AR^4B, -NHC(0)NR^4AR^4B, -N(0)_m4, -NR^4AR^4B, -NHNR^4AR^4B, -C(0)R^4A, -C(0)-0R^4A, -C(0)NR^4AR^4B, -C(0)NHNR^4AR^4B, -OR^4A, -NR^4AS0₂R^4B, -NR^4AC(0)R^4B, -NR^4AC(0)0R^4B, -NR^4AOR^4B, -N3, 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;

R³ and R³ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R⁵ is selected from hydrogen, halogen, -CX⁵₃, -CHX⁵2, -CH2X⁵, -OCX⁵₃, -OCH2X⁵, -OCHX⁵2, -CN, -SO„₅R^5A, -SO_V5NR^5AR^5B, -NHC(0)NR^5AR^5B, -N(0)_m5, -NR^5AR^5B, -NHNR^5AR^5B, -C(0)R^5A, -C(0)-0R^5A, -C(0)NR^5AR^5B, -C(0)NHNR^5AR^5B, -OR^5A, -NR^5AS0₂R^5B, -NR^5AC(0)R^5B, -NR^5AC(0)0R^5B, -NR^5AOR^5B, -N3, 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;

R⁶ is selected from hydrogen, halogen, -CX⁶₃, -CHX⁶2, -CH2X⁶, -OCX⁶₃, -OCH2X⁶, -OCHX⁶2, -CN, -SO„₆R^6A, -SO_V6NR^6AR^6B, -NHC(0)NR^6AR^6B, -N(0)_m6, -NR^6AR^6B, -NHNR^6AR^6B, -C(0)R^6A, -C(0)-0R^6A, -C(0)NR^6AR^6B, -C(0)NHNR^6AR^6B, -OR^6A, -NR^6AS0₂R^6B, -NR^6AC(0)R^6B, -NR^6AC(0)0R^6B, -NR^6AOR^6B, -N3, 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;

R⁷ is selected from hydrogen, halogen, -CX⁷₃, -CHX⁷2, -CH2X⁷, -OCX⁷₃, -OCH2X⁷, -OCHX⁷2, -CN, -SO„₇R^7A, -SO_V7NR^7AR^7B, -NHC(0)NR^7AR^7B, -N(0)_m7, -NR^7AR^7B, -NHNR^7AR^7B, -C(0)R^7A, -C(0)-0R^7A, -C(0)NR^7AR^7B, -C(0)NHNR^7AR^7B, -OR^7A, -NR^7AS0₂R^7B, -NR^7AC(0)R^7B, -NR^7AC(0)0R^7B, -NR^7AOR^7B, -N3, 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; R⁸ is selected from hydrogen, halogen, -CX⁸₃, -CHX⁸2, -CH2X⁸, -OCX⁸₃, -OCH2X⁸, -OCHX⁸2, -CN, -SO„₈R^8A, -SO_V8NR^8AR^8B, -NHC(0)NR^8AR^8B, -N(0)_m8, -NR^8A8^7B, -NHNR^8AR^8B, -C(0)R^8A, -C(0)-0R^8A, -C(0)NR^8AR^8B, -C(0)NHNR^8AR^8B, -OR^8A, -NR^8AS0₂R^8B, -NR^8AC(0)R^8B, -NR^8AC(0)0R^8B, -NR^8AOR^8B, -N3, 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;

R⁹ is selected from hydrogen, halogen, -CX⁹₃, -CHX⁹2, -CH2X⁹, -OCX⁹₃, -OCH2X⁹, -OCHX⁹2, -CN, -SO„₉R^9A, -SO_V9NR^9AR^9B, -NHC(0)NR^9AR^9B, -N(0)_m9, -NR^9AR^9B, -NHNR^9AR^9B, -C(0)R^9A, -C(0)-0R^9A, -C(0)NR^9AR^9B, -C(0)NHNR^9AR^9B, -OR^9A, -NR^9AS0₂R^9B, -NR^9AC(0)R^9B, -NR^9AC(0)0R^9B, -NR^9AOR^9B, -N3, 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;

R¹⁰ is selected from hydrogen, halogen, -CX¹⁰₃, -CHX¹⁰₂, -CH₂X¹⁰, -OCX¹⁰₃, -OCH₂X¹⁰, -OCHX¹⁰₂, -CN, -SO„ioR^10A, -SO_vioNR^10AR^10B, -NHC(O)NR^10AR^10B, -N(0)_mio, -NR^10AR^10B, -NHNR^10AR^10B, -C(O)R^10A, -C(O)-OR^10A, -C(O)NR^10AR^10B, -C(O)NHNR^10AR^10B, -OR^10A, -NR^10ASO₂R^10B, -NR^10AC(O)R^10B, -NR^10AC(O)OR^10B, -NR^10AOR^10B, -N₃, 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;

R¹¹ is selected from hydrogen, halogen, -CX^U3, -CHX^U2, -CH2X¹¹, -OCX^U3, -OCH2X¹¹, -OCHX^U2, -CN, -SO„iiR^11A, -SO_viiNR^11AR^11B, -NHC(0)NR^11AR^11B, -N(0)_mii, -NR^11AR^11B, -NHNR^11AR^11B, -C(0)R^11A, -C(0)-0R^11A, -C(0)NR^11AR^11B, -C(0)NHNR^11AR^11B, -OR^11A, -NR^11AS0₂R^11B, -NR^11AC(0)R^11B, -NR^11AC(0)0R^11B, -NR^11AOR^11B, -N3, 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;

R¹² is selected from hydrogen, halogen, -CX¹²₃, -CHX¹²₂, -CH₂X¹², -OCX¹²₃, -OCH₂X¹², -OCHX¹²₂, -CN, -SO„_I2R^12A, -SO_VI2NR^12AR^12B, -NHC(0)NR^12AR^12B, -N(0)_mi2, -NR^12AR^12B, -NHNR^12AR^12B, -C(0)R^12A, -C(0)-0R^12A, -C(0)NR^12AR^12B, -C(0)NHNR^12AR^12B, -OR^12A, -NR^12AS0₂R^12B, -NR^12AC(0)R^12B, -NR^12AC(0)0R^12B, -NR^12AOR^12B, -N₃, 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; R¹³ is selected from hydrogen, halogen, -CX¹³3, -CHX¹³2, -CH2X¹³, -OCX¹³3, -OCH2X¹³, -OCHX¹³2, -CN, -SO„_I3R^13A, -SO_VI3NR^13AR^13B, -NHC(0)NR^13AR^13B, -N(0)_mi3, -NR^13AR^13B, -NHNR^13AR^13B, -C(0)R^13A, -C(0)-0R^13A, -C(0)NR^13AR^13B, -C(0)NHNR^13AR^13B, -OR^13A, -NR^13AS0₂R^13B, -NR^13AC(0)R^13B, -NR^13AC(0)0R^13B, -NR^13AOR^13B, -N3, 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;

R¹⁴ is selected from hydrogen, halogen, -CX¹⁴₃, -CHX¹⁴₂, -CH₂X¹⁴, -OCX¹⁴₃, -OCH₂X¹⁴, -OCHX¹⁴₂, -CN, -SO„_I4R^14A, -SO_VI4NR^14AR^14B, -NHC(0)NR^14AR^14B, -N(0)_mi4, -NR^14AR^14B, -NHNR^14AR^14B, -C(0)R^14A, -C(0)-0R^14A, -C(0)NR^14AR^14B, -C(0)NHNR^14AR^14B, -OR^14A, -NR^14AS0₂R^14B, -NR^14AC(0)R^14B, -NR^14AC(0)0R^14B, -NR^14AOR^14B, -N₃, 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;

R¹⁵ is selected from hydrogen, halogen, -CX¹⁵₃, -CHX¹⁵₂, -CH₂X¹⁵, -OCX¹⁵₃, -OCH₂X¹⁵, -OCHX¹⁵₂, -CN, -SO„_I5R^15A, -SO_VI5NR^15AR^15B, -NHC(0)NR^15AR^15B, -N(0)mi₅, -NR^15AR^15B, -NHNR^15AR^15B, -C(0)R^15A, -C(0)-0R^15A, -C(0)NR^15AR^15B, -C(0)NHNR^15AR^15B, -OR^15A, -NR^15AS0₂R^15B, -NR^15AC(0)R^15B, -NR^15AC(0)0R^15B, -NR^15AOR^15B, -N₃, 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;

R¹⁶ is selected from hydrogen, halogen, -CX¹⁶₃, -CHX¹⁶₂, -CH₂X¹⁶, -OCX¹⁶₃, -OCH₂X¹⁶, -OCHX¹⁶₂, -CN, -SO„_I6R^16A, -SO_VI6NR^16AR^16B, -NHC(0)NR^16AR^16B, -N(0)mi₆, -NR^16AR^16B, -NHNR^16AR^16B, -C(0)R^16A, -C(0)-0R^16A, -C(0)NR^16AR^16B, -C(0)NHNR^16AR^16B, -OR^16A, -NR^16AS0₂R^16B, -NR^16AC(0)R^16B, -NR^16AC(0)0R^16B, -NR^16AOR^16B, -N3, 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;

