SUMO INHIBITOR COMPOUNDS AND USES THEREOF
20220177488 · 2022-06-09
Inventors
- Xiaohu Ouyang (Rosemead, CA, US)
- Miles Kubota (Monrovia, CA, US)
- Ted Charles Judd (Granada Hills, CA, US)
- Andrew S. Tasker (Simi Valley, CA)
Cpc classification
C07D333/54
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07D217/06
CHEMISTRY; METALLURGY
G01N2440/36
PHYSICS
C07D401/04
CHEMISTRY; METALLURGY
C07D209/08
CHEMISTRY; METALLURGY
International classification
C07D209/08
CHEMISTRY; METALLURGY
C07D217/06
CHEMISTRY; METALLURGY
C07D333/54
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D405/06
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
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.
Claims
1. A compound of formula I or an isomer or a pharmaceutically acceptable salt thereof: ##STR00446## wherein is selected from a single bond or double bond; l, m, and n are independently an integer from 0 to 2; M is selected from CR.sup.3R.sup.4, NR.sup.5, C═O, O, S═O, O═S═O, and S; Y is selected from CR.sup.6R.sup.7, NR.sup.8, C═O, O, S═O, O═S═O, and S; Z is CR.sup.9, 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 ##STR00447## ##STR00448## ##STR00449## R.sup.1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, —CX.sup.1.sub.3, —CHX.sup.1.sub.2, —CH.sub.2X.sup.1, —OCX.sup.1.sub.3, —OCH.sub.2X.sup.1, —OCHX.sup.1.sub.2, —SO.sub.n1R.sup.1A, —SO.sub.n1NR.sup.1AR.sup.1B, —NHC(O)NR.sup.1AR.sup.1B, —N(O).sub.m1, —NR.sup.1AR.sup.1B, —NHNR.sup.1AR.sup.1B, —C(O)R.sup.1A, —C(O)—OR.sup.1A, —C(O)NR.sup.1AR.sup.1B, —C(O)NHNR.sup.1AR.sup.1B, —OR.sup.1A, —NR.sup.1ASO.sub.2R.sup.1B, —NR.sup.1AC(O)R.sup.1B, —NR.sup.1AC(O)OR.sup.1B, —NR.sup.1AOR.sup.1B, azido, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.2 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, —CX.sup.2.sub.3, —CHX.sup.2.sub.2, —CH.sub.2X.sup.2, —OCX.sup.2.sub.3, —OCH.sub.2X.sup.2, —OCHX.sup.2.sub.2, —SO.sub.n2R.sup.2A, —SO.sub.v2NR.sup.2AR.sup.2B, —NHC(O)NR.sup.2AR.sup.2B, —N(O).sub.m2, —NR.sup.2AR.sup.2B, —NHNR.sup.2AR.sup.2B, —C(O)R.sup.2A, —C(O)—OR.sup.2A, —C(O)NR.sup.2AR.sup.2B, —C(O)NHNR.sup.2AR.sup.2B, —OR.sup.2A, —NR.sup.2ASO.sub.2R.sup.2B, —NR.sup.2AC(O)R.sup.2B, —NR.sup.2AC(O)OR.sup.2B, —NR.sup.2AOR.sup.2B, azido, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.1 and R.sup.2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.3 is selected from hydrogen, halogen, —CX.sup.3.sub.3, —CHX.sup.3.sub.2, —CH.sub.2X.sup.3, —OCX.sup.3.sub.3, —OCH.sub.2X.sup.3, —OCHX.sup.3.sub.2, —CN, —SO.sub.n3R.sup.3A, —SO.sub.v3NR.sup.3AR.sup.3B, —NHC(O)NR.sup.3AR.sup.3B, —N(O).sub.m3, —NR.sup.3AR.sup.3B, —NHNR.sup.3AR.sup.3B, —C(O)R.sup.3A, —C(O)—OR.sup.3A, —C(O)NR.sup.3AR.sup.3B, —OR.sup.3A, —NR.sup.3ASO.sub.2R.sup.3B, —NR.sup.3AC(O)R.sup.3B, —NR.sup.3AC(O)OR.sup.3B, —NR.sup.3AOR.sup.3B, —N.sub.3, 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.sup.4 is selected from hydrogen, halogen, —CX.sup.4.sub.3, —CHX.sup.4.sub.2, —CH.sub.2X.sup.4, —OCX.sup.4.sub.3, —OCH.sub.2X.sup.4, —OCHX.sup.4.sub.2, —CN, —SO.sub.n4R.sup.4A, —SO.sub.v4NR.sup.4AR.sup.4B, —NHC(O)NR.sup.4AR.sup.4B, —N(O).sub.m4, —NR.sup.4AR.sup.4B, —NHNR.sup.4AR.sup.4B, —C(O)R.sup.4A, —C(O)—OR.sup.4A, —C(O)NR.sup.4AR.sup.4B, —C(O)NHNR.sup.4AR.sup.4B, —OR.sup.4A, —NR.sup.4ASO.sub.2R.sup.4B, —NR.sup.4AC(O)R.sup.4B, —NR.sup.4AC(O)OR.sup.4B, —NR.sup.4AOR.sup.4B, —N.sub.3, 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.sup.3 and R.sup.3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.5 is selected from hydrogen, halogen, —CX.sup.5.sub.3, —CHX.sup.5.sub.2, —CH.sub.2X.sup.5, —OCX.sup.5.sub.3, —OCH.sub.2X.sup.5, —OCHX.sup.5.sub.2, —CN, —SO.sub.n5R.sup.5A, —SO.sub.v5NR.sup.5AR.sup.5B, —NHC(O)NR.sup.5AR.sup.5B, —N(O).sub.m5, —NR.sup.5AR.sup.5B, —NHNR.sup.5AR.sup.5B, C(O)R.sup.5A, —C(O)—OR.sup.5A, —C(O)NR.sup.5AR.sup.5B, —C(O)NHNR.sub.5AR.sup.5B, —OR.sup.5A, —NR.sup.5ASO.sub.2R.sup.5B, —NR.sup.5AC(O)R.sup.5B, —NR.sup.5AC(O)OR.sup.5B, —NR.sup.5AOR.sup.5B, —N.sub.3, 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.sup.6 is selected from hydrogen, halogen, —CX.sup.6.sub.3, —CHX.sup.6.sub.2, —CH.sub.2X.sup.6, —OCX.sup.6.sub.3, —OCH.sub.2X.sup.6, —OCHX.sup.6.sub.2, —CN, —SO.sub.n6R.sup.6A, —SO.sub.6NR.sup.6AR.sup.6B, —NHC(O)NR.sup.6AR.sup.6B, —N(O).sub.m6, —NR.sup.6AR.sup.6B, —NHNR.sup.6AR.sup.6B, —C(O)R.sup.6A, —C(O)—OR.sup.6A, —C(O)NR.sup.6AR.sup.6B, —C(O)NHNR.sup.6AR.sup.6B, —OR.sup.6A, —NR.sup.6ASO.sub.2R.sup.6B, —NR.sup.6AC(O)R.sup.6B, —NR.sup.6AC(O)OR.sup.6B, —NR.sup.6AOR.sup.6B, —N.sub.3, 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.sup.7 is selected from hydrogen, halogen, —CX.sup.7.sub.3, —CHX.sup.7.sub.2, —CH.sub.2X.sup.7, —OCX.sup.7.sub.3, —OCH.sub.2X.sup.7, —OCHX.sup.7.sub.2, —CN, —SO.sub.n7R.sup.7A, —SO.sub.7NR.sup.7AR.sup.7B, —NHC(O)NR.sup.7AR.sup.7B, —N(O).sub.m7, —NR.sup.7AR.sup.7B, —NHNR.sup.7AR.sup.7B, —C(O)R.sup.7A, —C(O)—OR.sup.7A, —C(O)NR.sup.7AR.sup.7B, —C(O)NHNR.sup.7AR.sup.7B, —OR.sup.7A, —NR.sup.7ASO.sub.2R.sup.7B, —NR.sup.7AC(O)R.sup.7B, —NR.sup.7AC(O)OR.sup.7B, —NR.sup.7AOR.sup.7B, —N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.8 is selected from hydrogen, halogen, —CX.sup.8.sub.3, —CHX.sup.8.sub.2, —CH.sub.2X.sup.8, —OCX.sup.8.sub.3, —OCH.sub.2X.sup.8, —OCHX.sup.8.sub.2, —CN, —SO.sub.n8R.sup.8A, —SO.sub.8NR.sup.8AR.sup.8B, —NHC(O)NR.sup.8AR.sup.8B, —N(O).sub.m8, —NR.sup.8AR.sup.8B, —NHNR.sup.8AR.sup.8B, —C(O)R.sup.8A, —C(O)—OR.sup.8A, —C(O)NR.sup.8AR.sup.8B, —C(O)NHNR.sup.8AR.sup.8B, —OR.sup.8A, —NR.sup.8ASO.sub.2R.sup.8B, —NR.sup.8AC(O)R.sup.8B, —NR.sup.8AC(O)OR.sup.8B, —NR.sup.8AOR.sup.8B, —N.sub.3, 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.sup.9 is selected from hydrogen, halogen, —CX.sup.9.sub.3, —CHX.sup.9.sub.2, —CH.sub.2X.sup.9, —OCX.sup.9.sub.3, —OCH.sub.2X.sup.9, —OCHX.sup.9.sub.2, —CN, —SO.sub.n9R.sup.9A, —SO.sub.v9NR.sup.9AR.sup.9B, —NHC(O)NR.sup.9AR.sup.9B, —N(O).sub.m9, —NR.sup.9AR.sup.9B, —NHNR.sup.9AR.sup.9B, —C(O)R.sup.9A, —C(O)—OR.sup.9A, —C(O)NR.sup.9AR.sup.9B, —C(O)NHNR.sup.9AR.sup.9B, —OR.sup.9A, —NR.sup.9ASO.sub.2R.sup.9B, —NR.sup.9AC(O)R.sup.9B, —NR.sup.9AC(O)OR.sup.9B, —NR.sup.9AOR.sup.9B, —N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.10 is selected from hydrogen, halogen, —CX.sup.10.sub.3, —CHX.sup.10.sub.2, —CH.sub.2X.sup.10, —OCX.sup.10.sub.3, —OCH.sub.2X.sup.10, —OCHX.sup.10.sub.2, —CN, —SO.sub.n10R.sup.10A, —SO.sub.v10NR.sup.10AR.sup.10B, —NHC(O)NR.sup.10AR.sup.10B, N(O).sub.m10, —NR.sup.10AR.sup.10B, —NHNR.sup.10AR.sup.10B, —C(O)R.sup.10A, —C(O)—OR.sup.10A, —C(O)NR.sup.10AR.sup.10B, —C(O)NHNR.sup.10AR.sup.10B, —OR.sup.10A, —NR.sup.10ASO.sub.2R.sup.10B, —NR.sup.10AC(O)R.sup.10B, —NR.sup.10AC(O)OR.sup.10B, —NR.sup.10AOR.sup.10B, —N.sub.3, 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.sup.11 is selected from hydrogen, halogen, —CX.sup.11.sub.3, —CHX.sup.11.sub.2, —CH.sub.2X.sup.11, —OCX.sup.11.sub.3, —OCH.sub.2X.sup.11, —OCHX.sup.11.sub.2, —CN, —SO.sub.n11R.sup.11A, —SO.sub.v11NR.sup.11AR.sup.11B, —NHC(O)NR.sup.11AR.sup.11B, —N(O).sub.m11, —NR.sup.11AR.sup.11B, —NHNR.sup.11AR.sup.11B, —C(O)R.sup.11A, —C(O)—OR.sup.11A, —C(O)NR.sup.11AR.sup.11B, —C(O)NHNR.sup.11AR.sup.11B, —OR.sup.11A, —NR.sup.11ASO.sub.2R.sup.11B, —NR.sup.11AC(O)R.sup.11B, —NR.sup.11AC(O)OR.sup.11B, —NR.sup.11AOR.sup.11B, —N.sub.3, 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.sup.12 is selected from hydrogen, halogen, —CX.sup.12.sub.3, —CHX.sup.12.sub.2, —CH.sub.2X.sup.12, —OCX.sup.12.sub.3, —OCH.sub.2X.sup.12, —OCHX.sup.12.sub.2, —CN, —SO.sub.n12R.sup.12A, —O.sub.v12NR.sup.12AR.sup.12B, —NHC(O)NR.sup.12AR.sup.12B, —N(O).sub.m12, —NR.sup.12AR.sup.12B, —NHNR.sup.12AR.sup.12B, —C(O)R.sup.12A, —C(O)—OR.sup.12A, —C(O)NR.sup.12AR.sup.12B, —C(O)NHNR.sup.12AR.sup.12B, —OR.sup.12A, —NR.sup.12ASO.sub.2R.sup.12B, —NR.sup.12AC(O)R.sup.12B, —NR.sup.12AC(O)OR.sup.12B, —NR.sup.12AOR.sup.12B, —N.sub.3, 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.sup.13 is selected from hydrogen, halogen, —CX.sup.13.sub.3, —CHX.sup.13.sub.2, —CH.sub.2X.sup.13, —OCX.sup.13.sub.3, —OCH.sub.2X.sup.13, —OCHX.sup.13.sub.2, —CN, —SO.sub.n13R.sup.13A, —SO.sub.v13NR.sup.13AR.sup.13B, —NHC(O)NR.sup.13AR.sup.13B, —N(O).sub.m13, —NR.sup.13AR.sup.13B, —NHNR.sup.13AR.sup.13B, —C(O)R.sup.13A, —C(O)—OR.sup.13A, —C(O)NR.sup.13AR.sup.13B, —C(O)NHNR.sup.13AR.sup.13B, —OR.sup.13A, —NR.sup.13ASO.sub.2R.sup.13B, —NR.sup.13AC(O)R.sup.13B, —NR.sup.13AC(O)OR.sup.13B, —NR.sup.13AOR.sup.13B, —N.sub.3, 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.sup.14 is selected from hydrogen, halogen, —CX.sup.14.sub.3, —CHX.sup.14.sub.2, —CH.sub.2X.sup.14, —OCX.sup.14.sub.3, —OCH.sub.2X.sup.14, —OCHX.sup.14.sub.2, —CN, —SO.sub.n14R.sup.14A, —SO.sub.v14NR.sup.14AR.sup.14B, —NHC(O)NR.sup.14AR.sup.14B, —N(O).sub.m14, —NR.sup.14AR.sup.14B, —NHNR.sup.14AR.sup.14B, —C(O)R.sup.14A, —C(O)—OR.sup.14A, —C(O)NR.sup.14AR.sup.14B, —C(O)NHNR.sup.14AR.sup.14B, —OR.sup.14A, —NR.sup.14ASO.sub.2R.sup.14B, —NR.sup.14AC(O)R.sup.14B, —NR.sup.14AC(O)OR.sup.14B, —NR.sup.14AOR.sup.14B, —N.sub.3, 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.sup.15 is selected from hydrogen, halogen, —CX.sup.15.sub.3, —CHX.sup.15.sub.2, —CH.sub.2X.sup.15, —OCX.sup.15.sub.3, —OCH.sub.2X.sup.15, —OCHX.sup.15.sub.2, —CN, —SO.sub.n1R.sup.15A, —SO.sub.v15NR.sup.15AR.sup.15B, —NHC(O)NR.sup.15AR.sup.15B, —N(O).sub.m15, —NR.sup.15AR.sup.15B, —NHNR.sup.15AR.sup.15B, —C(O)R.sup.15A, —C(O)—OR.sup.15A, —C(O)NR.sup.15AR.sup.15B, —C(O)NHNR.sup.15AR.sup.15B, —OR.sup.15A, —NR.sup.15ASO.sub.2R.sup.15B, —NR.sup.15AC(O)R.sup.15B, —NR.sup.15AC(O)OR.sup.15B, —NR.sup.15AOR.sup.15B, —N.sub.3, 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.sup.16 is selected from hydrogen, halogen, —CX.sup.16.sub.3, —CHX.sup.16.sub.2, —CH.sub.2X.sup.16, —OCX.sup.16.sub.3, —OCH.sub.2X.sup.16, —OCHX.sup.16.sub.2, —CN, —SO.sub.n16R.sup.16A, —SO.sub.v16NR.sup.16AR.sup.16B, —NHC(O)NR.sup.16AR.sup.16B, —N(O).sub.m16, —NR.sup.16AR.sup.16B, —NHNR.sup.16AR.sup.16B, —C(O)R.sup.16A, —C(O)—OR.sup.16A, —C(O)NR.sup.16AR.sup.16B, —C(O)NHNR.sup.16AR.sup.16B, —OR.sup.16A, —NR.sup.16ASO.sub.2R.sup.16B, —NR.sup.16AC(O)R.sup.16B, —NR.sup.16AC(O)OR.sup.16B, —NR.sup.16AOR.sup.16B, —N.sub.3, 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.sup.17 is selected from hydrogen, halogen, —CX.sup.17.sub.3, —CHX.sup.17.sub.2, —CH.sub.2X.sup.17, —OCX.sup.17.sub.3, —OCH.sub.2X.sup.17, —OCHX.sup.17.sub.2, —CN, —SO.sub.n17R.sup.17A, —SO.sub.v17NR.sup.17AR.sup.17B, —NHC(O)NR.sup.17AR.sup.17B, —N(O).sub.m17, —NR.sup.17AR.sup.17B, —NHNR.sup.17AR.sup.17B, —C(O)R.sup.17A, —C(O)—OR.sup.17A, —C(O)NR.sup.17AR.sup.17B, —C(O)NHNR.sup.17AR.sup.17B, —OR.sup.17A, —NR.sup.17ASO.sub.2R.sup.17B, —NR.sup.17AC(O)R.sup.17B, —NR.sup.17AC(O)OR.sup.17B, —NR.sup.17AOR.sup.17B, —N.sub.3, 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.sup.18 is selected from hydrogen, halogen, —CX.sup.18.sub.3, —CHX.sup.18.sub.2, —CH.sub.2X.sup.18, —OCX.sup.8.sub.3, —OCH.sub.2X.sup.18, —OCHX.sup.8.sub.2, —CN, —SO.sub.n18R.sup.18A, —SO.sub.v18NR.sup.18AR.sup.18B, —NHC(O)NR.sup.18AR.sup.18B, N(O).sub.m18, —NR.sup.18AR.sup.18B, —NHNR.sup.18AR.sup.18B, —C(O)R.sup.18A, —C(O)—OR.sup.18A, —C(O)NR.sup.18AR.sup.18B, —C(O)NHNR.sup.18AR.sup.18B, —OR.sup.18A, —NR.sup.18ASO.sub.2R.sup.18B, —NR.sup.18AC(O)R.sup.18B, —NR.sup.18AC(O)OR.sup.18B, —NR.sup.18AOR.sup.18B, —N.sub.3, 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.sup.17 and R.sup.18 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.19 is selected from