R¹⁷ is selected from hydrogen, halogen, -CX¹⁷₃, -CHX¹⁷₂, -CH₂X¹⁷, -OCX¹⁷₃, -OCH₂X¹⁷, -OCHX¹⁷₂, -CN, -SO„_I7R^17A, -SO_VI7NR^17AR^17B, -NHC(0)NR^17AR^17B, -N(0)_mi7, -NR^17AR^17B, -NHNR^17AR^17B, -C(0)R^17A, -C(0)-0R^17A, -C(0)NR^17AR^17B, -C(0)NHNR^17AR^17B, -OR^17A, -NR^17AS0₂R^17B, -NR^17AC(0)R^17B, -NR^17AC(0)0R^17B, -NR^17AOR^17B, -N3, 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;

R¹⁸ is selected from hydrogen, halogen, -CX¹⁸₃, -CHX¹⁸₂, -CH₂X¹⁸, -OCX¹⁸₃, -OCH₂X¹⁸, -OCHX¹⁸₂, -CN, -SO„_I8R^18A, -SO_VI8NR^18AR^18B, -NHC(0)NR^18AR^18B, -N(0)_mi8, -NR^18AR^18B, -NHNR^18AR^18B, -C(0)R^18A, -C(0)-0R^18A, -C(0)NR^18AR^18B, -C(0)NHNR^18AR^18B, -OR^18A, -NR^18AS0₂R^18B, -NR^18AC(0)R^18B, -NR^18AC(0)0R^18B, -NR^18AOR^18B, -N₃, 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; R¹⁷ and R¹⁸ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R¹⁹ is selected from hydrogen, halogen, -CX¹⁹₃, -CHX¹⁹₂, -CH₂X¹⁹, -OCX¹⁹₃, -OCH₂X¹⁹, -OCHX¹⁹₂, -CN, -SO„_I9R^19A, -SO_VI9NR^19AR^19B, -NHC(0)NR^19AR^19B, -N(0)_mi9, -NR^19AR^19B, -NHNR^19AR^19B, -C(0)R^19A, -C(0)-0R^19A, -C(0)NR^19AR^19B, -C(0)NHNR^19AR^19B, -OR^19A, -NR^19AS0₂R^19B, -NR^19AC(0)R^19B, -NR^19AC(0)0R^19B, -NR^19AOR^19B, -N₃, 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;

R²⁰ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, -CX²⁰₃, -CHX²⁰₂,

-CH₂X²⁰, -OCX²⁰₃, -0CH₂X²⁰, -OCHX²⁰₂, -CN, -SO„_2OR^20A, -SO_V20NR^20AR^20B,

-NHC(O)NR^20AR^20B, -N(0),_n2o. -NR^20AR^20B, -NHNR^20AR^20B, -C(O)R^20A, -C(O)-OR^20A,

-C(O)NR^20AR^20B, -C(O)NHNR^20AR^20B, -OR^20A, -NR^20ASO₂R^20B, -NR^20AC(O)R^20B,

-NR^20AC(O)OR^20B, -NR^20AOR^20B, -N₃, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R¹⁷ and R²⁰ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²¹ is selected from hydrogen, halogen, -CX²¹₃, -CHX²¹₂, -CH₂X²¹, -OCX²¹₃, -OCH₂X²¹, -OCHX²¹₂, -CN, -SO„_2iR^21A, -SO_V2INR^21AR^21B, -NHC(0)NR^21AR^21B, -N(0),_{n2 i} . -NR^21AR^21B, -NHNR^21AR^21B, -C(0)R^21A, -C(0)-0R^21A, -C(0)NR^21AR^21B, -C(0)NHNR^21AR^21B, -OR^21A, -NR^21AS0₂R^21B, -NR^21AC(0)R^21B, -NR^21AC(0)0R^21B, -NR^21AOR^21B, -N₃, 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;

R²² is selected from hydrogen, halogen, -CX²²₃, -CHX²²₂, -CH₂X²², -OCX²²₃, -OCH₂X²², -OCHX²²₂, -CN, -SO„₂₂R^22A, -SO_V22NR^22AR^22B, -NHC(0)NR^22AR^22B, -N(0)_m22. -NR^22AR^22B, -NHNR^22AR^22B, -C(0)R^22A, -C(0)-0R^22A, -C(0)NR^22AR^22B, -C(0)NHNR^22AR^22B, -OR^22A, -NR^22AS0₂R^22B, -NR^22AC(0)R^22B, -NR^22AC(0)0R^22B, -NR^22AOR^22B, -N₃, 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; R²¹ and R²² substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²³ is selected from hydrogen, halogen, -CX² -CHX²³₂, -CH₂X²³, -OCX²³₃, -OCH₂X²³, -OCHX²³₂, -CN, -SO„₂₃R^23A, -SO_V23NR^23AR^23B, -NHC(0)NR^23AR^23B, -N(0)_m23, -NR^23AR^23B, -NHNR^23AR^23B, -C(0)R^23A, -C(0)-0R^23A, -C(0)NR^23AR^23B, -C(0)NHNR^23AR^23B, -OR^23A, -NR^23AS0₂R^23B, -NR^23AC(0)R^23B, -NR^23AC(0)0R^23B, -NR^23AOR^23B, -N₃, 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;

R²⁴ is selected from hydrogen, halogen, -CX²⁴₃, -CHX²⁴₂, -CH₂X²⁴, -OCX²⁴₃, -OCH₂X²⁴, -OCHX²⁴₂,

-NR^24AC(0)R^24B, -NR^24AC(0)0R^24B, -NR^24AOR^24B, -N₃, 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;

R²⁵ is selected from hydrogen, halogen, -CX²⁵₃, -CHX²⁵₂, -CH₂X²⁵, -OCX²⁵₃, -OCH₂X²⁵, -OCHX²⁵₂, -CN, -SO„₂₅R^25A, -SO_V25NR^25AR^25B, -NHC(0)NR^25AR^25B, -N(0)_m2'. -NR^25AR^25B, -NHNR^25AR^25B, -C(0)R^25A, -C(0)-0R^25A, -C(0)NR^25AR^25B, -C(0)NHNR^25AR^25B, -OR^25A, -NR^25AS0₂R^25B, -NR^25AC(0)R^25B, -NR^25AC(0)0R^25B, -NR^25AOR^25B, -N₃, 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;

R²⁶ is selected from hydrogen, halogen, , substituted or unsubstituted alkyl, -CX²⁶₃, -CHX²⁶₂,

-CH₂X²⁶, -0CX²⁶₃, -OCH₂X²⁶, -0CHX²⁶₂, -CN, -SO„₂₆R^26A, -SO_V26NR^26AR^26B,

-NHC(0)NR^26AR^26B, -N(0)_m2(,. -NR^26AR^26B, -NHNR^26AR^26B, -C(0)R^26A, -C(0)-0R^26A,

-C(0)NR^26AR^26B, -C(0)NHNR^26AR^26B, -OR^26A, -NR^26AS0₂R^26B, -NR^26AC(0)R^26B, -NR^26AC(0)0 R^26B, -NR^26AOR^26B, -N₃, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R²⁷ is selected from hydrogen, halogen, , substituted or unsubstituted alkyl, -CX²⁷₃, -CHX²⁷₂, -CH₂X²⁷, -OCX²⁷₃, -OCH₂X²⁷, -0CHX²⁷₂, -CN, -SO„₂₇R^27A, -SO_V27NR^27AR^27B,

R^27A, ubstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R²⁸ is selected from hydrogen, halogen, , substituted or unsubstituted alkyl, -CX²⁸₃, -CHX²⁸₂,

-CH₂X²⁸, -OCX²⁸₃, -OCH₂X²⁸, -0CHX²⁸₂, -CN, -SO„₂₈R^28A, -SO_V28NR^28AR^28B,

R^28A, stituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R²⁹ is selected from hydrogen, halogen, -CX²⁹₃, -CHX²⁹₂, -CH₂X²⁹, -OCX²⁹₃, -OCH₂X²⁹, -OCHX²⁹₂,

-NR^29AC(0)R^29B, -NR^29AC(0)0R^29B, -NR^29AOR^29B, -N₃, 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;

R³⁰ is selected from hydrogen, halogen, , substituted or unsubstituted alkyl, -CX³⁰₃, -CHX³⁰₂,

-CH₂X³⁰, -OCX³⁰₃, -0CH₂X³⁰, -OCHX³⁰₂, -CN, -SO„_3OR^30A, -SO_V3ONR^30AR^30B,

-NHC(O)NR^30AR^30B, -N(0)_m3o, -NR^30AR^30B, -NHNR^30AR^30B, -C(O)R^30A, -C(O)-OR^30A,

-C(O)NR^30AR^30B, -C(O)NHNR^30AR^30B, -OR^30A, -NR^30ASO₂R^30B, -NR^30AC(O)R^30B,

-NR^30AC(O)OR^30B, -NR^30AOR^30B, -N3, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

Each R^1A, R^1B, R^2A, R^2B, R^3A, R^3B, R^4A, R^4B, R^5A, R^5B, R^6A, R^6B, R^7A, R^7B, R^8A, R^8B, R^9A, R^9B, R^10A,

R^27B, R^28A, R^28B, R^29A, R^29B, R^30A, R^30B is independently selected from hydrogen, -CX3, -CHX2, -

CH₂X, - C(0)0H, -C(0)NH₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -N0₂, -SH, -SO3H, -SO4H, -

S0₂NH₂, NHNH₂, -ONH₂, -NHC=(0)NHNH₂, -NHC=(0)NH₂, -NHSOZH, -NHC=(0)H, - NHC(0)0H, -NHOH, -OCX₃, -OCHX₂, -OCH₂X, 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^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^2A and R^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^4A and R^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^5A and R^5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^6A and R^6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^7A and R^7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^8A and R^8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^9A and R^9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^10A and R^10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^11A and R^11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^12A and R^12B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^13A and R^13B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^14A and R^14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^15A and R^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^16A and R^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^17A and R^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^18A and R^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^19A and R^19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^20A and R^20B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^21A and R^21B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^22A and R^22B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^23A and R^23B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^24A and R^24B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^25A and R^25B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^26A and R^26B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^27A and R^27B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^28A and R^28B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^29A and R^29B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R^30A and R^30B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

Each ml, m2, m3, iu4, iu5, iu6, iu7, iu8, iu9, mlO, ml 1, ml2, ml3, ml4, ml5, ml6, ml7, ml8, ml9, m20, iu21, iu22, iu23, iu24, iu25, iu26, iu27, iu28, iu29, and m30 are independently 1 or 2;

Each vl, v2, v3, v4, v5, v6, v7, v8, v9, vlO, vl l, vl2, vl3, vl4, vl5, vl6, vl7, vl8, vl9, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29 and v30 are independently 1 or 2;

Each nl, n2, n3, n4, n5, n6, n7, n8, n9, nlO, nl 1, nl2, nl3, nl4, nl5, nl6, nl7, nl8, nl9, n20, n21, n22, n23, n24, n25, n26, n27, n28, n29 and n30 are independently an integer from 0 to 2; and

X²², X²³, X²⁴, X²⁵, X²⁶, X²⁷, X²⁸, X²⁹ and X³⁰ are independently -Cl, -Br, -I or -F;

provided the compound is not l-{4-[4-amino-3-(3-fluoro-5-hydroxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl]-l,2,3,4-tetrahydroisoquinolin-2-yl}prop-2-en-l-one; further provided the compound is not ethyl 2-{4-chloro-2-[2-(prop-2-enoyl)-l,2,3,4-tetrahydroisoquinolin-l- yl]phenoxy}acetate; further provided the compound is not 1-(1 -cyclohexyl- 1,2, 3, 4- tetrahydroisoquinolin-2-yl)prop-2-en-l-one; further provided the compound is not l-(6,7- dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl)prop-2-en-l-one; further provided the compound is not l-(l,2,3,4-tetrahydroisoquinolin-2-yl)prop-2-en-l-one; further provided the compound is not substituted 2'-(prop-2-enoyl)-3 ',4'-dihydro-2'H-spiro [cyclohexane- 1 , 1 '-isoquinoline] -4- carboxylic acid; further provided the compound is not l-(7-chloro-l,2,3,4- tetrahydroisoquinolin-2-yl)prop-2-en- 1 -one .

2. The compound of Claim 1 wherein ring A is selected from dihydropyran, dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl, wherein ring A is optionally substituted with one or more substituent groups.

3. The compound of Claim 1 wherein ring A is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein ring A is optionally substituted with one or more substituent groups.

4. The compound of Claim 1 wherein ring A is selected from

5. The compound of Claim 1, wherein ring A is ring A is

6. The compound of Claim 1 wherein ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein ring A is optionally substituted with one or more substituent groups.

7. The compound of Claim 1 wherein ring A is selected from

8. The compound of Claim 1 wherein ring A is selected from phenyl or thienyl, wherein ring A is optionally substituted with one or more substituent groups.

9. The compound of any one of Claims 1-8 wherein R² is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted 5- or 6- membered heteroaryl.

10. The compound of any one of Claims 1-8 wherein R² is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl and substituted or unsubstituted pyridyl.

11. The compound of any one of Claims 1-10 wherein E is selected from -C(=0)CH=CH₂, - C(=0)-ethynyl, -C(=0)CH=CHCF₃, -C(=0)CH=CHCHF₂, -C(=0)CH=CHCH₂F, and -C(=0)CH₂Br.

12. The compound of Claim 1 selected from

1 -(6-bromo-4-(2-chlorophcnyl)-3.4-dihydroisoquinolin-2( l//)-yl)prop-2-cn- l -one:

1 -(2-chloro-4-(o-tolyl)-4.7-dihydrothicno| 2.3-c|pyridin-6(5//)-yl)prop-2-cn- 1 -one:

(/_' )- 1 -(2-chloro-4-(o-tolyl)-4.7-dihydrothicno|2.3-c |pyridin-6(5//)-yl)-4.4.4-trifluorobut-2-cn- l - one;

2-chloro- 1 -(2-chloro-4-(o-tolyl)-4,7 -dihydrothieno |2.3-c|pyridin-6(5//)-yl)cthan- 1 -one;

(/_' )- 1 -(2-chloro-4-(o-tolyl)-4.7-dihydrothicno|2.3-c |pyridin-6(5//)-yl)-4.4-difluorobut-2-cn- l -one: (/_' )- 1 -(2-chloro-4-(o-tolyl)-4.7-dihydrothicno|2.3-c |pyridin-6(5//)-yl)-4-fluorobut-2-cn- l -one: A'-(4-(o-tolyl)-4.5.6.7-tctrahydrobcnzo|/i |thiophcn-6-yl)acrylamidc:

1 -(4-([ 1 , r-biphenyl]-2-yl)-2-chloro-4,7-dihydrothieno[2,3-c]pyridin-6(57 )-yl)prop-2-en- 1 -one; (£)-4-bromo- 1 -(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(57 )-yl)but-2-en- 1 -one;

(/_' )- 1 -(2-chloro-4-(o-tolyl)-4.7-dihydrothicno|2.3-c |pyridin-6(5//)-yl)-4-(dimcthylamino)but-2-cn- 1-one;

1 -(7-chloro-4-(pyridin-2-yl)-3.4-dihydroisoquinolin-2( l//)-yl)prop-2-cn- 1 -one:

l-(3-bromo-8 -phenyl -7, 8-dihydro-l,6-naphthyridin-6(57 )-yl)prop-2-en-l-one;

1 -(2-chloro-4-cyclohcxyl-4.7-dihydrothicno|2.3-c|pyridin-6(5//)-yl)prop-2-cn- 1 -one:

1 -(4-mcthyl-4-phcnyl-3.4-dihydroisoquinolin-2( l//)-yl)prop-2-cn- l -one:

1 -(6-cthyl-4-phcnyl-3.4-dihydroisoquinolin-2( l//)-yl)prop-2-cn- 1 -one:

3-(2-acryloyl-7-chloro- l .2.3.4-tctrahydroisoquinolin-4-yl)pyridin-2( l//)-onc:

1 -(7-isobutoxy-4-phcnyl-3.4-dihydroisoquinolin-2( l//)-yl)prop-2-cn- 1 -one: and

1 -(2-chl oro-5 -methyl -4-phcnyl -4.7-dihydrothicno 12.3 -c|pyridin-6(5//)-yl)ptOp-2-cn- l -one.

13. A compound of Claim 1, comprising a compound of Formula VI:

wherein

Z is N, or CR⁹;

ring B is selected from

a) 5- or 6-membered cycloalkyl, saturated or partially saturated heterocyclyl, b) 5- or 6-membered aryl or heteroaryl,

c) 9-, 10- or 11-membered fused partially saturated heterocyclyl, d) 9- or 10-membered fused heteroaryl,

e) naphthyl, and

f) 4-, 5- or 6-membered cycloalkenyl;

wherein ring B is optionally substituted with one ore more substituent groups;

E is an electrophilic moiety, selected from

wherein R¹ is selected from hydrogen, halogen, -CXk. -CHXS, -CH2X¹, -OCX ¹ ,.