hydrogen, halogen, —CX.sup.19.sub.3, —CHX.sup.19.sub.2, —CH.sub.2X.sup.19, —OCX.sup.19.sub.3, —OCH.sub.2X.sup.19, —OCHX.sup.19.sub.2, —CN, —SO.sub.n19R.sup.19A, —SO.sub.v19NR.sup.19AR.sup.19B, —NHC(O)NR.sup.19AR.sup.19B, —N(O).sub.m19, —NR.sup.19AR.sup.19B, —NHNR.sup.19AR.sup.19B, —C(O)R.sup.19A, —C(O)—OR.sup.19A, —C(O)NR.sup.19AR.sup.19B, —C(O)NHNR.sup.19AR.sup.19B, —OR.sup.19A, —NR.sup.19ASO.sub.2R.sup.19B, —NR.sup.19AC(O)R.sup.19B, —NR.sup.19AC(O)OR.sup.19B, —NR.sup.19AOR.sup.19B, —N.sub.3, 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.sup.20 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, —CX.sup.20.sub.3, —CHX.sup.20.sub.2, —CH.sub.2X.sup.20, —OCX.sup.20.sub.3, —OCH.sub.2X.sup.20, —OCHX.sup.20.sub.2, —CN, —SO.sub.n20R.sup.20A, —SO.sub.v20NR.sup.20AR.sup.20B, —NHC(O)NR.sup.20AR.sup.20B, —N(O).sub.m20, —NR.sup.20AR.sup.20B, —NHNR.sup.20AR.sup.20B, —C(O)R.sup.20A, —C(O)—OR.sup.20A, —C(O)NR.sup.20AR.sup.20B, —C(O)NHNR.sup.20AR.sup.20B, OR.sup.20A, —NR.sup.20A, —SO.sub.2R.sup.20B, —NR.sup.20AC(O)R.sup.20B, —NR.sup.20AC(O)OR.sup.20B, —NR.sup.20AOR.sup.20B, —N.sub.3, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.17 and R.sup.20 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.21 is selected from hydrogen, halogen, —CX.sup.21.sub.3, —CHX.sup.21.sub.2, —CH.sub.2X.sup.21, —OCX.sup.21.sub.3, —OCH.sub.2X.sup.21, —OCHX.sup.21.sub.2, —CN, —SO.sub.n21R.sup.21A, —SO.sub.v21NR.sup.21AR.sup.21B, —NHC(O)NR.sup.21AR.sup.21B, —N(O).sub.m21, —NR.sup.21AR.sup.21B, —NHNR.sup.21AR.sup.21B, —C(O)R.sup.21A, —C(O)—OR.sup.21A, —C(O)NR.sup.21AR.sup.21B, —C(O)NHNR.sup.21AR.sup.21B, —OR.sup.21A, —NR.sup.21ASO.sub.2R.sup.21B, —NR.sup.21AC(O)R.sup.21B, —NR.sup.21AC(O)OR.sup.21B, —NR.sup.21AOR.sup.21B, —N.sub.3, 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.sup.22 is selected from hydrogen, halogen, —CX.sup.22.sub.3, —CHX.sup.22.sub.2, —CH.sub.2X.sup.22, —OCX.sup.22.sub.3, —OCH.sub.2X.sup.22, —OCHX.sup.22.sub.2, —CN, —SO.sub.n22R.sup.22A, —SO.sub.v22NR.sup.22AR.sup.22B, —NHC(O)NR.sup.22AR.sup.22B, —N(O).sub.m22, —NR.sup.22AR.sup.22B, —NHNR.sup.22AR.sup.22B, —C(O)R.sup.22A, —C(O)—OR.sup.22A, —C(O)NR.sup.22AR.sup.22B, —C(O)NHNR.sup.22AR.sup.22B, —OR.sup.22A, —NR.sup.22ASO.sub.2R.sup.22B, —NR.sup.22AC(O)R.sup.22B, —NR.sup.22AC(O)OR.sup.22B, —NR.sup.22AOR.sup.22B, —N.sub.3, 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.sup.21 and R.sup.22 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.23 is selected from hydrogen, halogen, —CX.sup.23.sub.3, —CHX.sup.23.sub.2, —CH.sub.2X.sup.23, —OCX.sup.23.sub.3, —OCH.sub.2X.sup.23, —OCHX.sup.23.sub.2, —CN, —SO.sub.n23R.sup.23A, —SO.sub.v23NR.sup.23AR.sup.23B, —NHC(O)NR.sup.23AR.sup.23B, —N(O).sub.m23, —NR.sup.23AR.sup.23B, —NHNR.sup.23AR.sup.23B, —C(O)R.sup.23A, —C(O)—OR.sup.23A, —C(O)NR.sup.23AR.sup.23B, —C(O)NHNR.sup.23AR.sup.23B, —OR.sup.23A, —NR.sup.23ASO.sub.2R.sup.23B, —NR.sup.23AC(O)R.sup.23B, —NR.sup.23AC(O)OR.sup.23B, —NR.sup.23AOR.sup.23B, —N.sub.3, 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.sup.24 is selected from hydrogen, halogen, —CX.sup.24.sub.3, —CHX.sup.24.sub.2, —CH.sub.2X.sup.24, —OCX.sup.24.sub.3, —OCH.sub.2X.sup.24, —OCHX.sup.24.sub.2, —CN, —SO.sub.n24R.sup.24A, —SO.sub.v24NR.sup.24AR.sup.24B, —NHC(O)NR.sup.24AR.sup.24B, —N(O).sub.m24, —NR.sup.24AR.sup.24B, —NHNR.sup.24AR.sup.24B, —C(O)R.sup.24A, —C(O)—OR.sup.24A, —C(O)NR.sup.24AR.sup.24B, —C(O)NHNR.sup.24AR.sup.24B, —OR.sup.24A, —NR.sup.24ASO.sub.2R.sup.24B, —NR.sup.24AC(O)R.sup.24B, —NR.sup.24AC(O)OR.sup.24B, —NR.sup.24AOR.sup.24B, —N.sub.3, 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.sup.25 is selected from hydrogen, halogen, —CX.sup.25.sub.3, —CHX.sup.25.sub.2, —CH.sub.2X.sup.25, —OCX.sup.25.sub.3, —OCH.sub.2X.sup.25, —OCHX.sup.25.sub.2, —CN, —SO.sub.n25R.sup.25A, —SO.sub.v25NR.sup.25AR.sup.25B, —NHC(O)NR.sup.25AR.sup.25B, —N(O).sub.m25, —NR.sup.25AR.sup.25B, —NHNR.sup.25AR.sup.25B, —C(O)R.sup.25A, —C(O)—OR.sup.25A, —C(O)NR.sup.25AR.sup.25B, —C(O)NHNR.sup.25AR.sup.25B, —OR.sup.25A, —NR.sup.25ASO.sub.2R.sup.25B, —NR.sup.25AC(O)R.sup.25B, —NR.sup.25AC(O)OR.sup.25B, —NR.sup.25AOR.sup.25B, —N.sub.3, 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.sup.26 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, —CX.sup.26.sub.3, —CHX.sup.26.sub.2, —CH.sub.2X.sup.26, —OCX.sup.26.sub.3, —OCH.sub.2X.sup.26, —OCHX.sup.26.sub.2, —CN, —SO.sub.n26R.sup.26A, —SO.sub.v26NR.sup.26AR.sup.26B, —NHC(O)NR.sup.26AR.sup.26B, —N(O).sub.m26, —NR.sup.26AR.sup.26B, —NHNR.sup.26AR.sup.26B, —C(O)R.sup.26A, —C(O)—OR.sup.26A, —C(O)NR.sup.26AR.sup.26B, —C(O)NHNR.sup.26AR.sup.26B, OR.sup.26A, —NR.sup.26ASO.sub.2R.sup.26B, —NR.sup.26AC(O)R.sup.26B, —NR.sup.26AC(O)O R.sup.26B, —NR.sup.26AOR.sup.26B, —N.sub.3, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.27 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, —CX.sup.27.sub.3, —CHX.sup.27.sub.2, —CH.sub.2X.sup.27, —OCX.sup.27.sub.3, —OCH.sub.2X.sup.27, —OCHX.sup.27.sub.2, —CN, —SO.sub.n27R.sup.27A, —SO.sub.v27NR.sup.27AR.sup.27B, —NHC(O)NR.sup.27AR.sup.27B, —N(O).sub.m27, —NR.sup.27AR.sup.27B, —NHNR.sup.27AR.sup.27B, C(O)R.sup.27A, —C(O)—OR.sup.27A, —C(O)NR.sup.27AR.sup.27B, —C(O)NHNR.sup.27AR.sup.27B, —OR.sup.27A, —NR.sup.27ASO.sub.2R.sup.27B, —NR.sup.27AC(O)R.sup.27B, —NR.sup.27AC(O)OR.sup.27B, —NR.sup.27AOR.sup.27B, —N.sub.3, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.28 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, —CX.sup.28.sub.3, —CHX.sup.28.sub.2, —CH.sub.2X.sup.28, —OCX.sup.28.sub.3, —OCH.sub.2X.sup.28, —OCHX.sup.28.sub.2, —CN, —SO.sub.n28R.sup.28A, —SO.sub.v28NR.sup.28AR.sup.28B, —NHC(O)NR.sup.28AR.sup.28B, —N(O).sub.m2, —NR.sup.28AR.sup.28B, —NHNR.sup.28AR.sup.28B, C(O)R.sup.28A, —C(O)—OR.sup.28A, —C(O)NR.sup.28AR.sup.28B, —C(O)NHNR.sup.28AR.sup.28B, —OR.sup.28A, —NR.sup.28ASO.sub.2R.sup.28B, —NR.sup.28AC(O)R.sup.28B, —NR.sup.28AC(O)OR.sup.28B, —NR.sup.28AOR.sup.28B, —N.sub.3 substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R.sup.29 is selected from hydrogen, halogen, —CX.sup.29.sub.3, —CHX.sup.29.sub.2, —CH.sub.2X.sup.29, —OCX.sup.29.sub.3, —OCH.sub.2X.sup.29, —OCHX.sup.29.sub.2, —CN, —SO.sub.n29R.sup.29A, —SO.sub.v29NR.sup.29AR.sup.29B, —NHC(O)NR.sup.29AR.sup.29B, —N(O).sub.m29, —NR.sup.29AR.sup.29B, —NHNR.sup.29AR.sup.29B, —C(O)R.sup.29A, —C(O)—OR.sup.29A, —C(O)NR.sup.29AR.sup.29B, —C(O)NHNR.sup.29AR.sup.29B, —OR.sup.29A, —NR.sup.29ASO.sub.2R.sup.29B, —NR.sup.29AC(O)R.sup.29B, —NR.sup.29AC(O)OR.sup.29B, —NR.sup.29AOR.sup.29B, —N.sub.3, 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.sup.30 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, —CX.sup.30.sub.3, —CHX.sup.30, —CH.sub.2X.sup.30, —OCX.sup.30.sub.3, —OCH.sub.2X.sup.30, —OCHX.sup.30.sub.2, —CN, —SO.sub.n30R.sup.30A, —SO.sub.v30NR.sup.30AR.sup.30B, —NHC(O)NR.sup.30AR.sup.30B, —N(O).sub.m30, —NR.sup.30AR.sup.30B, —NHNR.sup.30AR.sup.30B, C(O)R.sup.30A, —C(O)—OR.sup.30A, —C(O)NR.sup.30AR.sup.30B, —C(O)NHNR.sup.30AR.sup.30B, —OR.sup.30A, —NR.sup.30ASO.sub.2R.sup.30B, —NR.sup.30AC(O)R.sup.30B, —NR.sup.30AC(O)OR.sup.30B, —NR.sup.30AOR.sup.30B, —N.sub.3, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Each R.sup.1A, R.sup.1B, R.sup.2A, R.sup.2B, R.sup.3A, R.sup.3B, R.sup.4A, R.sup.4B, R.sup.5A, R.sup.5B, R.sup.6A, R.sup.6B, R.sup.7A, R.sup.7B, R.sup.8A, R.sup.8B, R.sup.9A, R.sup.9B, R.sup.10A, R.sup.10B, R.sup.11A, R.sup.11B, R.sup.12A, R.sup.12B, R.sup.13A, R.sup.13B, R.sup.14A, R.sup.14B, R.sup.15A, R.sup.15B, R.sup.16A, R.sup.16B, R.sup.17A, R.sup.17B, R.sup.18A, R.sup.18B, R.sup.19A, R.sup.19B, R.sup.20A, R.sup.20B, R.sup.21A, R.sup.21B, R.sup.22A, R.sup.22B, R.sup.23A, R.sup.23B, R.sup.24A, R.sup.24B, R.sup.25A, R.sup.25B, R.sup.26A, R.sup.26B, R.sup.27A, R.sup.27B, R.sup.28A, R.sup.28B, R.sup.29A, R.sup.29B, R.sup.30A, R.sup.30B is independently selected from hydrogen, —CX.sub.3, —CHX.sub.2, —CH.sub.2X, —C(O)OH, —C(O)NH.sub.2, —CN, —OH, —NH.sub.2, —COOH, —CONH.sub.2, —NO.sub.2, —SH, —SO.sub.3H, —SO.sub.4H, —SO.sub.2NH.sub.2, NHNH.sub.2, —ONH.sub.2, —NHC═(O)NHNH.sub.2, —NHC═(O)NH.sub.2, —NHSO.sub.2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX.sub.3, —OCHX.sub.2, —OCH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.5A and R.sup.5B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.6A and R.sup.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.sup.7A and R.sup.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.sup.8A and R.sup.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.sup.9A and R.sup.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.sup.10A and R.sup.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.sup.11A and R.sup.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.sup.12A and R.sup.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.sup.13A and R.sup.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.sup.14A and R.sup.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.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.19A and R.sup.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.sup.20A and R.sup.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.sup.21A and R.sup.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.sup.22A and R.sup.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.sup.23A and R.sup.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.sup.24A and R.sup.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.sup.25A and R.sup.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.sup.26A and R.sup.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.sup.27A and R.sup.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.sup.28A and R.sup.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.sup.29A and R.sup.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.sup.30A and R.sup.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 m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13, m14, m15, m16, m17, m18, m19, m20, m21, m22, m23, m24, m25, m26, m27, m28, m29, and m30 are independently 1 or 2; Each v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, v12, v13, v14, v15, v16, v17, v18, v19, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29 and v30 are independently 1 or 2; Each n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25, n26, n27, n28, n29 and n30 are independently an integer from 0 to 2; and Each X, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, X.sup.9, X.sup.10, X.sup.11, X.sup.12, X.sup.13, X.sup.14, X.sup.15, X.sup.16, X.sup.17, X.sup.18, X.sup.19, X.sup.20, X.sup.21, X.sup.22, X.sup.23, X.sup.24, X.sup.25, X.sup.26, X.sup.27, X.sup.28, X.sup.29 and X.sup.30 are independently —Cl, —Br, —I or —F; provided the compound is not 1-{4-[4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1,2,3,4-tetrahydroisoquinolin-2-yl}prop-2-en-1-one; further provided the compound is not ethyl 2-{4-chloro-2-[2-(prop-2-enoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]phenoxy}acetate; further provided the compound is not 1-(1-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-2-yl)prop-2-en-1-one; further provided the compound is not 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)prop-2-en-1-one; further provided the compound is not 1-(1,2,3,4-tetrahydroisoquinolin-2-yl)prop-2-en-1-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 1-(7-chloro-1,2,3,4-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, midazolinyl 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, midazolyl, 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 ##STR00450## ##STR00451##
5. The compound of claim 1, wherein ring A is ring A is ##STR00452##
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 ##STR00453##
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 R.sup.2 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 R.sup.2 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(═O)CH═CH.sub.2, —C(═O)-ethynyl, —C(═O)CH═CHCF.sub.3, —C(═O)CH═CHCHF.sub.2, —C(═O)CH═CHCH.sub.2F, and —C(═O)CH.sub.2Br.