-OCH2X¹, -OCHX '2. -CN, -SO„iR^1A, -SO_viNR^1AR^1B, -NHC(0)NR^1AR^1B, -N(0)_mi, -NR^1AR^1B, -NHNR^1AR^1B, -C(0)R^1A, -C(0)-0R^1A, -C(0)NR^1AR^1B, -C(0)NHNR^1AR^1B, -OR^1A, -NR^1AS0₂R^1B, -NR^1AC(0)R^1B, -NR^1AC(0)0R^1B, -NR^1AOR^1B, -N₃, 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;

R³ is selected from hydrogen, halogen, -CX³₃, -CHX³2, -CH2X³, -OCX³₃,

-OCH2X³, -OCHX³2, -CN, -SO„,R'^A. -SO_V3NR^3AR^3B, -NHC(0)NR^3AR^3B, -N(0)_pΰ, -NR^3AR^3B, -NHNR^3AR^3B, -C(0)R^3A, -C(0)-0R^3A, -C(0)NR^3AR^3B, -OR^3A, -NR^3AS0₂R^3B, -NR^3AC(0)R^3B, -NR^3AC(0)0R^3B, -NR^3AOR^3B, -N3, 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;

R⁴ is selected from hydrogen, halogen, -CX⁴₃, -CHX⁴2, -CH2X⁴, -OCX⁴₃,

-OCH2X⁴, -OCHX⁴2, -CN, -SO„₄R^4A, -SO_V4NR^4AR^4B, -NHC(0)NR^4AR^4B, -N(0)_m4, -NR^4AR^4B, -NHNR^4AR^4B, -C(0)R^4A, -C(0)-0R^4A, -C(0)NR^4AR^4B, -C(0)NHNR^4AR^4B, -OR^4A, -NR^4AS0₂R^4B, -NR^4AC(0)R^4B, -NR^4AC(0)0R^4B, -NR^4AOR^4B, -N₃, 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; R³ and R³ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R⁶ is selected from hydrogen, halogen, -CX⁶₃, -CHX⁶2, -CH2X⁶, -OCX⁶₃,

-OCH2X⁶, -OCHX⁶₂, -CN, -SO„₆R^6A, -SO_V6NR^6AR^6B, -NHC(0)NR^6AR^6B, -N(0)_m6, -NR^6AR^6B, -NHNR^6AR^6B, -C(0)R^6A, -C(0)-0R^6A, -C(0)NR^6AR^6B, -C(0)NHNR^6AR^6B, -OR^6A, -NR^6AS0₂R^6B, -NR^6AC(0)R^6B, -NR^6AC(0)0R^6B, -NR^6AOR^6B, -N₃, 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;

R⁷ is selected from hydrogen, halogen, -CX⁷₃, -CHX⁷2, -CH2X⁷, -OCX⁷₃,

-OCH2X⁷, -OCHX⁷2, -CN, -SO„₇R^7A, -SO_V7NR^7AR^7B, -NHC(0)NR^7AR^7B, -N(0)_m7, -NR^7AR^7B, -NHNR^7AR^7B, -C(0)R^7A, -C(0)-0R^7A, -C(0)NR^7AR^7B, -C(0)NHNR^7AR^7B, -OR^7A, -NR^7AS0₂R^7B, -NR^7AC(0)R^7B, -NR^7AC(0)0R^7B, -NR^7AOR^7B, -N₃, 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;

R⁹ is selected from hydrogen, halogen, -CX⁹₃, -CHX⁹2, -CH2X⁹, -OCX⁹₃,

-OCH2X⁹, -OCHX⁹2, -CN, -SO„₉R^9A, -SO_V9NR^9AR^9B, -NHC(0)NR^9AR^9B, -N(0)_m9, -NR^9AR^9B, -NHNR^9AR^9B, -C(0)R^9A, -C(0)-0R^9A, -C(0)NR^9AR^9B, -C(0)NHNR^9AR^9B, -OR^9A, -NR^9AS0₂R^9B, -NR^9AC(0)R^9B, -NR^9AC(0)0R^9B, -NR^9AOR^9B, -N₃, 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;

R¹³ is selected from hydrogen, halogen, -CX¹³₃, -CHX¹³2, -CH2X¹³, -OCX¹³₃,

-OCH2X¹³, -OCHX¹³2, -CN, -SO„_I3R^13A, -SO_VI3NR^13AR^13B, -NHC(0)NR^13AR^13B,

-N(0)mi₃, -NR^13AR^13B, -NHNR^13AR^13B, -C(0)R^13A, -C(0)-0R^13A, -C(0)NR^13AR^13B, -C(0)N HNR^13AR^13B, -OR^13A, -NR^13AS0₂R^13B, -NR^13AC(0)R^13B, -NR^13AC(0)0R^13B, -NR^13AOR^13B, - N3, 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;

R¹⁴ is selected from hydrogen, halogen, -CX¹⁴₃, -CHX¹⁴2, -CH2X¹⁴, -OCX¹⁴₃,

-OCH2X¹⁴, -OCHX¹⁴₂, -CN, -SO„_I4R^14A, -SO_VI4NR^14AR^14B, -NHC(0)NR^14AR^14B, -N(0)_mi4, -NR^14AR^14B, -NHNR^14AR^14B, -C(0)R^14A, -C(0)-0R^14A, -C(0)NR^14AR^14B, -C(0)NHNR^14AR^14B, -OR^14A, -NR^14AS0₂R^14B, -NR^14AC(0)R^14B, -NR^14AC(0)0R^14B, -NR^14AOR^14B, -N3, 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;

R¹⁵ is selected from hydrogen, halogen, -CX¹⁵3, -CHX¹⁵₂, -CH₂X¹⁵, -OCX¹⁵3,

-OCH2X¹⁵, -OCHX¹⁵2, -CN, -SO„_I5R^15A, -SO_VI5NR^15AR^15B, -NHC(0)NR^15AR^15B,

-N(0)mi₅, -NR^15AR^15B, -NHNR^15AR^15B, -C(0)R^15A, -C(0)-0R^15A, -C(0)NR^15AR^15B, -C(0)NHNR^15AR^15B, -OR^15A, -NR^15AS0₂R^15B, -NR^15AC(0)R^15B, -NR^15AC(0)0R^15B, -NR^15AOR^15B, -N3, 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;

R¹⁶ is selected from hydrogen, halogen, -CX¹⁶₃, -CHX¹⁶₂, -CH₂X¹⁶, -OCX¹⁶₃,

-OCH2X¹⁶, -OCHX¹⁶2, -CN, -SO„_I6R^16A, -SO_VI6NR^16AR^16B, -NHC(0)NR^16AR^16B, -N(0)mi6, -NR^16AR^16B, -NHNR^16AR^16B, -C(0)R^16A, -C(0)-0R^16A, -C(0)NR^16AR^16B,

-C(0)NHNR^16AR^16B, -OR^16A, -NR^16AS0₂R^16B, -NR^16AC(0)R^16B, -NR^16AC(0)0R^16B, -NR^16AOR^16B, -N3, 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;

R¹⁷ is selected from hydrogen, halogen, -CX¹⁷3, -CHX¹⁷₂, -CH₂X¹⁷, -OCX¹⁷3,

-OCH2X¹⁷, -OCHX¹⁷2, -CN, -SO„_I7R^17A, -SO_VI7NR^17AR^17B, -NHC(0)NR^17AR^17B, -N(0)mi7, -NR^17AR^17B, -NHNR^17AR^17B, -C(0)R^17A, -C(0)-0R^17A, -C(0)NR^17AR^17B,

-C(0)NHNR^17AR^17B, -OR^17A, -NR^17AS0₂R^17B, -NR^17AC(0)R^17B, -NR^17AC(0)0R^17B, -NR^17AOR^17B, -N3, 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;

R¹⁸ is selected from hydrogen, halogen, -CX¹⁸3, -CHX¹⁸₂, -CH₂X¹⁸, -OCX¹⁸3,

-OCH2X¹⁸, -OCHX¹⁸₂, -CN, -SO„_I8R^18A, -SO_VI8NR^18AR^18B, -NHC(0)NR^18AR^18B, -N(0)_mi8, -NR^18AR^18B, -NHNR^18AR^18B, -C(0)R^18A, -C(0)-0R^18A, -C(0)NR^18AR^18B,

-C(0)NHNR^18AR^18B, -OR^18A, -NR^18AS0₂R^18B, -NR^18AC(0)R^18B, -NR^18AC(0)0R^18B, -NR^18AOR^18B, -N3, 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; R¹⁶ and R¹⁸ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R¹⁹ is selected from hydrogen, halogen, -CX¹⁹₃, -CHX¹⁹2, -CH2X¹⁹, -OCX¹⁹₃,

-OCH2X¹⁹, -OCHX¹⁹₂, -CN, -SO„_I9R^19A, -SO_VI9NR^19AR^19B, -NHC(0)NR^19AR^19B, -N(0)_mi9, -NR^19AR^19B, -NHNR^19AR^19B, -C(0)R^19A, -C(0)-0R^19A, -C(0)NR^19AR^19B,

-C(0)NHNR^19AR^19B, -OR^19A, -NR^19AS0₂R^19B, -NR^19AC(0)R^19B, -NR^19AC(0)0R^19B, -NR^19AOR^19B, -N3, 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; R¹⁶ and R¹⁹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²⁰ is selected from hydrogen, halogen, -CX²⁰₃, -CHX²⁰2, -CH2X²⁰, -OCX²⁰₃,

-OCH2X²⁰, -OCHX²⁰2, -CN, -SO„2OR^20A. -SO_V2_ONR^20AR^20B, -NHC(O)NR^20AR^20B, -N(0)_m2o, -NR^20AR^20B, -NHNR^20AR^20B, -C(O)R^20A, -C(O)-OR^20A, -C(O)NR^20AR^20B,

-C(O)NHNR^20AR^20B, -OR^20A, -NR^20ASO₂R^20B, -NR^20AC(O)R^20B, -NR^20AC(O)OR^20B, -NR^20AOR^20B, -N3, 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;

R²¹ is selected from hydrogen, halogen, -CX²¹3, -CHX²¹₂, -CH₂X²¹, -OCX²¹3,

-NR^21AOR^21B, -N3, 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; R²⁰ and R²¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²² is selected from hydrogen, halogen, -CX²²₃, -CHX²²₂, -CH₂X²², -OCX²²₃,

-OCH2X²², -OCHX²²2, -CN, -SO_n22R^22A, -SO_V22NR^22AR^22B, -NHC(0)NR^22AR^22B, -N(0)_m22. -NR^22AR^22B, -NHNR^22AR^22B, -C(0)R^22A, -C(0)-0R^22A, -C(0)NR^22AR^22B,

-C(0)NHNR^22AR^22B, -OR^22A, -NR^22AS0₂R^22B, -NR^22AC(0)R^22B, -NR^22AC(0)0R^22B, -NR^22AOR^22B, -N3, 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;

R²³ is selected from hydrogen, halogen, -CX²³₃, -CHX²³2, -CH2X²³, -OCX²³₃, -

OCH2X²³, -OCHX²³2, -CN, -SO„₂₃R^23A, -SO_V23NR^23AR^23B, -NHC(0)NR^23AR^23B, -N(0)m₂₃, - NR^23AR^23B. -NHNR^23AR^23B, -C(0)R^23A, -C(0)-0R^23A, -C(0)NR^23AR^23B, -C(0)NHNR^23AR^23B , -OR^23A, -NR^23AS0₂R^23B, -NR^23AC(0)R^23B, -NR^23AC(0)0R^23B, -NR^23AOR^23B, -N₃, 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;

R²⁴ is selected from hydrogen, halogen, -CX²⁴₃, -CHX²⁴2, -CH2X²⁴, -OCX²⁴₃,

-OCH2X²⁴, -OCHX²⁴2, -CN, -SO_n24R^24A, -SO_V24NR^24AR^24B, -NHC(0)NR^24AR^24B, -N(0)_m24, -NR^24AR^24B, -NHNR^24AR^24B, -C(0)R^24A, -C(0)-0R^24A, -C(0)NR^24AR^24B,

-C(0)NHNR^24AR^24B, -OR^24A, -NR^24AS0₂R^24B, -NR^24AC(0)R^24B, -NR^24AC(0)0R^24B, -NR^24AOR^24B, -N₃, 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;

R²⁵ is selected from hydrogen, halogen, -CX²⁵₃, -CHX²⁵₂, -CH₂X²⁵, -OCX²⁵₃,

-OCH2X²⁵, -OCHX²⁵2, -CN, -SOn25R^25A, -SO_V25NR^25AR^25B, -NHC(0)NR^25AR^25B, -N(0)_m25, -NR^25AR^25B, -NHNR^25AR^25B, -C(0)R^25A, -C(0)-0R^25A, -C(0)NR^25AR^25B,

-C(0)NHNR^25AR^25B, -OR^25A, -NR^25AS0₂R^25B, -NR^25AC(0)R^25B, -NR^25AC(0)0R^25B, -NR^25AOR^25B, -N₃, 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;

R²⁶ is selected from hydrogen, halogen, -CX²⁶₃, -CHX²⁶2, -CH2X²⁶, -OCX²⁶₃,

-OCH2X²⁶, -OCHX²⁶2, -CN, -SO„2 ,R²ⁱ'^A. -SO_V26NR^26AR^26B, -NHC(0)NR^26AR^26B, -N(0)_m26, -NR^26AR^26B, -NHNR^26AR^26B, -C(0)R^26A, -C(0)-0R^26A, -C(0)NR^26AR^26B,

-C(0)NHNR^26AR^26B, -OR^26A, -NR^26AS0₂R^26B, -NR^26AC(0)R^26B, -NR^26AC(0)0R^26B, -NR^26AOR^26B, -N₃, 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;

R²⁷ is selected from hydrogen, halogen, -CX²⁷₃, -CHX²⁷₂, -CH₂X²⁷, -OCX²⁷₃,

-OCH₂X²⁷, -0CHX²⁷₂, -CN, -SO_n27R^27A, -SO_V27NR^27AR^27B, -NHC(0)NR^27AR^27B, -N(0)_m27, -NR^27AR^27B, -NHNR^27AR^27B, -C(0)R^27A, -C(0)-0R^27A, -C(0)NR^27AR^27B,

-C(0)NHNR^27AR^27B, -OR^27A, -NR^27AS0₂R^27B, -NR^27AC(0)R^27B, -NR^27AC(0)0R^27B, -NR^27AOR^27B, -N3, 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;

R²⁸ is selected from hydrogen, halogen, -CX²⁸₃, -CHX²⁸₂, -CH₂X²⁸, -OCX²⁸₃,

-NR^28AOR^28B, -N3, 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;

R²⁹ is selected from hydrogen, halogen, -CX²⁹₃, -CHX²⁹₂, -CH₂X²⁹, -OCX²⁹₃,

-NR^29AOR^29B, -N3, 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;

R³⁰ is selected from hydrogen, halogen, -CX³⁰₃, -CHX³⁰₂, -CH₂X³⁰, -OCX³⁰₃,

-0CH₂X³⁰, -OCHX³⁰₂, -CN, -SO_n3oR^30A, -SO_v3oNR^30AR^30B, -NHC(O)NR^30AR^30B, -N(O)_m30, -NR^30AR^30B, -NHNR^30AR^30B, -C(O)R^30A, -C(O)-OR^30A, -C(O)NR^30AR^30B,

-C(O)NHNR^30AR^30B, -OR^30A, -NR^30ASO₂R^30B, -NR^30AC(O)R^30B, -NR^30AC(O)OR^30B, -NR^30AOR^30B, -N3, 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; R³¹ is selected from hydrogen, halogen, -CX³¹₃, -CHX³¹2, -CH2X³¹, -OCX³¹₃,

-OCH2X³¹, -OCHX³¹2, -CN, -SO„ i R' ^{I A}. -SO_v3iNR^31AR^31B, -NHC(0)NR^31AR^31B, -N(0)_ffl3i, -NR^31AR^31B, -NHNR^31AR^31B, -C(0)R^31A, -C(0)-0R^31A, -C(0)NR^31AR^31B,

-C(0)NHNR^31AR^31B, -OR^31A, -NR^31AS0₂R^31B, -NR^31AC(0)R^31B, -NR^31AC(0)0R^31B, -NR^31AOR^31B, -N3, 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;

R³² is selected from hydrogen, halogen, -CX³²₃, -CHX³²2, -CH2X³², -OCX³²₃, -

OCH2X³², -OCHX³²₂, -CN, -SO_n’,2R'^2A. -SO_V32NR^32AR^32B, -NHC(0)NR^32AR^32B, -N(0)_m32, - NR^32AR^32B -NHNR^32AR^32B, -C(0)R^32A, -C(0)-0R^32A, -C(0)NR^32AR^32B, -C(0)NHNR^32AR^32B , -OR^32A, -NR^32AS0₂R^32B, -NR^32AC(0)R^32B, -NR^32AC(0)0R^32B, -NR^32AOR^32B, -N₃, 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;

R³³ is selected from hydrogen, halogen, -CX³³₃, -CHX³³2, -CH2X³³, -OCX³³₃,

-OCH2X³³, -OCHX³³2, -CN, -SOn33R^33A, -SO_V3₃NR^33AR^33B, -NHC(0)NR^33AR^33B, -N(0)_m33, -NR^33AR^33B, -NHNR^33AR^33B, -C(0)R^33A, -C(0)-0R^33A, -C(0)NR^33AR^33B,

-C(0)NHNR^33AR^33B, -OR^33A, -NR^33AS0₂R^33B, -NR^33AC(0)R^33B, -NR^33AC(0)0R^33B, -NR^33AOR^33B, -N3, 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;

R³⁴ is selected from hydrogen, halogen, -CX³⁴₃, -CHX³⁴2, -CH2X³⁴, -OCX³⁴₃,

-OCH2X³⁴, -OCHX³⁴2, -CN, -SO_n34R^34A, -SO_V3₄NR^34AR^34B, -NHC(0)NR^34AR^34B, -N(0)_m34, -NR^34AR^34B, -NHNR^34AR^34B, -C(0)R^34A, -C(0)-0R^34A, -C(0)NR^34AR^34B,

-C(0)NHNR^34AR^34B, -OR^34A, -NR^34AS0₂R^34B, -NR^34AC(0)R^34B, -NR^34AC(0)0R^34B, -NR^34AOR^34B, -N3, 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;

R³⁵ is selected from hydrogen, halogen, -CX³⁵₃, -CHX³⁵2, -CH2X³⁵, -OCX³⁵₃,

-OCH2X³⁵, -OCHX³⁵2, -CN, -SOn35R^35A, -SO_V35NR^35AR^35B, -NHC(0)NR^35AR^35B, -N(0)_m35, -NR^35AR^35B, -NHNR^35AR^35B, -C(0)R^35A, -C(0)-0R^35A, -C(0)NR^35AR^35B, -C(0)NHNR^35AR^35B, -OR^35A, -NR^35AS0₂R^35B, -NR^35AC(0)R^35B, -NR^35AC(0)0R^35B, -NR^35AOR^35B, -N₃, 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;