12. The compound of claim 1 selected from ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## 1-(6-bromo-4-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one; 1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one; (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4,4,4-trifluorobut-2-en-1-one; 2-chloro-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1-one; (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4,4-difluorobut-2-en-1-one; (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-fluorobut-2-en-1-one; N-(4-(o-tolyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)acrylamide; 1-(4-([1,1′-biphenyl]-2-yl)-2-chloro-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one; (E)-4-bromo-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)but-2-en-1-one; (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-(dimethylamino)but-2-en-1-one; 1-(7-chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one; 1-(3-bromo-8-phenyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one; 1-(2-chloro-4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one; 1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one; 1-(6-ethyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one; 3-(2-acryloyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-4-yl)pyridin-2(1H)-one; 1-(7-isobutoxy-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one; and 1-(2-chloro-5-methyl-4-phenyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one.
13. A compound of claim 1, comprising a compound of Formula VI: ##STR00503## wherein Z is N, or CR.sup.9; 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 ##STR00504## ##STR00505## ##STR00506## wherein R.sup.1 is selected from hydrogen, halogen, —CX.sup.1.sub.3, —CHX.sup.1.sub.2, —CH.sub.2X.sup.1, —OCX.sup.1.sub.3, —OCH.sub.2X.sup.1, —OCHX.sup.1.sub.2, —CN, —SO.sub.1R.sup.1A, —SO.sub.v1NR.sup.1AR.sup.1B, —NHC(O)NR.sup.1AR.sup.1B, —N(O).sub.m1, —NR.sup.1AR.sup.1B, —NHNR.sup.1AR.sup.1B, —C(O)R.sup.1A, —C(O)—OR.sup.1A, —C(O)NR.sup.1AR.sup.1B, —C(O)NHNR.sup.1AR.sup.1B, —OR.sup.1A, —NR.sup.1ASO.sub.2R.sup.1B, —NR.sup.1AC(O)R.sup.1B, —NR.sup.1AC(O)OR.sup.1B, —NR.sup.1AOR.sup.1B, —N.sub.3, 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.sup.3 is selected from hydrogen, halogen, —CX.sup.3.sub.3, —CHX.sup.3.sub.2, —CH.sub.2X.sup.3, —OCX.sup.3.sub.3, —OCH.sub.2X.sup.3, —OCHX.sup.3.sub.2, —CN, —SO.sub.3R3A, —SO.sub.v3NR.sup.3AR.sup.3B, —NHC(O)NR.sup.3AR.sup.3B, —N(O).sub.m3, —NR.sup.3AR.sup.3B, —NHNR.sup.3AR.sup.3B, —C(O)R.sup.3A, —C(O)—OR.sup.3A, —C(O)NR.sup.3AR.sup.3B, —OR.sup.3A, —NR.sup.3ASO.sub.2R.sup.3B, —NR.sup.3AC(O)R.sup.3B, —NR.sup.3AC(O)OR.sup.3B, —NR.sup.3AOR.sup.3B, —N.sub.3, 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.sup.4 is selected from hydrogen, halogen, —CX.sup.4.sub.3, —CHX.sup.4.sub.2, —CH.sub.2X.sup.4, —OCX.sup.4.sub.3, —OCH.sub.2X.sup.4, —OCHX.sup.4.sub.2, —CN, —SO.sub.n4R.sup.4A, —SO.sub.v4NR.sup.4AR.sup.4B, —NHC(O)NR.sup.4AR.sup.4B, —N(O).sub.m4, —NR.sup.4AR.sup.4B, —NHNR.sup.4AR.sup.4B, —C(O)R.sup.4A, —C(O)—OR.sup.4A, —C(O)NR.sup.4AR.sup.4B, —C(O)NHNR.sup.4AR.sup.4B, —OR.sup.4A, —NR.sup.4ASO.sub.2R.sup.4B, —NR.sup.4AC(O)R.sup.4B, —NR.sup.4AC(O)OR.sup.4B, —NR.sup.4AOR.sup.4B, —N.sub.3, 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.sup.3 and R.sup.3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.6 is selected from hydrogen, halogen, —CX.sup.6.sub.3, —CHX.sup.6.sub.2, —CH.sub.2X.sup.6, —OCX.sup.6.sub.3, —OCH.sub.2X.sup.6, —OCHX.sup.6.sub.2, —CN, —SO.sub.v6R.sup.6A, —SO.sub.v6NR.sup.6AR.sup.6B, —NHC(O)NR.sup.6AR.sup.6B, —N(O).sub.m6, —NR.sup.6AR.sup.6B, —NHNR.sup.6AR.sup.6B, —C(O)R.sup.6A, —C(O)—OR.sup.6A, —C(O)NR.sup.6AR.sup.6B, —C(O)NHNR.sup.6AR.sup.6B, —OR.sup.6A, —NR.sup.6ASO.sub.2R.sup.6B, —NR.sup.6AC(O)R.sup.6B, —NR.sup.6AC(O)OR.sup.6B, —NR.sup.6AOR.sup.6B, —N.sub.3, 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.sup.7 is selected from hydrogen, halogen, —CX.sup.7.sub.3, —CHX.sup.7.sub.2, —CH.sub.2X.sup.7, —OCX.sup.7.sub.3, —OCH.sub.2X.sup.7, —OCHX.sup.7.sub.2, —CN, —SO.sub.7R.sup.7A, —SO.sub.v7NR.sup.7AR.sup.7B, —NHC(O)NR.sup.7AR.sup.7B, —N(O).sub.m7, —NR.sup.7AR.sup.7B, —NHNR.sup.7AR.sup.7B, —C(O)R.sup.7A, —C(O)—OR.sup.7A, —C(O)NR.sup.7AR.sup.7B, —C(O)NHNR.sup.7AR.sup.7B, —OR.sup.7A, —NR.sup.7ASO.sub.2R.sup.7B, —NR.sup.7AC(O)R.sup.7B, —NR.sup.7AC(O)OR.sup.7B, —NR.sup.7AOR.sup.7B, —N.sub.3, 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.sup.9 is selected from hydrogen, halogen, —CX.sup.9.sub.3, —CHX.sup.9.sub.2, —CH.sub.2X.sup.9, —OCX.sup.9.sub.3, —OCH.sub.2X.sup.9, —OCHX.sup.9.sub.2, —CN, —SO.sub.v9R.sup.9A, —SO.sub.v9NR.sup.9AR.sup.9B, —NHC(O)NR.sup.9AR.sup.9B, —N(O).sub.m9, —NR.sup.9AR.sup.9B, —NHNR.sup.9AR.sup.9B, —C(O)R.sup.9A, —C(O)—OR.sup.9A, —C(O)NR.sup.9AR.sup.9B, —C(O)NHNR.sup.9AR.sup.9B, —OR.sup.9A, —NR.sup.9ASO.sub.2R.sup.9B, —NR.sup.9AC(O)R.sup.9B, —NR.sup.9AC(O)OR.sup.9B, —NR.sup.9AOR.sup.9B, —N.sub.3, 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.sup.13 is selected from hydrogen, halogen, —CX.sup.13.sub.3, —CHX.sup.13.sub.2, —CH.sub.2X.sup.13, —OCX.sup.13.sub.3, —OCH.sub.2X.sup.13, —OCHX.sup.13.sub.2, —CN, —SO.sub.n13R.sup.13A, —SO.sub.v13NR.sup.13AR.sup.13B, —NHC(O)NR.sup.13AR.sup.13B, —N(O).sub.m13, —NR.sup.13AR.sup.13B, —NHNR.sup.13AR.sup.13B, —C(O)R.sup.13A, —C(O)—OR.sup.13A, —C(O)NR.sup.13AR.sup.13B, —C(O)N HNR.sup.13AR.sup.13B, —OR.sup.13A, —NR.sup.13ASO.sub.2R.sup.13B, —NR.sup.13AC(O)R.sup.13B, —NR.sup.13AC(O)OR.sup.13B, —NR.sup.13AOR.sup.13B, —N.sub.3, 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.sup.14 is selected from hydrogen, halogen, —CX.sup.14.sub.3, —CHX.sup.14.sub.2, —CH.sub.2X.sup.14, —OCX.sup.14.sub.3, —OCH.sub.2X.sup.14, —OCHX.sup.14.sub.2, —CN, —SO.sub.n14R.sup.14A, —SO.sub.v14NR.sup.14AR.sup.14B, —NHC(O)NR.sup.14AR.sup.14B, —N(O).sub.m14, —NR.sup.14AR.sup.14B, —NHNR.sup.14AR.sup.14B, —C(O)R.sup.14A, —C(O)—OR.sup.14A, —C(O)NR.sup.14AR.sup.14B, —C(O)NHNR.sup.14AR.sup.14B, —OR.sup.14A, —NR.sup.14ASO.sub.2R.sup.14B, —NR.sup.14AC(O)R.sup.14B, —NR.sup.14AC(O)OR.sup.14B, —NR.sup.14AOR.sup.14B, —N.sub.3, 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.sup.15 is selected from hydrogen, halogen, —CX.sup.15.sub.3, —CHX.sup.5.sub.2, —CH.sub.2X.sup.15, —OCX.sup.15.sub.3, —OCH.sub.2X.sup.15, —OCHX.sup.15.sub.2, —CN, —SO.sub.n15R.sup.15A, —SO.sub.v15NR.sup.15AR.sup.15B, —NHC(O)NR.sup.15AR.sup.15B, —N(O).sub.m5, —NR.sup.15AR.sup.15B, —NHNR.sup.15AR.sup.15B, —C(O)R.sup.15A, —C(O)—OR.sup.15A, —C(O)NR.sup.15AR.sup.15B, —C(O)NHNR.sup.15AR.sup.15B, —OR.sup.15A, —NR.sup.15ASO.sub.2R.sup.15B, —NR.sup.15AC(O)R.sup.15B, —NR.sup.15AC(O)OR.sup.15B, —NR.sup.15AOR.sup.15B, —N.sub.3, 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.sup.16 is selected from hydrogen, halogen, —CX.sup.16.sub.3, —CHX.sup.16.sub.2, —CH.sub.2X.sup.16, —OCX.sup.16.sub.3, —OCH.sub.2X.sup.16, —OCHX.sup.16.sub.2, —CN, —SO.sub.n16R.sup.16A, —SO.sub.v16NR.sup.16AR.sup.16B, —NHC(O)NR.sup.16AR.sup.16B, —N(O).sub.m16, —NR.sup.16AR.sup.16B, —NHNR.sup.16AR.sup.16B, —C(O)R.sup.16A, —C(O)—OR.sup.16A, —C(O)NR.sup.16AR.sup.16B, —C(O)NHNR.sup.16AR.sup.16B, —OR.sup.16A, —NR.sup.16ASO.sub.2R.sup.16B, —NR.sup.16AC(O)R.sup.16B, —NR.sup.16AC(O)OR.sup.16B, —NR.sup.16AOR.sup.16B, —N.sub.3, 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.sup.17 is selected from hydrogen, halogen, —CX.sup.17.sub.3, —CHX.sup.17.sub.2, —CH.sub.2X.sup.17, —OCX.sup.17.sub.3, —OCH.sub.2X.sup.17, —OCHX.sup.17.sub.2, —CN, —SO.sub.n17R.sup.17A, —SO.sub.v17NR.sup.17AR.sup.17B, —NHC(O)NR.sup.17AR.sup.17B, —N(O).sub.m17, —NR.sup.17AR.sup.17B, —NHNR.sup.17AR.sup.7B, —C(O)R.sup.17A, —C(O)—OR.sup.17A, —C(O)NR.sup.17AR.sup.17B, —C(O)NHNR.sup.17AR.sup.17B, —OR.sup.17A, —NR.sup.17ASO.sub.2R.sup.17B, —NR.sup.17AC(O)R.sup.17B, —NR.sup.17AC(O)OR.sup.17B, —NR.sup.17AOR.sup.17B, —N.sub.3, 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.sup.18 is selected from hydrogen, halogen, —CX.sup.18.sub.3, —CHX.sup.18.sub.2, —CH.sub.2X.sup.18, —OCX.sup.18.sub.3, —OCH.sub.2X.sup.18, —OCHX.sup.18.sub.2, —CN, —SO.sub.n18R.sup.18A, —SO.sub.v18NR.sup.18AR.sup.18B, —NHC(O)NR.sup.18AR.sup.18B, —N(O).sub.m18, —NR.sup.18AR.sup.18B, —NHNR.sup.18AR.sup.18B, —C(O)R.sup.18A, —C(O)—OR.sup.18A, —C(O)NR.sup.18AR.sup.18B, —C(O)NHNR.sup.18AR.sup.18B, —OR.sup.18A, —NR.sup.18ASO.sub.2R.sup.18B, —NR.sup.18AC(O)R.sup.18B, —NR.sup.18AC(O)OR.sup.18B, —NR.sup.18AOR.sup.18B, —N.sub.3, 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.sup.16 and R.sup.18 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.19 is selected from hydrogen, halogen, —CX.sup.19.sub.3, —CHX.sup.19.sub.2, —CH.sub.2X.sup.19, —OCX.sup.19.sub.3, —OCH.sub.2X.sup.19, —OCHX.sup.19.sub.2, —CN, —SO.sub.n19R.sup.19A, —SO.sub.v19NR.sup.19AR.sup.19B, —NHC(O)NR.sup.19AR.sup.19B, —N(O).sub.m19, —NR.sup.19AR.sup.19B, —NHNR.sup.19AR.sup.19B, —C(O)R.sup.19A, —C(O)—OR.sup.19A, —C(O)NR.sup.19AR.sup.19B, —C(O)NHNR.sup.19AR.sup.19B, —OR.sup.19A, —NR.sup.19ASO.sub.2R.sup.19B, —NR.sup.19AC(O)R.sup.19B, —NR.sup.19AC(O)OR.sup.19B, —NR.sup.19AOR.sup.19B, —N.sub.3, 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.sup.16 and R.sup.19 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.20 is selected from hydrogen, halogen, —CX.sup.20.sub.3, —CHX.sup.20.sub.2, —CH.sub.2X.sup.20, —OCX.sup.20.sub.3, —OCH.sub.2X.sup.20, —OCHX.sup.20.sub.2, —CN, —SO.sub.n20R.sup.20A, —SO.sub.v20NR.sup.20AR.sup.20B, —NHC(O)NR.sup.20AR.sup.20B, —N(O).sub.m20, —NR.sup.20AR.sup.20B, —NHNR.sup.20AR.sup.20B, —C(O)R.sup.20A, —C(O)—OR.sup.20A, —C(O)NR.sup.20AR.sup.20B, —C(O)NHNR.sup.20AR.sup.20B, —OR.sup.20A, —NR.sup.20A, —SO.sub.2R.sup.20B, —NR.sup.20AC(O)R.sup.20B, —NR.sup.20AC(O)OR.sup.20B, —NR.sup.20AOR.sup.20B, —N.sub.3, 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.sup.21 is selected from hydrogen, halogen, —CX.sup.21.sub.3, —CHX.sup.21.sub.2, —CH.sub.2X.sup.21, —OCX.sup.21.sub.3, —OCH.sub.2X.sup.21, —OCHX.sup.21.sub.2, —CN, —SO.sub.n21R.sup.21A, —SO.sub.v21NR.sup.21AR.sup.21B, —NHC(O)NR.sup.21AR.sup.21B, —N(O).sub.m21, —NR.sup.21AR.sup.21B, —NHNR.sup.21AR.sup.21B, —C(O)R.sup.21A, —C(O)—OR.sup.21A, —C(O)NR.sup.21AR.sup.21B, —C(O)NHNR.sup.21AR.sup.21B, —OR.sup.21A, —NR.sup.21ASO.sub.2R.sup.21B, —NR.sup.21AC(O)R.sup.21B, —NR.sup.21AC(O)OR.sup.21B, —NR.sup.21AOR.sup.21B, —N.sub.3, 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.sup.20 and R.sup.21 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.22 is selected from hydrogen, halogen, —CX.sup.22.sub.3, —CHX.sup.22.sub.2, —CH.sub.2X.sup.22, —OCX.sup.22.sub.3, —OCH.sub.2X.sup.22, —OCHX.sup.22.sub.2, —CN, —SO.sub.n22R.sup.22A, —SO.sub.v22NR.sup.22AR.sup.22B, —NHC(O)NR.sup.22AR.sup.22B, —N(O).sub.m22, —NR.sup.22AR.sup.22B, —NHNR.sup.22AR.sup.22B, —C(O)R.sup.22A, —C(O)—OR.sup.22A, —C(O)NR.sup.22AR.sup.22B, —C(O)NHNR.sup.22AR.sup.22B, —OR.sup.22A, —NR.sup.22ASO.sub.2R.sup.22B, —NR.sup.22AC(O)R.sup.22B, —NR.sup.22AC(O)OR.sup.22B, —NR.sup.22AOR.sup.22B, —N.sub.3, 