-CX₃, -CHX₂, -CH₂X, -C(0)0H, -C(0)NH₂, -CN, -OH, -NH₂, -COOH, -CONH2, -NO2,

-SH, -S0₃H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH₂, -NHC=(0)NH₂,

-NHSO2H, -NHC=(0)H, -NHC(0)0H, -NHOH, -OCX₃, -OCHX₂, -OCH₂X, 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^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^2A and R^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^4A and R^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^6A and R^6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^7A and R^7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^9A and R^9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^13A and R^13B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^14A and R^14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^15A and R^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^16A and R^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^17A and R^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted

heterocycloalkyl or substituted or unsubstituted heteroaryl; R^18A and R^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^19A and R^19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^20A and R^20B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^21A and R^21B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^22A and R^22B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^23A and R^23B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^24A and R^24B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted

heterocycloalkyl or substituted or unsubstituted heteroaryl; R^25A and R^25B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^26A and R^26B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^27A and R^27B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^28A and R^28B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^29A and R^29B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^30A and R^30B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; Each ml, m3, m4, m6, m7, m9, ml3, ml4, ml5, ml6, ml7, ml8, ml9, m20, m21, m22, m23, m24, m25, m26, m27, m28, m29, m30, m31, m32, m33, m34 and m35 is independently 1 or 2;

Each vl, v3, v4, v6, v7, v9, vl3, vl4, vl5, vl6, vl7, vl8, vl9, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v30, v31, v32, v33, v34 and v35 is independently 1 or 2;

Each nl, n3, n4, n6, n7, n9, nl3, nl4, nl5, nl6, nl7, nl8, nl9, n20, n21, n22, n23, n24, n25, n26, n27, n28, n29, n30, n31, n32, n33, n34 and n35 is independently an integer from 0 to 2; and

X²⁷, X²⁸, X²⁹, X³⁰, X³¹, X³², X³³, X³⁴, and X³⁵ is independently -Cl, -Br, -I or -F; provided ring B is not 4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl when E is ethenylcarbonyl.

14. Compound of claim 13 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein ring B is optionally substituted with one or more substituent groups.

15. Compound of claim 13 wherein ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein ring B is optionally substituted with one or more substituent groups.

16. Compound of claim 13 wherein ring B is selected from selected from

17. Compound of claim 13 wherein ring B is selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isolindolyl, wherein ring B is optionally substituted with one or more substituent groups.

18. Compound of claim 13 wherein ring B is selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl, wherein ring B is optionally substituted with one or more substituent groups.

19. Compound of any one of Claims 13-18 wherein E is selected from -C(=0)CH=CH₂, -C(=0)- ethynyl, -C(=0)CH=CHCF₃, -C(=0)CH=CHCHF₂, -C(=0)CH=CHCH₂F, and -C(=0)CH₂Br.

20. A compound of Claim 1, comprising a compound of Formula VII:

wherein

Z is N, or CR⁹;

U is selected from NR¹², O, S, S=0, 0=S=0, and Se;

ring B is selected from

a) 5- or 6-membered cycloalkyl, saturated or partially saturated heterocyclyl, b) 5- or 6-membered aryl or heteroaryl,

c) 9-, 10- or 11-membered fused partially saturated heterocyclyl, d) 9- or 10-membered fused heteroaryl,

e) naphthyl, and

f) 4-, 5- or 6-membered cycloalkenyl;

wherein ring B is optionally substituted with one ore more substituent groups;

E is an electrophilic moiety, selected from

R¹ is selected from hydrogen, halogen, -CX , -CHXS, -CH₂X¹, -OCXS,

-OCH2X¹, -OCHXS, -CN, -SO„iR^1A, -SO_viNR^1AR^1B, -NHC(0)NR^1AR^1B, -N(0)mi,

-NR^1AR^1B, -NHNR^1AR^1B, -C(0)R^1A, -C(0)-0R^1A, -C(0)NR^1AR^1B, -C(0)NHNR^1AR^1B, -OR^1A, -NR^1AS0₂R^1B, -NR^1AC(0)R^1B, -NR^1AC(0)0R^1B, -NR^1AOR^1B, -N₃, 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;

R³ is selected from hydrogen, halogen, -CX³3, -CHX³₂, -CH₂X³, -OCX³3,

-OCH2X³, -OCHX³2, -CN, -SO„,R '^A. -SO_V3NR^3AR^3B, -NHC(0)NR^3AR^3B, -N(0)_pΰ,

-NR^3AR^3B, -NHNR^3AR^3B, -C(0)R^3A, -C(0)-0R^3A, -C(0)NR^3AR^3B, -OR^3A, -NR^3AS0₂R^3B, -NR^3AC(0)R^3B, -NR^3AC(0)0R^3B, -NR^3AOR^3B, -N3, 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;

R⁴ is selected from hydrogen, halogen, -CX⁴3, -CHX⁴₂, -CH₂X⁴, -OCX⁴3,

-OCH2X⁴, -OCHX⁴2, -CN, -SO„₄R^4A, -SO_V4NR^4AR^4B, -NHC(0)NR^4AR^4B, -N(0)_m4, -NR^4AR^4B, -NHNR^4AR^4B, -C(0)R^4A, -C(0)-0R^4A, -C(0)NR^4AR^4B, -C(0)NHNR^4AR^4B, -OR^4A, -NR^4AS0₂R^4B, -NR^4AC(0)R^4B, -NR^4AC(0)0R^4B, -NR^4AOR^4B, -N₃, 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; R³ and R³ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R⁶ is selected from hydrogen, halogen, -CX⁶₃, -CHX⁶2, -CH2X⁶, -OCX⁶₃,

-OCH2X⁶, -OCHX⁶₂, -CN, -SO„₆R^6A, -SO_V6NR^6AR^6B, -NHC(0)NR^6AR^6B, -N(0)_m6,

-NR^6AR^6B, -NHNR^6AR^6B, -C(0)R^6A, -C(0)-0R^6A, -C(0)NR^6AR^6B, -C(0)NHNR^6AR^6B, -OR^6A, -NR^6AS0₂R^6B, -NR^6AC(0)R^6B, -NR^6AC(0)0R^6B, -NR^6AOR^6B, -N₃, 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;

R⁷ is selected from hydrogen, halogen, -CX⁷₃, -CHX⁷2, -CH2X⁷, -OCX⁷₃,

-OCH2X⁷, -OCHX⁷2, -CN, -SO„₇R^7A, -SO_V7NR^7AR^7B, -NHC(0)NR^7AR^7B, -N(0)_m7,

-NR^7AR^7B, -NHNR^7AR^7B, -C(0)R^7A, -C(0)-0R^7A, -C(0)NR^7AR^7B, -C(0)NHNR^7AR^7B, -OR^7A, -NR^7AS0₂R^7B, -NR^7AC(0)R^7B, -NR^7AC(0)0R^7B, -NR^7AOR^7B, -N₃, 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;

R⁹ is selected from hydrogen, halogen, -CX⁹₃, -CHX⁹2, -CH2X⁹, -OCX⁹₃,

-OCH2X⁹, -OCHX⁹2, -CN, -SO„₉R^9A, -SO_V9NR^9AR^9B, -NHC(0)NR^9AR^9B, -N(0)_m9,

-NR^9AR^9B, -NHNR^9AR^9B, -C(0)R^9A, -C(0)-0R^9A, -C(0)NR^9AR^9B, -C(0)NHNR^9AR^9B, -OR^9A, -NR^9AS0₂R^9B, -NR^9AC(0)R^9B, -NR^9AC(0)0R^9B, -NR^9AOR^9B, -N₃, 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;

R¹⁰ is selected from hydrogen, halogen, -CX¹⁰₃, -CHX¹⁰2, -CH2X¹⁰, -OCX¹⁰₃,

-OCH2X¹⁰, -OCHX¹⁰2, -CN, -SO„ioR^10A, -SO_vioNR^10AR^10B, -NHC(O)NR^10AR^10B, -N(0)mio, -NR^10AR^10B, -NHNR^10AR^10B, -C(O)R^10A, -C(O)-OR^10A, -C(O)NR^10AR^10B,

-C(O)NHNR^10AR^10B, -OR^10A, -NR^10ASO₂R^10B, -NR^10AC(O)R^10B, -NR^10AC(O)OR^10B,

-NR^10AOR^10B, -N₃, 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;

R¹¹ is selected from hydrogen, halogen, -CX^U3, -CHX^U2, -CH2X¹¹, -OCX^U3,

-OCH2X¹¹, -OCHX^U2, -CN, -SO„iiR^11A, -SO_viiNR^11AR^11B, -NHC(0)NR^11AR^11B, -N(0)_mii, -NR^11AR^11B, -NHNR^11AR^11B, -C(0)R^11A, -C(0)-0R^11A, -C(0)NR^11AR^11B,

-C(0)NHNR^11AR^11B, -OR^11A, -NR^11AS0₂R^11B, -NR^11AC(0)R^11B, -NR^11AC(0)0R^11B, -NR^11AOR^11B, -N3, 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;