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.sup.23 is selected from hydrogen, halogen, —CX.sup.23.sub.3, —CHX.sup.23.sub.2, —CH.sub.2X.sup.23, —OCX.sup.23.sub.3, —OCH.sub.2X.sup.23, —OCHX.sup.23.sub.2, —CN, —SO.sub.n23R.sup.23A, —SO.sub.v23NR.sup.23AR.sup.23B, —NHC(O)NR.sup.23AR.sup.23B, —N(O).sub.m23, —NR.sup.23AR.sup.23B, —NHNR.sup.23AR.sup.23B, —C(O)R.sup.23A, —C(O)—OR.sup.23A, —C(O)NR.sup.23AR.sup.23B, —C(O)NHNR.sup.23AR.sup.23B, —OR.sup.23A, —NR.sup.23ASO.sub.2R.sup.23B, —NR.sup.23AC(O)R.sup.23B, —NR.sup.23AC(O)OR.sup.23B, —NR.sup.23AOR.sup.23B, —N.sub.3, 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.sup.24 is selected from hydrogen, halogen, —CX.sup.24.sub.3, —CHX.sup.24.sub.2, —CH.sub.2X.sup.24, —OCX.sup.24.sub.3, —OCH.sub.2X.sup.24, —OCHX.sup.24.sub.2, —CN, —SO.sub.n24R.sup.24A, —SO.sub.v24NR.sup.24AR.sup.24B, —NHC(O)NR.sup.24AR.sup.24B, —N(O).sub.m24, —NR.sup.24AR.sup.24B, —NHNR.sup.24AR.sup.24B, —C(O)R.sup.24A, —C(O)—OR.sup.24A, —C(O)NR.sup.24AR.sup.24B, —C(O)NHNR.sup.24AR.sup.24B, —OR.sup.24A, —NR.sup.24ASO.sub.2R.sup.24B, —NR.sup.24AC(O)R.sup.24B, —NR.sup.24AC(O)OR.sup.24B, —NR.sup.24AOR.sup.24B, —N.sub.3, 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.sup.25 is selected from hydrogen, halogen, —CX.sup.25.sub.3, —CHX.sup.25.sub.2, —CH.sub.2X.sup.25, —OCX.sup.25.sub.3, —OCH.sub.2X.sup.25, —OCHX.sup.25.sub.2, —CN, —SO.sub.n25R.sup.25A, —SO.sub.v25NR.sup.25AR.sup.25B, —NHC(O)NR.sup.25AR.sup.25B, —N(O).sub.m25, —NR.sup.25AR.sup.25B, —NHNR.sup.25AR.sup.25B, —C(O)R.sup.25A, —C(O)—OR.sup.25A, —C(O)NR.sup.25AR.sup.25B, —C(O)NHNR.sup.25AR.sup.25B, —OR.sup.25A, —NR.sup.25ASO.sub.2R.sup.25B, —NR.sup.25AC(O)R.sup.25B, —NR.sup.25AC(O)OR.sup.25B, —NR.sup.25AOR.sup.25B, —N.sub.3, 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.sup.26 is selected from hydrogen, halogen, —CX.sup.26.sub.3, —CHX.sup.26.sub.2, —CH.sub.2X.sup.26, —OCX.sup.26.sub.3, —OCH.sub.2X.sup.26, —OCHX.sup.26.sub.2, —CN, —SO.sub.n26R.sup.26A, —SO.sub.v26NR.sup.26AR.sup.26B, —NHC(O)NR.sup.26AR.sup.26B, —N(O).sub.m26, —NR.sup.26AR.sup.26B, —NHNR.sup.26AR.sup.26B, —C(O)R.sup.26A, —C(O)—OR.sup.26A, —C(O)NR.sup.26AR.sup.26B, —C(O)NHNR.sup.26AR.sup.26B, —OR.sup.26A, —NR.sup.26ASO.sub.2R.sup.26B, —NR.sup.26AC(O)R.sup.26B, —NR.sup.26AC(O)OR.sup.26B, —NR.sup.26AOR.sup.26B, —N.sub.3, 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.sup.27 is selected from hydrogen, halogen, —CX.sup.27.sub.3, —CHX.sup.27.sub.2, —CH.sub.2X.sup.27, —OCX.sup.27.sub.3, —OCH.sub.2X.sup.27, —OCHX.sup.27.sub.2, —CN, —SO.sub.n27R.sup.27A, —SO.sub.v27NR.sup.27AR.sup.27B, —NHC(O)NR.sup.27AR.sup.27B, —N(O).sub.m27, —NR.sup.27AR.sup.27B, —NHNR.sup.27AR.sup.27B, —C(O)R.sup.27A, —C(O)—OR.sup.27A, —C(O)NR.sup.27AR.sup.27B, —C(O)NHNR.sup.27AR.sup.27B, OR.sup.27A, —NR.sup.27ASO.sub.2R.sup.27B, —NR.sup.27AC(O)R.sup.27B, —NR.sup.27AC(O)OR.sup.27B, —NR.sup.27AOR.sup.27B, —N.sub.3, 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.sup.28 is selected from hydrogen, halogen, —CX.sup.28.sub.3, —CHX.sup.28.sub.2, —CH.sub.2X.sup.28, —OCX.sup.28.sub.3, —OCH.sub.2X.sup.28, —OCHX.sup.28.sub.2, —CN, —SO.sub.n2R.sup.28A, —SO.sub.v28NR.sup.28AR.sup.28B, —NHC(O)NR.sup.28AR.sup.28B, —N(O).sub.m28, —NR.sup.28AR.sup.28B, —NHNR.sup.28AR.sup.28B, C(O)R.sup.28A, —C(O)—OR.sup.28A, —C(O)NR.sup.28AR.sup.28B, —C(O)NHNR.sup.28AR.sup.28B, —OR.sup.28A, —NR.sup.28ASO.sub.2R.sup.28B, —NR.sup.28AC(O)R.sup.28B, —NR.sup.28AC(O)OR.sup.28B, —NR.sup.28AOR.sup.28B, —N.sub.3, 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.sup.29 is selected from hydrogen, halogen, —CX.sup.29.sub.3, —CHX.sup.29.sub.2, —CH.sub.2X.sup.29, —OCX.sup.29.sub.3, —OCH.sub.2X.sup.29, —OCHX.sup.29.sub.2, —CN, —SO.sub.n29R.sup.29A, —SO.sub.v29NR.sup.29AR.sup.29B, —NHC(O)NR.sup.29AR.sup.29B, —N(O).sub.m29, —NR.sup.29AR.sup.29B, —NHNR.sup.29AR.sup.29B, —C(O)R.sup.29A, —C(O)—OR.sup.29A, —C(O)NR.sup.29AR.sup.29B, —C(O)NHNR.sup.29AR.sup.29B, —OR.sup.29A, —NR.sup.29ASO.sub.2R.sup.29B, —NR.sup.29AC(O)R.sup.29B, —NR.sup.29AC(O)OR.sup.29B, —NR.sup.29AOR.sup.29B, —N.sub.3, 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.sup.30 is selected from hydrogen, halogen, —CX.sup.30.sub.3, —CHX.sup.30.sub.2, —CH.sub.2X.sup.30, —OCX.sup.30.sub.3, —OCH.sub.2X.sup.30, —OCHX.sup.30.sub.2, —CN, —SO.sub.n30R.sup.30A, —SO.sub.v30NR.sup.30AR.sup.30B, —NHC(O)NR.sup.30AR.sup.30B, —N(O).sub.m30, —NR.sup.30AR.sup.30B, —NHNR.sup.30AR.sup.30B, —C(O)R.sup.30A, —C(O)—OR.sup.30A, —C(O)NR.sup.30AR.sup.30B, —C(O)NHNR.sup.30AR.sup.30B, OR.sup.30A, —NR.sup.30ASO.sub.2R.sup.30B, —NR.sup.30AC(O)R.sup.30B, —NR.sup.30AC(O)OR.sup.30B, —NR.sup.30AOR.sup.30B, —N.sub.3, 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.sup.31 is selected from hydrogen, halogen, —CX.sup.31.sub.3, —CHX.sup.31.sub.2, —CH.sub.2X.sup.31, —OCX.sup.31.sub.3, —OCH.sub.2X.sup.31, —OCHX.sup.31.sub.2, —CN, —SO.sub.n31R.sup.31A, —SO.sub.v31NR.sup.31AR.sup.31B, —NHC(O)NR.sup.31AR.sup.31B, —N(O).sub.m31, —NR.sup.31AR.sup.31B, —NHNR.sup.31AR.sup.31B, —C(O)R.sup.31A, —C(O)—OR.sup.31A, —C(O)NR.sup.31AR.sup.31B, —C(O)NHNR.sup.31AR.sup.31B, —OR.sup.31A, —NR.sup.31ASO.sub.2R.sup.31B, —NR.sup.31AC(O)R.sup.31B, —NR.sup.31AC(O)OR.sup.31B, —NR.sup.31AOR.sup.31B, —N.sub.3, 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.sup.32 is selected from hydrogen, halogen, —CX.sup.32.sub.3, —CHX.sup.32.sub.2, —CH.sub.2X.sup.32, —OCX.sup.32.sub.3, —OCH.sub.2X.sup.32, —OCHX.sup.32.sub.2, —CN, —SO.sub.n32R.sup.32A, —SO.sub.v32NR.sup.32AR.sup.32B, —NHC(O)NR.sup.32AR.sup.32B, —N(O).sub.m32, —NR.sup.32AR.sup.32B, —NHNR.sup.32AR.sup.32B, C(O)R.sup.32A, —C(O)—OR.sup.32A, —C(O)NR.sup.32AR.sup.32B, —C(O)NHNR.sup.32AR.sup.32B, —OR.sup.32A, —NR.sup.32ASO.sub.2R.sup.32B, —NR.sup.32AC(O)R.sup.32B, —NR.sup.32AC(O)OR.sup.32B, —NR.sup.32AOR.sup.32B, —N.sub.3, 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.sup.33 is selected from hydrogen, halogen, —CX.sup.33.sub.3, —CHX.sup.33.sub.2, —CH.sub.2X.sup.33, —OCX.sup.33.sub.3, —OCH.sub.2X.sup.33, —OCHX.sup.33.sub.2, —CN, —SO.sub.n33R.sup.33A, —SO.sub.v33NR.sup.33AR.sup.33B, —NHC(O)NR.sup.33AR.sup.33B, —N(O).sub.m33, —NR.sup.33AR.sup.33B, —NHNR.sup.33AR.sup.33B, —C(O)R.sup.33A, —C(O)—OR.sup.33A, —C(O)NR.sup.33AR.sup.33B, —C(O)NHNR.sup.33AR.sup.33B, OR.sup.33A, —NR.sup.33ASO.sub.2R.sup.33B, —NR.sup.33AC(O)R.sup.33B, —NR.sup.33AC(O)OR.sup.33B, —NR.sup.33AOR.sup.33B, —N.sub.3, 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.sup.34 is selected from hydrogen, halogen, —CX.sup.34.sub.3, —CHX.sup.34.sub.2, —CH.sub.2X.sup.34, —OCX.sup.34.sub.3, —OCH.sub.2X.sup.34, —OCHX.sup.34.sub.2, —CN, —SO.sub.n34R.sup.34A, —SO.sub.v34NR.sup.34AR.sup.34B, —NHC(O)NR.sup.34AR.sup.34B, —N(O).sub.m34, —NR.sup.34AR.sup.34B, —NHNR.sup.34AR.sup.34B, C(O)R.sup.34A, —C(O)—OR.sup.34A, —C(O)NR.sup.34AR.sup.34B, —C(O)NHNR.sup.34AR.sup.34B, OR.sup.34A, —NR.sup.34ASO.sub.2R.sup.34B, —NR.sup.34AC(O)R.sup.34B, —NR.sup.34AC(O)OR.sup.34B, —NR.sup.34AOR.sup.34B, —N.sub.3, 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.sup.35 is selected from hydrogen, halogen, —CX.sup.35.sub.3, —CHX.sup.35.sub.2, —CH.sub.2X.sup.35, —OCX.sup.35.sub.3, —OCH.sub.2X.sup.35, —OCHX.sup.35.sub.2, —CN, —SO.sub.n35R.sup.35A, —SO.sub.v35NR.sup.35AR.sup.35B, —NHC(O)NR.sup.35AR.sup.35B, —N(O).sub.m35, —NR.sup.35AR.sup.35B, —NHNR.sup.35AR.sup.35B, —C(O)R.sup.35A, —C(O)—OR.sup.35A, —C(O)NR.sup.35AR.sup.35B, —C(O)NHNR.sup.35AR.sup.35B, —OR.sup.35A, —NR.sup.35ASO.sub.2R.sup.35B, —NR.sup.35AC(O)R.sup.35B, —NR.sup.35AC(O)OR.sup.35B, —NR.sup.35AOR.sup.35B, —N.sub.3, 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; Each R.sup.1A, R.sup.1B, R.sup.3A, R.sup.3B, R.sup.4A, R.sup.4B, R.sup.6A, R.sup.6B, R.sup.7A, R.sup.7B, R.sup.9A, R.sup.9B, R.sup.13A, R.sup.13B, R.sup.14A, R.sup.14B, R.sup.15A, R.sup.15B, R.sup.16A, R.sup.16B, R.sup.17A, R.sup.17B, R.sup.18A, R.sup.18B, R.sup.19A, R.sup.19B, R.sup.20A, R.sup.20B, R.sup.21A, R.sup.21B, R.sup.22A, R.sup.22B, R.sup.23A, R.sup.23B, R.sup.24A, R.sup.24B, R.sup.25A, R.sup.25B, R.sup.26A, R.sup.26B, R.sup.27A, R.sup.27B, R.sup.28A, R.sup.28B, R.sup.29A, R.sup.29B, R.sup.30A, R.sup.30B, R.sup.31A, R.sup.31B, R.sup.32A, R.sup.32B, R.sup.33A, R.sup.33B, R.sup.34A, R.sup.34B, R.sup.35A, R.sup.35B is independently selected from hydrogen, —CX.sub.3, —CHX.sub.2, —CH.sub.2X, —C(O)OH, —C(O)NH.sub.2, —CN, —OH, —NH.sub.2, —COOH, —CONH.sub.2, —NO.sub.2, —SH, —SO.sub.3H, —SO.sub.4H, —SO.sub.2NH.sub.2, —NHNH.sub.2, —ONH.sub.2, —NHC═(O)NHNH.sub.2, —NHC═(O)NH.sub.2, —NHSO.sub.2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX.sub.3, —OCHX.sub.2, —OCH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.6A and R.sup.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.sup.7A and R.sup.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.sup.9A and R.sup.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.sup.13A and R.sup.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.sup.14A and R.sup.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.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.19A and R.sup.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.sup.20A and R.sup.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.sup.21A and R.sup.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.sup.22A and R.sup.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.sup.23A and R.sup.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.sup.24A and R.sup.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.sup.25A and R.sup.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.sup.26A and R.sup.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.sup.27A and R.sup.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.sup.28A and R.sup.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.sup.29A and R.sup.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.sup.30A and R.sup.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 m1, m3, m4, m6, m7, m9, m13, m14, m15, m16, m17, m18, m19, m20, m21, m22, m23, m24, m25, m26, m27, m28, m29, m30, m31, m32, m33, m34 and m35 is independently 1 or 2; Each v1, v3, v4, v6, v7, v9, v13, v14, v15, v16, v17, v18, v19, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v30, v31, v32, v33, v34 and v35 is independently 1 or 2; Each n1, n3, n4, n6, n7, n9, n13, n14, n15, n16, n17, n18, n19, 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 Each X.sup.1, X.sup.3, X.sup.4, X.sup.6, X.sup.7, X.sup.9, X.sup.13, X.sup.14, X.sup.15, X.sup.16, X.sup.17, X.sup.18, X.sup.9, X.sup.20, X.sup.21, X.sup.22, X.sup.23, X.sup.24, X.sup.25, X.sup.26, X.sup.27, X.sup.28, X.sup.29, X.sup.30, X.sup.31, X.sup.32, X.sup.33, X.sup.34, and X.sup.35 is independently —Cl, —Br, —I or —F; provided ring B is not 4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl when E is ethenylcarbonyl.
14. Compound of claim 13 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, midazolyl, 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 ##STR00507##
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(═O)CH═CH.sub.2, —C(═O)-ethynyl, —C(═O)CH═CHCF.sub.3, —C(═O)CH═CHCHF.sub.2, —C(═O)CH═CHCH.sub.2F, and —C(═O)CH.sub.2Br.
20. A compound of claim 1, comprising a compound of Formula VII: ##STR00508## wherein Z is N, or CR.sup.9; U is selected from NR.sup.12, O, S, S═O, O═S═O, 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 ##STR00509## ##STR00510## ##STR00511## R.sup.1 is selected from hydrogen, halogen, —CX.sup.1.sub.3, —CHX.sup.1.sub.2, —CH.sub.2X.sup.1, —OCX.sup.1.sub.3, —OCH.sub.2X.sup.1, —OCHX.sup.1.sub.2, —CN, —SO.sub.n1R.sup.1A, —SO.sub.v1NR.sup.1AR.sup.1B, —NHC(O)NR.sup.1AR.sup.1B, —N(O).sub.m1, —NR.sup.1AR.sup.1B, —NHNR.sup.1AR.sup.1B, —C(O)R.sup.1A, —C(O)—OR.sup.1A, —C(O)NR.sup.1AR.sup.1B, —C(O)NHNR.sup.1AR.sup.1B, —OR.sup.1A, —NR.sup.1ASO.sub.2R.sup.1B, —NR.sup.1AC(O)R.sup.1B, —NR.sup.1AC(O)OR.sup.1B, —NR.sup.1AOR.sup.1B, —N.sub.3, 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.sup.3 is selected from hydrogen, halogen, —CX.sup.3.sub.3, —CHX.sup.3.sub.2, —CH.sub.2X.sup.3, —OCX.sup.3.sub.3, —OCH.sub.2X.sup.3, —OCHX.sup.3.sub.2, —CN, —SO.sub.v3R.sup.3A, —SO.sub.v3NR.sup.3AR.sup.3B, —NHC(O)NR.sup.3AR.sup.3B, —N(O).sub.m3, —NR.sup.3AR.sup.3B, —NHNR.sup.3AR.sup.3B, —C(O)R.sup.3A, —C(O)—OR.sup.3A, —C(O)NR.sup.3AR.sup.3B, —OR.sup.3A, —NR.sup.3ASO.sub.2R.sup.3B, —NR.sup.3AC(O)R.sup.3B, —NR.sup.3AC(O)OR.sup.3B, —NR.sup.3AOR.sup.3B, —N.sub.3, 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.sup.4 is selected from hydrogen, halogen, —CX.sup.4.sub.3, —CHX.sup.4.sub.2, —CH.sub.2X.sup.4, —OCX.sup.4.sub.3, —OCH.sub.2X.sup.4, —OCHX.sup.4.sub.2, —CN, —SO.sub.v4R.sup.4A, —SO.sub.4NR.sup.4AR.sup.4B, —NHC(O)NR.sup.4AR.sup.4B, —N(O).sub.m4, —NR.sup.4AR.sup.4B, —NHNR.sup.4AR.sup.4B, —C(O)R.sup.4A, —C(O)—OR.sup.4A, —C(O)NR.sup.4AR.sup.4B, —C(O)NHNR.sup.4AR.sup.4B, —OR.sup.4A, —NR.sup.4ASO.sub.2R.sup.4B, —NR.sup.4AC(O)R.sup.4B, —NR.sup.4AC(O)OR.sup.4B, —NR.sup.4AOR.sup.4B, —N.sub.3, 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.sup.3 and R.sup.3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.6 is selected from hydrogen, halogen, —CX.sup.6.sub.3, —CHX.sup.6.sub.2, —CH.sub.2X.sup.6, —OCX.sup.6.sub.3, —OCH.sub.2X.sup.6, —OCHX.sup.6.sub.2, —CN, —SO.sub.v6R.sup.6A, —SO.sub.6NR.sup.6AR.sup.6B, —NHC(O)NR.sup.6AR.sup.6B, —N(O).sub.m6, —NR.sup.6AR.sup.6B, —NHNR.sup.6AR.sup.6B, —C(O)R.sup.6A, —C(O)—OR.sup.6A, —C(O)NR.sup.6AR.sup.6B, —C(O)NHNR.sup.6AR.sup.6B, —OR.sup.6A, —NR.sup.6ASO.sub.2R.sup.6B, —NR.sup.6AC(O)R.sup.6B, —NR.sup.6AC(O)OR.sup.6B, —NR.sup.6AOR.sup.6B, —N.sub.3, 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.sup.7 is selected from hydrogen, halogen, —CX.sup.7.sub.3, —CHX.sup.7.sub.2, —CH.sub.2X.sup.7, —OCX.sup.7.sub.3, —OCH.sub.2X.sup.7, —OCHX.sup.7.sub.2, —CN, —SO.sub.7R.sup.7A, —SO.sub.v7NR.sup.7AR.sup.7B, —NHC(O)NR.sup.7AR.sup.7B, —N(O).sub.m7, —NR.sup.7AR.sup.7B, —NHNR.sup.7AR.sup.7B, —C(O)R.sup.7A, —C(O)—OR.sup.7A, —C(O)NR.sup.7AR.sup.7B, —C(O)NHNR.sup.7AR.sup.7B, —OR.sup.7A, —NR.sup.7ASO.sub.2R.sup.7B, —NR.sup.7AC(O)R.sup.7B, —NR.sup.7AC(O)OR.sup.7B, —NR.sup.7AOR.sup.7B, —N.sub.3, 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.sup.9 is selected from hydrogen, halogen, —CX.sup.9.sub.3, —CHX.sup.9.sub.2, —CH.sub.2X.sup.9, —OCX.sup.9.sub.3, —OCH.sub.2X.sup.9, —OCHX.sup.9.sub.2, —CN, —SO.sub.v9R.sup.9A, —SO.sub.v9NR.sup.9AR.sup.9B, —NHC(O)NR.sup.9AR.sup.9B, —N(O).sub.m9, —NR.sup.9AR.sup.9B, —NHNR.sup.9AR.sup.9B, —C(O)R.sup.9A, —C(O)—OR.sup.9A, —C(O)NR.sup.9AR.sup.9B, —C(O)NHNR.sup.9AR.sup.9B, —OR.sup.9A, —NR.sup.9ASO.sub.2R.sup.9B, —NR.sup.9AC(O)R.sup.9B, —NR.sup.9AC(O)OR.sup.9B, —NR.sup.9AOR.sup.9B, —N.sub.3, 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.sup.10 is selected from hydrogen, halogen, —CX.sup.10.sub.3, —CHX.sup.10.sub.2, —CH.sub.2X.sup.10, —OCX.sup.10.sub.3, —OCH.sub.2X.sup.10, —OCHX.sup.10.sub.2, —CN, —SO.sub.n10R.sup.10A, —SO.sub.v10NR.sup.10AR.sup.10B, —NHC(O)NR.sup.10AR.sup.10B, —N(O).sub.m10, —NR.sup.10AR.sup.10B, —NHNR.sup.10AR.sup.10B, —C(O)R.sup.10A, —C(O)—OR.sup.10A, —C(O)NR.sup.10AR.sup.10B, —C(O)NHNR.sup.10AR.sup.10B, —OR.sup.10A, —NR.sup.10ASO.sub.2R.sup.10B, —NR.sup.10AC(O)R.sup.10B, —NR.sup.10AC(O)OR.sup.10B, —NR.sup.10AOR.sup.10B, —N.sub.3, 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.sup.11 is selected from hydrogen, halogen, —CX.sup.11.sub.3, —CHX.sup.11.sub.2, —CH.sub.2X.sup.11, —OCX.sup.11.sub.3, —OCH.sub.2X.sup.11, —OCHX.sup.11.sub.2, —CN, —SO.sub.n11R.sup.11A, —SO.sub.v11NR.sup.11AR.sup.11B, —NHC(O)NR.sup.11AR.sup.11B, —N(O).sub.m11, —NR.sup.11AR.sup.11B, —NHNR.sup.11AR.sup.11B, —C(O)R.sup.11A, —C(O)—OR.sup.11A, —C(O)NR.sup.11AR.sup.11B, —C(O)NHNR.sup.11AR.sup.11B, —OR.sup.11A, —NR.sup.11ASO.sub.2R.sup.11B, —NR.sup.11AC(O)R.sup.11B, —NR.sup.11AC(O)OR.sup.11B, —NR.sup.11AOR.sup.11B, —N.sub.3, 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.sup.12 is selected from hydrogen, halogen, —CX.sup.12.sub.3, —CHX.sup.12.sub.2, —CH.sub.2X.sup.12, —OCX.sup.12.sub.3, —OCH.sub.2X.sup.12, —OCHX.sup.12.sub.2, —CN, —SO.sub.n12R.sup.12A, —SO.sub.v12NR.sup.12AR.sup.12B, —NHC(O)NR.sup.12AR.sup.12B, —N(O).sub.m12, —NR.sup.12AR.sup.12B, —NHNR.sup.12AR.sup.12B, —C(O)R.sup.12A, —C(O)—OR.sup.12A, —C(O)NR.sup.12AR.sup.12B, —C(O)NHNR.sup.12AR.sup.12B, —OR.sup.12A, —NR.sup.12ASO.sub.2R.sup.12B, —NR.sup.12AC(O)R.sup.12B, —NR.sup.12AC(O)OR.sup.12B, —NR.sup.12AOR.sup.12B, —N.sub.3, 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.sup.17 is selected from hydrogen, halogen, —CX.sup.17.sub.3, —CHX.sup.17.sub.2, —CH.sub.2X.sup.17, —OCX.sup.17.sub.3, —OCH.sub.2X.sup.17, —OCHX.sup.17.sub.2, —CN, —SO.sub.n17R.sup.17A, —SO.sub.v17NR.sup.17AR.sup.17B, NHC(O)NR.sup.17AR.sup.17B, —N(O).sub.m17, —NR.sup.17AR.sup.17B, —NHNR.sup.17AR.sup.17B, —C(O)R.sup.17A, —C(O)—OR.sup.17A, —C(O)NR.sup.17AR.sup.17B, —C(O)NHNR.sup.17AR.sup.17B, —OR.sup.17A, —NR.sup.17ASO.sub.2R.sup.17B, —NR.sup.17AC(O)R.sup.17B, —NR.sup.17AC(O)OR.sup.17B, —NR.sup.17AOR.sup.17B, —N.sub.3, 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.sup.18 is selected from hydrogen, halogen, —CX.sup.18.sub.3, —CHX.sup.18.sub.2, —CH.sub.2X.sup.18, —OCX.sup.18.sub.3, —OCH.sub.2X.sup.18, —OCHX.sup.18.sub.2, —CN, —SO.sub.n18R.sup.18A, —SO.sub.v18NR.sup.1AR.sup.18B, —NHC(O)NR.sup.18AR.sup.18B, —N(O).sub.m18, —NR.sup.18AR.sup.18B, —NHNR.sup.18AR.sup.18B, —C(O)R.sup.18A, —C(O)—OR.sup.18A, —C(O)NR.sup.18AR.sup.18B, —C(O)NHNR.sup.18AR.sup.18B, —OR.sup.18A, —NR.sup.18ASO.sub.2R.sup.18B, —NR.sup.18AC(O)R.sup.18B, —NR.sup.18AC(O)OR.sup.18B, —NR.sup.18AOR.sup.18B, —N.sub.3, 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.sup.16 and R.sup.18 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.19 is selected from hydrogen, halogen, —CX.sup.19.sub.3, —CHX.sup.19.sub.2, —CH.sub.2X.sup.19, —OCX.sup.19.sub.3, —OCH.sub.2X.sup.19, —OCHX.sup.19.sub.2, —CN, —SO.sub.n19R.sup.19A, —SO.sub.v19NR.sup.19AR.sup.19B, —NHC(O)NR.sup.19AR.sup.19B, —N(O).sub.m19, —NR.sup.19AR.sup.19B, —NHNR.sup.19AR.sup.19B, —C(O)R.sup.19A, —C(O)—OR.sup.19A, —C(O)NR.sup.19AR.sup.19B, —C(O)NHNR.sup.19AR.sup.19B, —OR.sup.19A, —NR.sup.19ASO.sub.2R.sup.19B, —NR.sup.19AC(O)R.sup.19B, —NR.sup.19AC(O)OR.sup.19B, —NR.sup.19AOR.sup.19B, —N.sub.3, 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.sup.16 and R.sup.19 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.20 is selected from hydrogen, halogen, —CX.sup.20.sub.3, —CHX.sup.20.sub.2, —CH.sub.2X.sup.20, —OCX.sup.20.sub.3, —OCH.sub.2X.sup.20, —OCHX.sup.20.sub.2, —CN, —SO.sub.n20R.sup.20A, —SO.sub.v20NR.sup.20AR.sup.20B, —NHC(O)NR.sup.20AR.sup.20B, —N(O).sup.20B, —NR.sup.20AR.sup.20B, —NHNR.sup.20AR.sup.20B, —C(O)R.sup.20A, —C(O)—OR.sup.20A, —C(O)NR.sup.20AR.sup.20B, —C(O)NHNR.sup.20AR.sup.20B, —OR.sup.20A, —NR.sup.20A, —SO.sub.2R.sup.20B, —NR.sup.20AC(O)R.sup.20B, —NR.sup.20AC(O)OR.sup.20B, —NR.sup.20AOR.sup.20B, —N.sub.3, 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.sup.21 is selected from hydrogen, halogen, —CX.sup.21.sub.3, —CHX.sup.21.sub.2, —CH.sub.2X.sup.21, —OCX.sup.21.sub.3, —OCH.sub.2X.sup.21, —OCHX.sup.21.sub.2, —CN, —SO.sub.n21R.sup.21A, —SO.sub.v21NR.sup.21AR.sup.21B, —NHC(O)NR.sup.21AR.sup.21B, —N(O).sub.m21, —NR.sup.21AR.sup.21B, —NHNR.sup.21AR.sup.21B, —C(O)R.sup.21A, —C(O)—OR.sup.21A, —C(O)NR.sup.21AR.sup.21B, —C(O)NHNR.sup.21AR.sup.21B, —OR.sup.21A, —NR.sup.21ASO.sub.2R.sup.21B, —NR.sup.21AC(O)R.sup.21B, —NR.sup.21AC(O)OR.sup.21B, —NR.sup.21AOR.sup.21B, —N.sub.3, 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.sup.20 and R.sup.21 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.22 is selected from hydrogen, halogen, —CX.sup.22.sub.3, —CHX.sup.22.sub.2, —CH.sub.2X.sup.22, —OCX.sup.22.sub.3, —OCH.sub.2X.sup.22, —OCHX.sup.22.sub.2, —CN, —SO.sub.n22R.sup.22A, —SO.sub.v22NR.sup.22AR.sup.22B, —NHC(O)NR.sup.22AR.sup.22B, —N(O).sub.m22, —NR.sup.22AR.sup.22B, —NHNR.sup.22AR.sup.22B, —C(O)R.sup.22A, —C(O)—OR.sup.22A, —C(O)NR.sup.22AR.sup.22B, —C(O)NHNR.sup.22AR.sup.22B, —OR.sup.22A, —NR.sup.22ASO.sub.2R.sup.22B, —NR.sup.22AC(O)R.sup.22B, —NR.sup.22AC(O)OR.sup.22B, —NR.sup.22AOR.sup.22B, —N.sub.3, 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.sup.23 is selected from hydrogen, halogen, —CX.sup.23.sub.3, —CHX.sup.23.sub.2, —CH.sub.2X.sup.23, —OCX.sup.23.sub.3, —OCH.sub.2X.sup.23, —OCHX.sup.23.sub.2, —CN, —SO.sub.n23R.sup.23A, —SO.sub.v23NR.sup.23AR.sup.23B, —NHC(O)NR.sup.23AR.sup.23B, —N(O).sub.m23, —NR.sup.23AR.sup.23B, —NHNR.sup.23AR.sup.23B, —C(O)R.sup.23A, —C(O)—OR.sup.23A, —C(O)NR.sup.23AR.sup.23B, —C(O)NHNR.sup.23AR.sup.23B, —OR.sup.23A, —NR.sup.23ASO.sub.2R.sup.23B, —NR.sup.23AC(O)R.sup.23B, —NR.sup.23AC(O)OR.sup.23B, —NR.sup.23AOR.sup.23B, —N.sub.3, 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.sup.24 is selected from