R¹² is selected from hydrogen, halogen, -CX¹²₃, -CHX¹²2, -CH2X¹², -OCX¹²₃,

-OCH2X¹², -OCHX¹²2, -CN, -SO„_I2R^12A, -SO_VI2NR^12AR^12B, -NHC(0)NR^12AR^12B, -N(0)mi2, -NR^12AR^12B, -NHNR^12AR^12B, -C(0)R^12A, -C(0)-0R^12A, -C(0)NR^12AR^12B,

-C(0)NHNR^12AR^12B, -OR^12A, -NR^12AS0₂R^12B, -NR^12AC(0)R^12B, -NR^12AC(0)0R^12B, -NR^12AOR^12B, -N3, 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;

R¹⁷ is selected from hydrogen, halogen, -CX¹⁷₃, -CHX¹⁷2, -CH2X¹⁷, -OCX¹⁷₃,

-OCH2X¹⁷, -OCHX¹⁷2, -CN, -SO„_I7R^17A, -SO_VI7NR^17AR^17B, -NHC(0)NR^17AR^17B, -N(0)mi7, -NR^17AR^17B, -NHNR^17AR^17B, -C(0)R^17A, -C(0)-0R^17A, -C(0)NR^17AR^17B,

-C(0)NHNR^17AR^17B, -OR^17A, -NR^17AS0₂R^17B, -NR^17AC(0)R^17B, -NR^17AC(0)0R^17B, -NR^17AOR^17B, -N3, 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;

R¹⁸ is selected from hydrogen, halogen, -CX¹⁸₃, -CHX¹⁸2, -CH2X¹⁸, -OCX¹⁸₃,

-OCH2X¹⁸, -OCHX¹⁸₂, -CN, -SO„_I8R^18A, -SO_VI8NR^18AR^18B, -NHC(0)NR^18AR^18B, -N(0)_mi8, -NR^18AR^18B, -NHNR^18AR^18B, -C(0)R^18A, -C(0)-0R^18A, -C(0)NR^18AR^18B,

-C(0)NHNR^18AR^18B, -OR^18A, -NR^18AS0₂R^18B, -NR^18AC(0)R^18B, -NR^18AC(0)0R^18B, -NR^18AOR^18B, -N3, 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; R¹⁶ and R¹⁸ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R¹⁹ is selected from hydrogen, halogen, -CX¹⁹3, -CHX¹⁹₂, -CH₂X¹⁹, -OCX¹⁹3,

-OCH2X¹⁹, -OCHX¹⁹₂, -CN, -SO„_I9R^19A, -SO_VI9NR^19AR^19B, -NHC(0)NR^19AR^19B, -N(0)_mi9, -NR^19AR^19B, -NHNR^19AR^19B, -C(0)R^19A, -C(0)-0R^19A, -C(0)NR^19AR^19B,

-C(0)NHNR^19AR^19B, -OR^19A, -NR^19AS0₂R^19B, -NR^19AC(0)R^19B, -NR^19AC(0)0R^19B, -NR^19AOR^19B, -N3, 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; R¹⁶ and R¹⁹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²⁰ is selected from hydrogen, halogen, -CX²⁰3, -CHX²⁰₂, -CH₂X²⁰, -OCX²⁰3,

-OCH₂X²⁰, -OCHX²⁰₂, -CN, -SO„_2OR^20A, -SO_V2ONR^20AR^20B, -NHC(O)NR^20AR^20B, -N(0)m2o, -NR^20AR^20B, -NHNR^20AR^20B, -C(O)R^20A, -C(O)-OR^20A, -C(O)NR^20AR^20B,

-C(O)NHNR^20AR^20B, -OR^20A, -NR^20ASO₂R^20B, -NR^20AC(O)R^20B, -NR^20AC(O)OR^20B, -NR^20AOR^20B, -N3, 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;

R²¹ is selected from hydrogen, halogen, -CX²¹₃, -CHX²¹₂, -CH₂X²¹, -OCX²¹₃,

-OCH2X²¹, -OCHX²¹₂, -CN, -SO„_2iR^21A, -SO_V2_INR^21AR^21B, -NHC(0)NR^21AR^21B, -N(0)_{m2 i}. -NR^21AR^21B, -NHNR^21AR^21B, -C(0)R^21A, -C(0)-0R^21A, -C(0)NR^21AR^21B,

-C(0)NHNR^21AR^21B, -OR^21A, -NR^21AS0₂R^21B, -NR^21AC(0)R^21B, -NR^21AC(0)0R^21B, -NR^21AOR^21B, -N3, 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; R²⁰ and R²¹ substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;

R²² is selected from hydrogen, halogen, -CX²²₃, -CHX²²₂, -CH₂X²², -OCX²²₃,

-OCH2X²², -OCHX²²2, -CN, -SO„₂₂R^22A, -SO_V22NR^22AR^22B, -NHC(0)NR^22AR^22B, -N(0)_m22. -NR^22AR^22B, -NHNR^22AR^22B, -C(0)R^22A, -C(0)-0R^22A, -C(0)NR^22AR^22B,

-C(0)NHNR^22AR^22B, -OR^22A, -NR^22AS0₂R^22B, -NR^22AC(0)R^22B, -NR^22AC(0)0R^22B, -NR^22AOR^22B, -N3, 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;

R²³ is selected from hydrogen, halogen, -CX²³₃, -CHX²³2, -CH2X²³, -OCX²³₃,

-OCH2X²³, -OCHX²³2, -CN, -SO„2₃R^23A, -SO_V23NR^23AR^23B, -NHC(0)NR^23AR^23B, -N(0)m₂₃, -NR^23AR^23B, -NHNR^23AR^23B, -C(0)R^23A, -C(0)-0R^23A, -C(0)NR^23AR^23B,

-C(0)NHNR^23AR^23B, -OR^23A, -NR^23AS0₂R^23B, -NR^23AC(0)R^23B, -NR^23AC(0)0R^23B, -NR^23AOR^23B, -N₃, 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;

R²⁴ is selected from hydrogen, halogen, -CX²⁴₃, -CHX²⁴2, -CH2X²⁴, -OCX²⁴₃,

-OCH2X²⁴, -OCHX²⁴2, -CN, -SO„₂₄R^24A, -SO_V24NR^24AR^24B, -NHC(0)NR^24AR^24B, -N(0)_m24, -NR^24AR^24B, -NHNR^24AR^24B, -C(0)R^24A, -C(0)-0R^24A, -C(0)NR^24AR^24B,

-C(0)NHNR^24AR^24B, -OR^24A, -NR^24AS0₂R^24B, -NR^24AC(0)R^24B, -NR^24AC(0)0R^24B, -NR^24AOR^24B, -N₃, 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;

R²⁵ is selected from hydrogen, halogen, -CX²⁵₃, -CHX²⁵₂, -CH₂X²⁵, -OCX²⁵₃,

-OCH2X²⁵, -OCHX²⁵2, -CN, -SO„₂₅R^25A, -SO_V25NR^25AR^25B, -NHC(0)NR^25AR^25B, -N(0)m₂₅, -NR^25AR^25B, -NHNR^25AR^25B, -C(0)R^25A, -C(0)-0R^25A, -C(0)NR^25AR^25B,

-C(0)NHNR^25AR^25B, -OR^25A, -NR^25AS0₂R^25B, -NR^25AC(0)R^25B, -NR^25AC(0)0R^25B, -NR^25AOR^25B, -N₃, 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;

R²⁶ is selected from hydrogen, halogen, -CX²⁶₃, -CHX²⁶2, -CH2X²⁶, -OCX²⁶₃,

-OCH2X²⁶, -OCHX²⁶2, -CN, -SO„₂₆R^26A, -SO_V26NR^26AR^26B, -NHC(0)NR^26AR^26B, -N(0)m₂₆, -NR^26AR^26B, -NHNR^26AR^26B, -C(0)R^26A, -C(0)-0R^26A, -C(0)NR^26AR^26B,

-C(0)NHNR^26AR^26B, -OR^26A, -NR^26AS0₂R^26B, -NR^26AC(0)R^26B, -NR^26AC(0)0R^26B, -NR^26AOR^26B, -N₃, 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; R²⁷ is selected from hydrogen, halogen, -CX²⁷₃, -CHX²⁷₂, -CH₂X²⁷, -OCX²⁷₃,

-OCH₂X²⁷, -0CHX²⁷₂, -CN, -SO„₂₇R^27A, -SO_V27NR^27AR^27B, -NHC(0)NR^27AR^27B, -N(0)_m27, -NR^27AR^27B, -NHNR^27AR^27B, -C(0)R^27A, -C(0)-0R^27A, -C(0)NR^27AR^27B,

-C(0)NHNR^27AR^27B, -OR^27A, -NR^27AS0₂R^27B, -NR^27AC(0)R^27B, -NR^27AC(0)0R^27B, -NR^27AOR^27B, -N3, 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;

R²⁸ is selected from hydrogen, halogen, -CX²⁸₃, -CHX²⁸₂, -CH₂X²⁸, -OCX²⁸₃,

-NR^28AOR^28B, -N3, 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;

R²⁹ is selected from hydrogen, halogen, -CX²⁹₃, -CHX²⁹₂, -CH₂X²⁹, -OCX²⁹₃,

-NR^29AOR^29B, -N3, 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;