hydrogen, halogen, —CX.sup.24.sub.3, —CHX.sup.24.sub.2, —CH.sub.2X.sup.24, —OCX.sup.24.sub.3, —OCH.sub.2X.sup.24, —OCHX.sup.24.sub.2, —CN, —SO.sub.n24R.sup.24A, —SO.sub.v24NR.sup.24AR.sup.24B, —NHC(O)NR.sup.24AR.sup.24B, —N(O).sub.m24, —NR.sup.24AR.sup.24B, —NHNR.sup.24AR.sup.24B, —C(O)R.sup.24A, —C(O)—OR.sup.24A, —C(O)NR.sup.24AR.sup.24B, —C(O)NHNR.sup.24AR.sup.24B, —OR.sup.24A, —NR.sup.24ASO.sub.2R.sup.24B, —NR.sup.24AC(O)R.sup.24B, —NR.sup.24AC(O)OR.sup.24B, —NR.sup.24AOR.sup.24B, —N.sub.3, 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.sup.25 is selected from hydrogen, halogen, —CX.sup.25.sub.3, —CHX.sup.25.sub.2, —CH.sub.2X.sup.25, —OCX.sup.25.sub.3, —OCH.sub.2X.sup.25, —OCHX.sup.25.sub.2, —CN, —SO.sub.n25R.sup.25A, —SO.sub.v25NR.sup.25AR.sup.25B, —NHC(O)NR.sup.25AR.sup.25B, —N(O).sub.m25, —NR.sup.25AR.sup.25B, —NHNR.sup.25AR.sup.25B, —C(O)R.sup.25A, —C(O)—OR.sup.25A, —C(O)NR.sup.25AR.sup.25B, —C(O)NHNR.sup.25AR.sup.25B, —OR.sup.25A, —NR.sup.25ASO.sub.2R.sup.25B, —NR.sup.25AC(O)R.sup.25B, —NR.sup.25AC(O)OR.sup.25B, —NR.sup.25AOR.sup.25B, —N.sub.3, 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.sup.26 is selected from hydrogen, halogen, —CX.sup.26.sub.3, —CHX.sup.26.sub.2, —CH.sub.2X.sup.26, —OCX.sup.26.sub.3, —OCH.sub.2X.sup.26, —OCHX.sup.26.sub.2, —CN, —SO.sub.n26R.sup.26A, —SO.sub.v26NR.sup.26AR.sup.26B, —NHC(O)NR.sup.26AR.sup.26B, —N(O).sub.m26, —NR.sup.26AR.sup.26B, —NHNR.sup.26AR.sup.26B, —C(O)R.sup.26A, —C(O)—OR.sup.26A, —C(O)NR.sup.26AR.sup.26B, —C(O)NHNR.sup.26AR.sup.26B, —OR.sup.26A, —NR.sup.26ASO.sub.2R.sup.26B, —NR.sup.26AC(O)R.sup.26B, —NR.sup.26AC(O)OR.sup.26B, —NR.sup.26AOR.sup.26B, —N.sub.3, 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.sup.27 is selected from hydrogen, halogen, —CX.sup.27.sub.3, —CHX.sup.27.sub.2, —CH.sub.2X.sup.27, —OCX.sup.27.sub.3, —OCH.sub.2X.sup.27, —OCHX.sup.27.sub.2, —CN, —SO.sub.n27R.sup.27A, —SO.sub.v27NR.sup.27AR.sup.27B, —NHC(O)NR.sup.27AR.sup.27B, —N(O).sub.m27, —NR.sup.27AR.sup.27B, —NHNR.sup.27AR.sup.27B, —C(O)R.sup.27A, —C(O)—OR.sup.27A, —C(O)NR.sup.27AR.sup.27B, —C(O)NHNR.sup.27AR.sup.27B, —OR.sup.27A, —NR.sup.27ASO.sub.2R.sup.27B, —NR.sup.27AC(O)R.sup.27B, —NR.sup.27AC(O)OR.sup.27B, —NR.sup.27AOR.sup.27B, —N.sub.3, 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.sup.28 is selected from hydrogen, halogen, —CX.sup.28.sub.3, —CHX.sup.28.sub.2, —CH.sub.2X.sup.28, —OCX.sup.28.sub.3, —OCH.sub.2X.sup.28, —OCHX.sup.28.sub.2, —CN, —SO.sub.n28R.sup.28A, —SO.sub.v28NR.sup.28AR.sup.28B, —NHC(O)NR.sup.28AR.sup.28B, —N(O).sub.m28, —NR.sup.28AR.sup.28B, —NHNR.sup.28AR.sup.28B, —C(O)R.sup.28A, —C(O)—OR.sup.28A, —C(O)NR.sup.28AR.sup.28B, —C(O)NHNR.sup.28AR.sup.28B, —OR.sup.28A, —NR.sup.28ASO.sub.2R.sup.28B, —NR.sup.28AC(O)R.sup.28B, —NR.sup.28AC(O)OR.sup.28B, —NR.sup.28AOR.sup.28B, —N.sub.3, 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.sup.29 is selected from hydrogen, halogen, —CX.sup.29.sub.3, —CHX.sup.29.sub.2, —CH.sub.2X.sup.29, —OCX.sup.29.sub.3, —OCH.sub.2X.sup.29, —OCHX.sup.29.sub.2, —CN, —SO.sub.n29R.sup.29A, —SO.sub.v29NR.sup.29AR.sup.29B, —NHC(O)NR.sup.29AR.sup.29B, —N(O).sub.m29, —NR.sup.29AR.sup.29B, —NHNR.sup.29AR.sup.29B, —C(O)R.sup.29A, —C(O)—OR.sup.29A, —C(O)NR.sup.29AR.sup.29B, —C(O)NHNR.sup.29AR.sup.29B, —OR.sup.29A, —NR.sup.29ASO.sub.2R.sup.29B, —NR.sup.29AC(O)R.sup.29B, —NR.sup.29AC(O)OR.sup.29B, —NR.sup.29AOR.sup.29B, —N.sub.3, 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.sup.30 is selected from hydrogen, halogen, —CX.sup.30.sub.3, —CHX.sup.30.sub.2, —CH.sub.2X.sup.30, —OCX.sup.30.sub.3, —OCH.sub.2X.sup.30, —OCHX.sup.30.sub.2, —CN, —SO.sub.n30R.sup.30A, —SO.sub.v30NR.sup.30AR.sup.30B, —NHC(O)NR.sup.30AR.sup.30B, —N(O).sub.m30, —NR.sup.30AR.sup.30B, —NHNR.sup.30AR.sup.30B, —C(O)R.sup.30A, —C(O)—OR.sup.30A, —C(O)NR.sup.30AR.sup.30B, —C(O)NHNR.sup.30AR.sup.30B, —OR.sup.30A, —NR.sup.30ASO.sub.2R.sup.30B, —NR.sup.30AC(O)R.sup.30B, —NR.sup.30AC(O)OR.sup.30B, —NR.sup.30AOR.sup.30B, —N.sub.3, 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.sup.31 is selected from hydrogen, halogen, —CX.sup.31.sub.3, —CHX.sup.31.sub.2, —CH.sub.2X.sup.31, —OCX.sup.31.sub.3, —OCH.sub.2X.sup.31, —OCHX.sup.31.sub.2, —CN, —SO.sub.n31R.sup.31A, —SO.sub.v31NR.sup.31AR.sup.31B, —NHC(O)NR.sup.31AR.sup.31B, —N(O).sub.m31, —NR.sup.31AR.sup.31B, —NHNR.sup.31AR.sup.31B, —C(O)R.sup.31A, —C(O)—OR.sup.31A, —C(O)NR.sup.31AR.sup.31B, —C(O)NHNR.sup.31AR.sup.31B, —OR.sup.31A, —NR.sup.31ASO.sub.2R.sup.31B, —NR.sup.31AC(O)R.sup.31B, —NR.sup.31AC(O)OR.sup.31B, —NR.sup.31AOR.sup.31B, —N.sub.3, 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.sup.32 is selected from hydrogen, halogen, —CX.sup.32.sub.3, —CHX.sup.32.sub.2, —CH.sub.2X.sup.32, —OCX.sup.32.sub.3, —OCH.sub.2X.sup.32, —OCHX.sup.32.sub.2, —CN, —SO.sub.n32R.sup.32A, —SO.sub.v32NR.sup.32AR.sup.32B, —NHC(O)NR.sup.32AR.sup.32B, —N(O).sub.m32, —NR.sup.32AR.sup.32B, —NHNR.sup.32AR.sup.32B, —C(O)R.sup.32A, —C(O)—OR.sup.32A, —C(O)NR.sup.32AR.sup.32B, —C(O)NHNR.sup.32AR.sup.32B, —OR.sup.32A, —NR.sup.32ASO.sub.2R.sup.32B, —NR.sup.32AC(O)R.sup.32B, —NR.sup.32AC(O)OR.sup.32B, —NR.sup.32AOR.sup.32B, —N.sub.3, 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.sup.33 is selected from hydrogen, halogen, —CX.sup.33.sub.3, —CHX.sup.33.sub.2, —CH.sub.2X.sup.33, —OCX.sup.33.sub.3, —OCH.sub.2X.sup.33, —OCHX.sup.33.sub.2, —CN, —SO.sub.n33R.sup.33A, —SO.sub.v33NR.sup.33AR.sup.33B, —NHC(O)NR.sup.33AR.sup.33B, —N(O).sub.m33, —NR.sup.33AR.sup.33B, —NHNR.sup.33AR.sup.33B, —C(O)R.sup.33A, —C(O)—OR.sup.33A, —C(O)NR.sup.33AR.sup.33B, —C(O)NHNR.sup.33AR.sup.33B, —OR.sup.33A, —NR.sup.33ASO.sub.2R.sup.33B, —NR.sup.33AC(O)R.sup.33B, —NR.sup.33AC(O)OR.sup.33B, —NR.sup.33AOR.sup.33B, —N.sub.3, 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.sup.34 is selected from hydrogen, halogen, —CX.sup.34.sub.3, —CHX.sup.34.sub.2, —CH.sub.2X.sup.34, —OCX.sup.34.sub.3, —OCH.sub.2X.sup.34, —OCHX.sup.34.sub.2, —CN, —SO.sub.n34R.sup.34A, —SO.sub.v34NR.sup.34AR.sup.34B, —NHC(O)NR.sup.34AR.sup.34B, —N(O).sub.m34, —NR.sup.34AR.sup.34B, —NHNR.sup.34AR.sup.34B, —C(O)R.sup.34A, —C(O)—OR.sup.34A, —C(O)NR.sup.34AR.sup.34B, —C(O)NHNR.sup.34AR.sup.34B, —OR.sup.34A, —NR.sup.34ASO.sub.2R.sup.34B, —NR.sup.34AC(O)R.sup.34B, —NR.sup.34AC(O)OR.sup.34B, —NR.sup.34AOR.sup.34B, —N.sub.3, 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.sup.35 is selected from hydrogen, halogen, —CX.sup.35.sub.3, —CHX.sup.35.sub.2, —CH.sub.2X.sup.35, —OCX.sup.35.sub.3, —OCH.sub.2X.sup.35, —OCHX.sup.35.sub.2, —CN, —SO.sub.n35R.sup.35A, —SO.sub.v35NR.sup.35AR.sup.35B, —NHC(O)NR.sup.35AR.sup.35B, —N(O).sub.m35, —NR.sup.35AR.sup.35B, —NHNR.sup.35AR.sup.35B, —C(O)R.sup.35A, —C(O)—OR.sup.35A, —C(O)NR.sup.35AR.sup.35B, —C(O)NHNR.sup.35AR.sup.35B, —OR.sup.35A, —NR.sup.35ASO.sub.2R.sup.35B, —NR.sup.35AC(O)R.sup.35B, —NR.sup.35AC(O)OR.sup.35B, —NR.sup.35AOR.sup.35B, —N.sub.3, 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; Each R.sup.1A, R.sup.1B, R.sup.3A, R.sup.3B, R.sup.4A, R.sup.4B, R.sup.6A, R.sup.6B, R.sup.7A, R.sup.7B, R.sup.9A, R.sup.9B, R.sup.10A, R.sup.10B, R.sup.11A, R.sup.11B, R.sup.17A, R.sup.17B, R.sup.18A, R.sup.18B, R.sup.19A, R.sup.19B, R.sup.20A, R.sup.20B, R.sup.21A, R.sup.21B, R.sup.22A, R.sup.22B, R.sup.23A, R.sup.23B, R.sup.24A, R.sup.24B, R.sup.25A, R.sup.25B, R.sup.26A, R.sup.26B, R.sup.27A, R.sup.27B, R.sup.28A, R.sup.28B, R.sup.29A, R.sup.29B, R.sup.30A, R.sup.30B, R.sup.31A, R.sup.31B, R.sup.32A, R.sup.32B, R.sup.33A, R.sup.33B, R.sup.34A, R.sup.34B, R.sup.35A, R.sup.35B is independently selected from hydrogen, —CX.sub.3, —CHX.sub.2, —CH.sub.2X, —C(O)OH, —C(O)NH.sub.2, —CN, —OH, —NH.sub.2, —COOH, —CONH.sub.2, —NO.sub.2, —SH, —SO.sub.3H, —SO.sub.4H, —SO.sub.2NH.sub.2, —NHNH.sub.2, —ONH.sub.2, —NHC═(O)NHNH.sub.2, —NHC═(O)NH.sub.2, —NHSO.sub.2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX.sub.3, —OCHX.sub.2, —OCH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.6A and R.sup.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.sup.7A and R.sup.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.sup.9A and R.sup.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.sup.13A and R.sup.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.sup.14A and R.sup.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.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.19A and R.sup.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.sup.20A and R.sup.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.sup.21A and R.sup.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.sup.22A and R.sup.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.sup.23A and R.sup.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.sup.24A and R.sup.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.sup.25A and R.sup.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.sup.26A and R.sup.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.sup.27A and R.sup.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.sup.28A and R.sup.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.sup.29A and R.sup.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.sup.30A and R.sup.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 m1, m3, m4, m6, m7, m9, m10, m11, m17, m18, m19, m20, m21, m22, m23, m24, m25, m26, m27, m28, m29, m30, m31, m32, m33, m34 and m35 is independently 1 or 2; Each v1, v3, v4, v6, v7, v9, v10, v11, v17, v18, v19, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v30, v31, v32, v33, v34 and v35 is independently 1 or 2; Each n1, n3, n4, n6, n7, n9, n10, n11, n17, n18, n19, 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 Each X.sup.1, X.sup.3, X.sup.4, X.sup.6, X.sup.7, X.sup.9, X.sup.10, X.sup.11, X.sup.17, X.sup.18, X.sup.19, X.sup.20, X.sup.21, X.sup.22, X.sup.23, X.sup.24, X.sup.25, X.sup.26, X.sup.27, X.sup.28, X.sup.29, X.sup.30, X.sup.31, X.sup.32, X.sup.33, X.sup.34, and X.sup.35 is independently —Cl, —Br, —I or —F.
21. Compound of claim 20 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, midazolyl, 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 ##STR00512##
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(═O)CH═CH.sub.2, —C(═O)-ethynyl, —C(═O)CH═CHCF.sub.3, —C(═O)CH═CHCHF.sub.2, —C(═O)CH═CHCH.sub.2F, and —C(═O)CH.sub.2Br.
27. Compound of any one of claims 20-26 wherein U is O, NR.sup.12 or S.
28. A compound of claim 1, comprising a compound of Formula VIII: ##STR00513## wherein Z is N, or CR.sup.9; W is selected from NR.sup.12, O, S, S═O, O═S═O, 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 ##STR00514## ##STR00515## ##STR00516## wherein R.sup.1 is selected from hydrogen, halogen, —CX.sup.1.sub.3, —CHX.sup.1.sub.2, —CH.sub.2X.sup.1, —OCX.sup.1.sub.3, —OCH.sub.2X.sup.1, —OCHX.sup.1.sub.2, —CN, —SO.sub.n1R.sup.1A, —SO.sub.v1NR.sup.1AR.sup.1B, —NHC(O)NR.sup.1AR.sup.1B, —N(O).sub.m1, —NR.sup.1AR.sup.1B, —NHNR.sup.1AR.sup.1B, —C(O)R.sup.1A, —C(O)—OR.sup.1A, —C(O)NR.sup.1AR.sup.1B, —C(O)NHNR.sup.1AR.sup.1B, —OR.sup.1A, —NR.sup.1ASO.sub.2R.sup.1B, —NR.sup.1AC(O)R.sup.1B, —NR.sup.1AC(O)OR.sup.1B, —NR.sup.1AOR.sup.1B, —N.sub.3, 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; R.sup.3 is selected from hydrogen, halogen, —CX.sup.3.sub.3, —CHX.sup.3.sub.2, —CH.sub.2X.sup.3, —OCX.sup.3.sub.3, —OCH.sub.2X.sup.3, —OCHX.sup.3.sub.2, —CN, —SO.sub.v3R.sup.3A, —SO.sub.v3NR.sup.3AR.sup.3B, —NHC(O)NR.sup.3AR.sup.3B, —N(O).sub.m3, —NR.sup.3AR.sup.3B, —NHNR.sup.3AR.sup.3B, —C(O)R.sup.3A, —C(O)—OR.sup.3A, —C(O)NR.sup.3AR.sup.3B, —OR.sup.3A, —NR.sup.3ASO.sub.2R.sup.3B, —NR.sup.3AC(O)R.sup.3B, —NR.sup.3AC(O)OR.sup.3B, —NR.sup.3AOR.sup.3B, —N.sub.3, 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.sup.4 is selected from hydrogen, halogen, —CX.sup.4.sub.3, —CHX.sup.4.sub.2, —CH.sub.2X.sup.4, —OCX.sup.4.sub.3, —OCH.sub.2X.sup.4, —OCHX.sup.4.sub.2, —CN, —SO.sub.v4R.sup.4A, —SO.sub.v4NR.sup.4AR.sup.4B, —NHC(O)NR.sup.4AR.sup.4B, —N(O).sub.m4, —NR.sup.4AR.sup.4B, —NHNR.sup.4AR.sup.4B, —C(O)R.sup.4A, —C(O)—OR.sup.4A, —C(O)NR.sup.4AR.sup.4B, —C(O)NHNR.sup.4AR.sup.4B, —OR.sup.4A, —NR.sup.4ASO.sub.2R.sup.4B, —NR.sup.4AC(O)R.sup.4B, —NR.sup.4AC(O)OR.sup.4B, —NR.sup.4AOR.sup.4B, —N.sub.3, 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.sup.3 and R.sup.3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.6 is selected from hydrogen, halogen, —CX.sup.6.sub.3, —CHX.sup.6.sub.2, —CH.sub.2X.sup.6, —OCX.sup.6.sub.3, —OCH.sub.2X.sup.6, —OCHX.sup.6.sub.2, —CN, —SO.sub.v6R.sup.6A, —SO.sub.6NR.sup.6AR.sup.6B, —NHC(O)NR.sup.6AR.sup.6B, —N(O).sub.m6, —NR.sup.6AR.sup.6B, —NHNR.sup.6AR.sup.6B, —C(O)R.sup.6A, —C(O)—OR.sup.6A, —C(O)NR.sup.6AR.sup.6B, —C(O)NHNR.sup.6AR.sup.6B, —OR.sup.6A, —NR.sup.6ASO.sub.2R.sup.6B, —NR.sup.6AC(O)R.sup.6B, —NR.sup.6AC(O)OR.sup.6B, —NR.sup.6AOR.sup.6B, —N.sub.3, 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.sup.7 is selected from hydrogen, halogen, —CX.sup.7.sub.3, —CHX.sup.7.sub.2, —CH.sub.2X.sup.7, —OCX.sup.7.sub.3, —OCH.sub.2X.sup.7, —OCHX.sup.7.sub.2, —CN, —SO.sub.7R.sup.7A, —SO.sub.v7NR.sup.7AR.sup.7B, —NHC(O)NR.sup.7AR.sup.7B, —N(O).sub.m7, —NR.sup.7AR.sup.7B, —NHNR.sup.7AR.sup.7B, —C(O)R.sup.7A, —C(O)—OR.sup.7A, —C(O)NR.sup.7AR.sup.7B, —C(O)NHNR.sup.7AR.sup.7B, —OR.sup.7A, —NR.sup.7ASO.sub.2R.sup.7B, —NR.sup.7AC(O)R.sup.7B, —NR.sup.7AC(O)OR.sup.7B, —NR.sup.7AOR.sup.7B, —N.sub.3, 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.sup.9 is selected from hydrogen, halogen, —CX.sup.9.sub.3, —CHX.sup.9.sub.2, —CH.sub.2X.sup.9, —OCX.sup.9.sub.3, —OCH.sub.2X.sup.9, —OCHX.sup.9.sub.2, —CN, —SO.sub.v9R.sup.9A, —SO.sub.9NR.sup.9AR.sup.9B, —NHC(O)NR.sup.9AR.sup.9B, —N(O).sub.m9, —NR.sup.9AR.sup.9B, —NHNR.sup.9AR.sup.9B, —C(O)R.sup.9A, —C(O)—OR.sup.9A, —C(O)NR.sup.9AR.sup.9B, —C(O)NHNR.sup.9AR.sup.9B, —OR.sup.9A, —NR.sup.9ASO.sub.2R.sup.9B, —NR.sup.9AC(O)R.sup.9B, —NR.sup.9AC(O)OR.sup.9B, —NR.sup.9AOR.sup.9B, —N.sub.3, 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.sup.10 is selected from hydrogen, halogen, —CX.sup.10.sub.3, —CHX.sup.10.sub.2, —CH.sub.2X.sup.10, —OCX.sup.10.sub.3, —OCH.sub.2X.sup.10, —OCHX.sup.10.sub.2, —CN, —SO.sub.n10R.sup.10A, —SO.sub.v10NR.sup.10AR.sup.10B, —NHC(O)NR.sup.10AR.sup.10B, —N(O).sub.m10, —NR.sup.10AR.sup.10B, —NHNR.sup.10AR.sup.10B, —C(O)R.sup.10A, —C(O)—OR.sup.10A, —C(O)NR.sup.10AR.sup.10B, —C(O)NHNR.sup.10AR.sup.10B, —OR.sup.10A, —NR.sup.10ASO.sub.2R.sup.10B, —NR.sup.10AC(O)R.sup.10B, —NR.sup.10AC(O)OR.sup.10B, —NR.sup.10AOR.sup.10B, —N.sub.3, 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.sup.11 is selected from hydrogen, halogen, —CX.sup.11.sub.3, —CHX.sup.11.sub.2, —CH.sub.2X.sup.11, —OCX.sup.11.sub.3, —OCH.sub.2X.sup.11, —OCHX.sup.11.sub.2, —CN, —SO.sub.n11R.sup.11A, —SO.sub.v11NR.sup.11AR.sup.11B, —NHC(O)NR.sup.11AR.sup.11B, —N(O).sub.mii, —NR.sup.11AR.sup.11B, —NHNR.sup.11AR.sup.11B, —C(O)R.sup.11A, —C(O)—OR.sup.11A, —C(O)NR.sup.11AR.sup.11B, —C(O)NHNR.sup.11AR.sup.11B, —OR.sup.11A, —NR.sup.11ASO.sub.2R.sup.11B, —NR.sup.11AC(O)R.sup.11B, —NR.sup.11AC(O)OR.sup.11B, —NR.sup.11AOR.sup.11B, —N.sub.3, 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.sup.12 is selected from hydrogen, halogen, —CX.sup.12.sub.3, —CHX.sup.12.sub.2, —CH.sub.2X.sup.12, —OCX.sup.12.sub.3, —OCH.sub.2X.sup.12, —OCHX.sup.12.sub.2, —CN, —SO.sub.n12R.sup.12A, —SO.sub.v12NR.sup.12AR.sup.12B, —NHC(O)NR.sup.12AR.sup.12B, —N(O).sub.m12, —NR.sup.12AR.sup.12B, —NHNR.sup.12AR.sup.12B, —C(O)R.sup.12A, —C(O)—OR.sup.12A, —C(O)NR.sup.12AR.sup.12B, —C(O)NHNR.sup.12AR.sup.12B, —OR.sup.12A, —NR.sup.12ASO.sub.2R.sup.12B, —NR.sup.12AC(O)R.sup.12B, —NR.sup.12AC(O)OR.sup.12B, —NR.sup.12AOR.sup.12B, —N.sub.3, 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.sup.17 is selected from hydrogen, halogen, —CX.sup.17.sub.3, —CHX.sup.17.sub.2, —CH.sub.2X.sup.17, —OCX.sup.17.sub.3, —OCH.sub.2X.sup.17, —OCHX.sup.17.sub.2, —CN, —SO.sub.n17R.sup.17A, —SO.sub.v17NR.sup.17AR.sup.17B, —NHC(O)NR.sup.17AR.sup.17B, —N(O).sub.m17, —NR.sup.17AR.sup.17B, —NHNR.sup.17AR.sup.17B, —C(O)R.sup.17A, —C(O)—OR.sup.17A, —C(O)NR.sup.17AR.sup.17B, —C(O)NHNR.sup.17AR.sup.17B, —OR.sup.17A, —NR.sup.17ASO.sub.2R.sup.17B, —NR.sup.17AC(O)R.sup.17B, —NR.sup.17AC(O)OR.sup.17B, —NR.sup.17AOR.sup.17B, —N.sub.3, 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.sup.18 is selected from hydrogen, halogen, —CX.sup.18.sub.3, —CHX.sup.18.sub.2, —CH.sub.2X.sup.18, —OCX.sup.18.sub.3, —OCH.sub.2X.sup.18, —OCHX.sup.18.sub.2, —CN, —SO.sub.n18R.sup.18A, —SO.sub.v18NR.sup.18AR.sup.18B, —NHC(O)NR.sup.18AR.sup.18B, —N(O).sub.m18, —NR.sup.18AR.sup.18B, —NHNR.sup.18AR.sup.18B, —C(O)R.sup.18A, —C(O)—OR.sup.18A, —C(O)NR.sup.18AR.sup.18B, —C(O)NHNR.sup.18AR.sup.18B, OR.sup.18A, —NR.sup.18ASO.sub.2R.sup.18B, —NR.sup.18AC(O)R.sup.18B, —NR.sup.18AC(O)OR.sup.18B, —NR.sup.18AOR.sup.18B, —N.sub.3, 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.sup.16 and R.sup.18 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.19 is selected from hydrogen, halogen, —CX.sup.19.sub.3, —CHX.sup.19.sub.2, —CH.sub.2X.sup.19, —OCX.sup.19.sub.3, —OCH.sub.2X.sup.19, —OCHX.sup.19.sub.2, —CN, —SO.sub.n19R.sup.19A, —SO.sub.v19NR.sup.19AR.sup.19B, —NHC(O)NR.sup.19AR.sup.19B, —N(O).sub.m19, —NR.sup.19AR.sup.19B, —NHNR.sup.19AR.sup.19B, —C(O)R.sup.19A, —C(O)—OR.sup.19A, —C(O)NR.sup.19AR.sup.19B, —C(O)NHNR.sup.19AR.sup.19B, —OR.sup.19A, —NR.sup.19ASO.sub.2R.sup.19B, —NR.sup.19AC(O)R.sup.19B, —NR.sup.19AC(O)OR.sup.19B, —NR.sup.19AOR.sup.19B, —N.sub.3, 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.sup.16 and R.sup.19 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.20 is selected from hydrogen, halogen, —CX.sup.20.sub.3, —CHX.sup.20.sub.2, —CH.sub.2X.sup.20, —OCX.sup.20.sub.3, —OCH.sub.2X.sup.20, —OCHX.sup.20.sub.2, —CN, —SO.sub.n20R.sup.20A, —SO.sub.v20NR.sup.20AR.sup.20B, —NHC(O)NR.sup.20AR.sup.20B, —N(O).sub.m20, —NR.sup.20AR.sup.20B, —NHNR.sup.20AR.sup.20B, —C(O)R.sup.20A, —C(O)—OR.sup.20A, —C(O)NR.sup.20AR.sup.20B, —C(O)NHNR.sup.20AR.sup.20B, —OR.sup.20A, —NR.sup.20A, —SO.sub.2R.sup.20B, —NR.sup.20AC(O)R.sup.20B, —NR.sup.20AC(O)OR.sup.20B, —NR.sup.20AOR.sup.20B, —N.sub.3, 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.sup.21 is selected from hydrogen, halogen, —CX.sup.21.sub.3, —CHX.sup.21.sub.2, —CH.sub.2X.sup.21, —OCX.sup.21.sub.3, —OCH.sub.2X.sup.21, —OCHX.sup.21.sub.2, —CN, —SO.sub.n21R.sup.21A, —SO.sub.v21NR.sup.21AR.sup.21B, —NHC(O)NR.sup.21AR.sup.21B, —N(O).sub.m21, —NR.sup.21AR.sup.21B, —NHNR.sup.21AR.sup.21B, —C(O)R.sup.21A, —C(O)—OR.sup.21A, —C(O)NR.sup.21AR.sup.21B, —C(O)NHNR.sup.21AR.sup.21B, —OR.sup.21A, NR.sup.21ASO.sub.2R.sup.21B, —NR.sup.21AC(O)R.sup.21B, —NR.sup.21AC(O)OR.sup.21B, —NR.sup.21AOR.sup.21B, —N.sub.3, 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.sup.20 and R.sup.21 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; R.sup.22 is selected from hydrogen, halogen, —CX.sup.22.sub.3, —CHX.sup.22.sub.2, —CH.sub.2X.sup.22, —OCX.sup.22.sub.3, —OCH.sub.2X.sup.22, —OCHX.sup.22.sub.2, —CN, —SO.sub.n22R.sup.22A, —SO.sub.v22NR.sup.22AR.sup.22B, —NHC(O)NR.sup.22AR.sup.22B, —N(O).sub.m22, —NR.sup.22AR.sup.22B, —NHNR.sup.22AR.sup.22B, —C(O)R.sup.22A, —C(O)—OR.sup.22A, —C(O)NR.sup.22AR.sup.22B, —C(O)NHNR.sup.22AR.sup.22B, —OR.sup.22A, —NR.sup.22ASO.sub.2R.sup.22B, —NR.sup.22AC(O)R.sup.22B, —NR.sup.22AC(O)OR.sup.22B, —NR.sup.22AOR.sup.22B, —N.sub.3, 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.sup.23 is selected from