R³⁰ is selected from hydrogen, halogen, -CX³⁰₃, -CHX³⁰₂, -CH₂X³⁰, -OCX³⁰₃,

-0CH₂X³⁰, -OCHX³⁰₂, -CN, -SO„_3OR^30A, -SO_V3ONR^30AR^30B, -NHC(O)NR^30AR^30B, -N(O)_B30, -NR^30AR^30B, -NHNR^30AR^30B, -C(O)R^30A, -C(O)-OR^30A, -C(O)NR^30AR^30B,

-C(O)NHNR^30AR^30B, -OR^30A, -NR^30ASO₂R^30B, -NR^30AC(O)R^30B, -NR^30AC(O)OR^30B, -NR^30AOR^30B, -N3, 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;

R³¹ is selected from hydrogen, halogen, -CX³¹₃, -CHX³¹₂, -CH₂X³¹, -OCX³¹₃,

-OCH₂X³¹, -0CHX³¹₂, -CN, -SO„_3iR^31A, -SO_V3INR^31AR^31B, -NHC(0)NR^31AR^31B, -N(0)_ffl3i, -NR^31AR^31B, -NHNR^31AR^31B, -C(0)R^31A, -C(0)-0R^31A, -C(0)NR^31AR^31B,

-C(0)NHNR^31AR^31B, -OR^31A, -NR^31AS0₂R^31B, -NR^31AC(0)R^31B, -NR^31AC(0)0R^31B, -NR^31AOR^31B, -N3, 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;

R³² is selected from hydrogen, halogen, -CX³²₃, -CHX³²₂, -CH₂X³², -OCX³²₃,

-OCH₂X³², -0CHX³²₂, -CN, -SO„₂R'^2A. -SO_V32NR^32AR^32B, -NHC(0)NR^32AR^32B, -N(0)_m32, -NR^32AR^32B, -NHNR^32AR^32B, -C(0)R^32A, -C(0)-0R^32A, -C(0)NR^32AR^32B,

-C(0)NHNR^32AR^32B, -OR^32A, -NR^32AS0₂R^32B, -NR^32AC(0)R^32B, -NR^32AC(0)0R^32B, -NR^32AOR^32B, -N3, 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;

R³³ is selected from hydrogen, halogen, -CX³³₃, -CHX³³₂, -CH₂X³³, -OCX³³₃,

-OCH₂X³³, -0CHX³³₂, -CN, -SO„₃₃R^33A, -SO_V33NR^33AR^33B, -NHC(0)NR^33AR^33B, -N(0)B33, -NR^33AR^33B, -NHNR^33AR^33B, -C(0)R^33A, -C(0)-0R^33A, -C(0)NR^33AR^33B,

-C(0)NHNR^33AR^33B, -OR^33A, -NR^33AS0₂R^33B, -NR^33AC(0)R^33B, -NR^33AC(0)0R^33B, -NR^33AOR^33B, -N3, 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;

R³⁴ is selected from hydrogen, halogen, -CX³⁴₃, -CHX³⁴₂, -CH₂X³⁴, -OCX³⁴₃,

-OCH₂X³⁴, -0CHX³⁴₂, -CN, -SO„₃₄R^34A, -SO_V3₄NR^34AR^34B, -NHC(0)NR^34AR^34B, -N(0)_m34, -NR^34AR^34B, -NHNR^34AR^34B, -C(0)R^34A, -C(0)-0R^34A, -C(0)NR^34AR^34B,

-C(0)NHNR^34AR^34B, -OR^34A, -NR^34AS0₂R^34B, -NR^34AC(0)R^34B, -NR^34AC(0)0R^34B, -NR^34AOR^34B, -N3, 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;

R³⁵ is selected from hydrogen, halogen, -CX³⁵₃, -CHX³⁵₂, -CH₂X³⁵, -OCX³⁵₃,

-OCH₂X³⁵, -0CHX³⁵₂, -CN, -SO„₃₅R^35A, -SO_V35NR^35AR^35B, -NHC(0)NR^35AR^35B, -N(0)B35, -NR^35AR^35B, -NHNR^35AR^35B, -C(0)R^35A, -C(0)-0R^35A, -C(0)NR^35AR^35B,

-C(0)NHNR^35AR^35B, -OR^35A, -NR^35AS0₂R^35B, -NR^35AC(0)R^35B, -NR^35AC(0)0R^35B, -NR^35AOR^35B, -N₃, 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;

R'^4A. R^34B, R^35A, R^35B, is independently selected from hydrogen,

-CH₂X, -C(0)0H, -C(0)NH₂, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H,

-SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC=(0)NHNH₂, -NHC=(0)NH₂, -NHSO₂H, -NHC=(0)H, -NHC(0)0H, -NHOH, -OCX₃, -OCHX₂, -OCH₂X, 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^1A and R^1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^2A and R^2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^4A and R^4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^6A and R^6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^7A and R^7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^9A and R^9B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^13A and R^13B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^14A and R^14B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^15A and R^15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^16A and R^16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^17A and R^17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^18A and R^18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^19A and R^19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^20A and R^20B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^21A and R^21B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^22A and R^22B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^23A and R^23B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^24A and R^24B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^25A and R^25B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^26A and R^26B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^27A and R^27B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^28A and R^28B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^29A and R^29B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R^30A and R^30B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

Each ml, m3, iu4, iu6, iu7, iu9, mlO, mi l, ml7, ml8, ml9, m20, iu21, iu22, iu23, iu24, iu25, iu26, iu27, iu28, iu29, m30, m31, iu32, iu33, iu34 and iu35 is independently 1 or 2;

Each vl, v3, v4, v6, v7, v9, vlO, vl l, vl7, vl8, vl9, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v30, v31, v32, v33, v34 and v35 is independently 1 or 2;

Each nl, n3, n4, n6, n7, n9, nlO, nl 1, nl7, nl8, nl9, n20, n21, n22, n23, n24, n25, n26, n27, n28, n29, n30, n31, n32, n33, n34 and n35 is independently an integer from 0 to 2; and

X²⁹, X³⁰, X³¹, X³², X³³, X³⁴, and X³⁵ is independently -Cl, -Br, -I or -F.

21. Compound of claim 20 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein ring B is optionally substituted with one or more substituent groups.

22. Compound of claim 20 wherein ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein ring B is optionally substituted with one or more substituent groups.

23. Compound of claim 21 wherein ring B is selected from selected from

24. Compound of claim 20 wherein ring B is selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isolindolyl, wherein ring B is optionally substituted with one or more substituent groups.

25. Compound of claim 20 wherein ring B is selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl, wherein ring B is optionally substituted with one or more substituent groups.

26. Compound of any one of claims 20-25 wherein E is selected from -C(=0)CH=CH₂, -C(=0)-ethynyl, -C(=0)CH=CHCF₃, -C(=0)CH=CHCHF₂, -C(=0)CH=CHCH₂F, and -C(=0)CH₂Br.

27. Compound of any one of claims 20-26 wherein U is O, NR¹² or S.

28. A compound of Claim I, comprising a compound of Formula VIII:

wherein

Z is N, or CR⁹;

W is selected from NR¹², O, S, S=0, 0=S=0, and Se;

ring B is selected from

a) 5- or 6-membered cycloalkyl, saturated or partially saturated heterocyclyl, b) 5- or 6-membered aryl or heteroaryl,

c) 9-, 10- or 11-membered fused partially saturated heterocyclyl, d) 9- or 10-membered fused heteroaryl,

e) naphthyl, and

f) 4-, 5- or 6-membered cycloalkenyl;

wherein ring B is optionally substituted with one or more substituent groups;

E is selected from an electrophilic moiety, selected from

wherein R¹ is selected from hydrogen, halogen, -CX , -CHX^, -CH₂X¹, -OCXS,

-OCH2X¹, -OCHXS, -CN, -SO„iR^1A, -SO_viNR^1AR^1B, -NHC(0)NR^1AR^1B, -N(0)_mi, -NR^1AR^1B, -NHNR^1AR^1B, -C(0)R^1A, -C(0)-0R^1A, -C(0)NR^1AR^1B, -C(0)NHNR^1AR^1B, -OR^1A, -NR^1AS0₂R^1B, -NR^1AC(0)R^1B, -NR^1AC(0)0R^1B, -NR^1AOR^1B, -N₃, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, rand substituted or unsubstituted heteroaryl;

R³ is selected from hydrogen, halogen, -CX³3, -CHX³₂, -CH₂X³, -OCX³3,

-OCH2X³, -OCHX³2, -CN, -SO„,R '^A. -SO_V3NR^3AR^3B, -NHC(0)NR^3AR^3B, -N(0)_pΰ, -NR^3AR^3B, -NHNR^3AR^3B, -C(0)R^3A, -C(0)-0R^3A, -C(0)NR^3AR^3B, -OR^3A, -NR^3AS0₂R^3B, -NR^3AC(0)R^3B, -NR^3AC(0)0R^3B, -NR^3AOR^3B, -N3, 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; R⁴ is selected from hydrogen, halogen, -CX⁴₃, -CHX⁴2, -CH2X⁴, -OCX⁴₃,