hydrogen, halogen, —CX.sup.23.sub.3, —CHX.sup.23.sub.2, —CH.sub.2X.sup.23, —OCX.sup.23.sub.3, —OCH.sub.2X.sup.23, —OCHX.sup.23.sub.2, —CN, —SO.sub.n23R.sup.23A, —SO.sub.v23NR.sup.23AR.sup.23B, —NHC(O)NR.sup.23AR.sup.23B, —N(O).sub.m23, —NR.sup.23AR.sup.23B, —NHNR.sup.23AR.sup.23B, C(O)R.sup.23A, —C(O)—OR.sup.23A, —C(O)NR.sup.23AR.sup.23B, —C(O)NHNR.sup.23AR.sup.23B, OR.sup.23A, —NR.sup.23ASO.sub.2R.sup.23B, —NR.sup.23AC(O)R.sup.23B, —NR.sup.23AC(O)OR.sup.23B, —NR.sup.23AOR.sup.23B, —N.sub.3, 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.sup.24 is selected from hydrogen, halogen, —CX.sup.24.sub.3, —CHX.sup.24.sub.2, —CH.sub.2X.sup.24, —OCX.sup.24.sub.3, —OCH.sub.2X.sup.24, —OCHX.sup.24.sub.2, —CN, —SO.sub.n24R.sup.24A, —SO.sub.v24NR.sup.24AR.sup.24B, —NHC(O)NR.sup.24AR.sup.24B, —N(O).sub.m24, —NR.sup.24AR.sup.24B, —NHNR.sup.24AR.sup.24B, C(O)R.sup.24A, —C(O)—OR.sup.24A, —C(O)NR.sup.24AR.sup.24B, —C(O)NHNR.sup.24AR.sup.24B, OR.sup.24A, —NR.sup.24ASO.sub.2R.sup.24B, —NR.sup.24AC(O)R.sup.24B, —NR.sup.24AC(O)OR.sup.24B, —NR.sup.24AOR.sup.24B, —N.sub.3, 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.sup.25 is selected from hydrogen, halogen, —CX.sup.25.sub.3, —CHX.sup.25.sub.2, —CH.sub.2X.sup.25, —OCX.sup.25.sub.3, —OCH.sub.2X.sup.25, —OCHX.sup.25.sub.2, —CN, —SO.sub.n25R.sup.25A, —SO.sub.v25NR.sup.25AR.sup.25B, —NHC(O)NR.sup.25AR.sup.25B, —N(O).sub.m25, —NR.sup.25AR.sup.25B, —NHNR.sup.25AR.sup.25B, C(O)R.sup.25A, —C(O)—OR.sup.25A, —C(O)NR.sup.25AR.sup.25B, —C(O)NHNR.sup.25AR.sup.25B, OR.sup.25A, —NR.sup.25ASO.sub.2R.sup.25B, —NR.sup.25AC(O)R.sup.25B, —NR.sup.25AC(O)OR.sup.25B, —NR.sup.25AOR.sup.25B, —N.sub.3, 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.sup.26 is selected from hydrogen, halogen, —CX.sup.26.sub.3, —CHX.sup.26.sub.2, —CH.sub.2X.sup.26, —OCX.sup.26.sub.3, —OCH.sub.2X.sup.26, —OCHX.sup.26.sub.2, —CN, —SO.sub.n26R.sup.26A, —SO.sub.v26NR.sup.26AR.sup.26B, —NHC(O)NR.sup.26AR.sup.26B, —N(O).sub.m26, —NR.sup.26AR.sup.26B, —NHNR.sup.26AR.sup.26B, —C(O)R.sup.26A, —C(O)—OR.sup.26A, —C(O)NR.sup.26AR.sup.26B, —C(O)NHNR.sup.26AR.sup.26B, OR.sup.26A, —NR.sup.26ASO.sub.2R.sup.26B, —NR.sup.26AC(O)R.sup.26B, —NR.sup.26AC(O)OR.sup.26B, —NR.sup.26AOR.sup.26B, —N.sub.3, 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.sup.27 is selected from hydrogen, halogen, —CX.sup.27.sub.3, —CHX.sup.27.sub.2, —CH.sub.2X.sup.27, —OCX.sup.27.sub.3, —OCH.sub.2X.sup.27, —OCHX.sup.27.sub.2, —CN, —SO.sub.n27R.sup.27A, —SO.sub.v27NR.sup.27AR.sup.27B, —NHC(O)NR.sup.27AR.sup.27B, —N(O).sub.m27, —NR.sup.27AR.sup.27B, —NHNR.sup.27AR.sup.27B, C(O)R.sup.27A, —C(O)—OR.sup.27A, —C(O)NR.sup.27AR.sup.27B, —C(O)NHNR.sup.27AR.sup.27B, OR.sup.27A, —NR.sup.27ASO.sub.2R.sup.27B, —NR.sup.27AC(O)R.sup.27B, —NR.sup.27AC(O)OR.sup.27B, —NR.sup.27AOR.sup.27B, —N.sub.3, 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.sup.28 is selected from hydrogen, halogen, —CX.sup.28.sub.3, —CHX.sup.28.sub.2, —CH.sub.2X.sup.28, —OCX.sup.28.sub.3, —OCH.sub.2X.sup.28, —OCHX.sup.28.sub.2, —CN, —SO.sub.n2R.sup.28A, —SO.sub.v28NR.sup.28AR.sup.28B, —NHC(O)NR.sup.28AR.sup.28B, —N(O).sub.m28, —NR.sup.28AR.sup.28B, —NHNR.sup.28AR.sup.28B, C(O)R.sup.28A, —C(O)—OR.sup.28A, —C(O)NR.sup.28AR.sup.28B, —C(O)NHNR.sup.28AR.sup.28B, —OR.sup.28A, —NR.sup.28ASO.sub.2R.sup.28B, —NR.sup.28AC(O)R.sup.28B, —NR.sup.28AC(O)OR.sup.28B, —NR.sup.28AOR.sup.28B, —N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted and unsubstituted heteroaryl; R.sup.29 is selected from hydrogen, halogen, —CX.sup.29.sub.3, —CHX.sup.29.sub.2, —CH.sub.2X.sup.29, —OCX.sup.29.sub.3, —OCH.sub.2X.sup.29, —OCHX.sup.29.sub.2, —CN, —SO.sub.n29R.sup.29A, —SO.sub.v29NR.sup.29AR.sup.29B, —NHC(O)NR.sup.29AR.sup.29B, —N(O).sub.m29, —NR.sup.29AR.sup.29B, —NHNR.sup.29AR.sup.29B, C(O)R.sup.29A, —C(O)—OR.sup.29A, —C(O)NR.sup.29AR.sup.29B, —C(O)NHNR.sup.29AR.sup.29B, —OR.sup.29A, —NR.sup.29ASO.sub.2R.sup.29B, —NR.sup.29AC(O)R.sup.29B, —NR.sup.29AC(O)OR.sup.29B, —NR.sup.29AOR.sup.29B, —N.sub.3, 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.sup.30 is selected from hydrogen, halogen, —CX.sup.30.sub.3, —CHX.sup.30.sub.2, —CH.sub.2X.sup.30, —OCX.sup.30.sub.3, —OCH.sub.2X.sup.30, —OCHX.sup.30.sub.2, —CN, —SO.sub.n30R.sup.30A, —SO.sub.v30NR.sup.30AR.sup.30B, —NHC(O)NR.sup.30AR.sup.30B, —N(O).sub.m30, —NR.sup.30AR.sup.30B, —NHNR.sup.30AR.sup.30B, C(O)R.sup.30A, —C(O)—OR.sup.30A, —C(O)NR.sup.30AR.sup.30B, —C(O)NHNR.sup.30AR.sup.30B, OR.sup.30A, —NR.sup.30ASO.sub.2R.sup.30B, —NR.sup.30AC(O)R.sup.30B, —NR.sup.30AC(O)OR.sup.30B, —NR.sup.30AOR.sup.30B, —N.sub.3, 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.sup.31 is selected from hydrogen, halogen, —CX.sup.31.sub.3, —CHX.sup.31.sub.2, —CH.sub.2X.sup.31, —OCX.sup.31.sub.3, —OCH.sub.2X.sup.31, —OCHX.sup.31.sub.2, —CN, —SO.sub.n31R.sup.31A, —SO.sub.v31NR.sup.31AR.sup.31B, —NHC(O)NR.sup.31AR.sup.31B, —N(O).sub.m13, —NR.sup.31AR.sup.31B, —NHNR.sup.31AR.sup.31B, —C(O)R.sup.31A, —C(O)—OR.sup.31A, —C(O)NR.sup.31AR.sup.31B, —C(O)NHNR.sup.31AR.sup.31B, —OR.sup.31A, —NR.sup.31ASO.sub.2R.sup.31B, —NR.sup.31AC(O)R.sup.31B, —NR.sup.31AC(O)OR.sup.31B, —NR.sup.31AOR.sup.31B, —N.sub.3, 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.sup.32 is selected from hydrogen, halogen, —CX.sup.33.sub.3, —CHX.sup.32.sub.2, —CH.sub.2X.sup.32, —OCX.sup.33.sub.3, —OCH.sub.2X.sup.32, —OCHX.sup.32.sub.2, —CN, —SO.sub.n32R.sup.32A, —SO.sub.v32NR.sup.32AR.sup.32B, —NHC(O)NR.sup.32AR.sup.32B, —N(O).sub.m32, —NR.sup.32AR.sup.32B, —NHNR.sup.32AR.sup.32B, C(O)R.sup.32A, —C(O)—OR.sup.32A, —C(O)NR.sup.32AR.sup.32B, —C(O)NHNR.sup.32AR.sup.32B, OR.sup.32A, —NR.sup.32ASO.sub.2R.sup.32B, —NR.sup.32AC(O)R.sup.32B, —NR.sup.32AC(O)OR.sup.32B, —NR.sup.32AOR.sup.32B, —N.sub.3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted and unsubstituted heteroaryl; R.sup.33 is selected from hydrogen, halogen, —CX.sup.33.sub.3, —CHX.sup.33.sub.2, —CH.sub.2X.sup.33, —OCX.sup.33.sub.3, —OCH.sub.2X.sup.33, —OCHX.sup.33.sub.2, —CN, —SO.sub.n33R.sup.33A, —SO.sub.v33NR.sup.33AR.sup.33B, —NHC(O)NR.sup.33AR.sup.33B, —N(O).sub.m33, —NR.sup.33AR.sup.33B, —NHNR.sup.33AR.sup.33B, —C(O)R.sup.33A, —C(O)—OR.sup.33A, —C(O)NR.sup.33AR.sup.33B, —C(O)NHNR.sup.33AR.sup.33B, —OR.sup.33A, —NR.sup.33ASO.sub.2R.sup.33B, —NR.sup.33AC(O)R.sup.33B, —NR.sup.33AC(O)OR.sup.33B, —NR.sup.33AOR.sup.33B, —N.sub.3, 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.sup.34 is selected from hydrogen, halogen, —CX.sup.34.sub.3, —CHX.sup.34.sub.2, —CH.sub.2X.sup.34, —OCX.sup.34.sub.3, —OCH.sub.2X.sup.34, —OCHX.sup.34.sub.2, —CN, —SO.sub.n34R.sup.34A, —SO.sub.v34NR.sup.34AR.sup.34B, —NHC(O)NR.sup.34AR.sup.34B, —N(O).sub.m34, —NR.sup.34AR.sup.34B, —NHNR.sup.34AR.sup.34B, —C(O)R.sup.34A, —C(O)—OR.sup.34A, —C(O)NR.sup.34AR.sup.34B, —C(O)NHNR.sup.34AR.sup.34B, —OR.sup.34A, —NR.sup.34ASO.sub.2R.sup.34B, —NR.sup.34AC(O)R.sup.34B, —NR.sup.34AC(O)OR.sup.34B, —NR.sup.34AOR.sup.34B, —N.sub.3, 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.sup.35 is selected from hydrogen, halogen, —CX.sup.35.sub.3, —CHX.sup.35.sub.2, —CH.sub.2X.sup.35, —OCX.sup.35.sub.3, —OCH.sub.2X.sup.35, —OCHX.sup.35.sub.2, —CN, —SO.sub.n35R.sup.35A, —SO.sub.v35NR.sup.35AR.sup.35B, —NHC(O)NR.sup.35AR.sup.35B, —N(O).sub.m35, —NR.sup.35AR.sup.35B, —NHNR.sup.35AR.sup.35B, C(O)R.sup.35A, —C(O)—OR.sup.35A, —C(O)NR.sup.35AR.sup.35B, —C(O)NHNR.sup.35AR.sup.35B, OR.sup.35A, —NR.sup.35ASO.sub.2R.sup.35B, —NR.sup.35AC(O)R.sup.35B, —NR.sup.35AC(O)OR.sup.35B, —NR.sup.35AOR.sup.35B, —N.sub.3, 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; Each R.sup.1A, R.sup.1B, R.sup.3A, R.sup.3B, R.sup.4A, R.sup.4B, R.sup.6A, R.sup.6B, R.sup.7A, R.sup.7B, R.sup.9A, R.sup.9B, R.sup.10A, R.sup.10B, R.sup.11A, R.sup.11B, R.sup.17A, R.sup.17B, R.sup.18A, R.sup.18B, R.sup.19A, R.sup.19B, R.sup.20A, R.sup.20B, R.sup.21A, R.sup.21B, R.sup.22A, R.sup.22B, R.sup.23A, R.sup.23B, R.sup.24A, R.sup.24B, R.sup.25A, R.sup.25B, R.sup.26A, R.sup.26B, R.sup.27A, R.sup.27B, R.sup.28A, R.sup.28B, R.sup.29A, R.sup.29B, R.sup.30A, R.sup.30B, R.sup.31A, R.sup.31B, R.sup.32A, R.sup.32B, R.sup.33A, R.sup.33B, R.sup.34A, R.sup.34B, R.sup.35A, R.sup.35B is independently selected from hydrogen, —CX.sub.3, —CHX.sub.2, —CH.sub.2X, —C(O)OH, —C(O)NH.sub.2, —CN, —OH, —NH.sub.2, —COOH, —CONH.sub.2, —NO.sub.2, —SH, —SO.sub.3H, —SO.sub.4H, —SO.sub.2NH.sub.2, —NHNH.sub.2, —ONH.sub.2, —NHC═(O)NHNH.sub.2, —NHC═(O)NH.sub.2, —NHSO.sub.2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX.sub.3, —OCHX.sub.2, —OCH.sub.2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1A and R.sup.1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.2A and R.sup.2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.4A and R.sup.4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.6A and R.sup.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.sup.7A and R.sup.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.sup.9A and R.sup.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.sup.13A and R.sup.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.sup.14A and R.sup.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.sup.15A and R.sup.15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.16A and R.sup.16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.17A and R.sup.17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.18A and R.sup.18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R.sup.19A and R.sup.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.sup.20A and R.sup.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.sup.21A and R.sup.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.sup.22A and R.sup.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.sup.23A and R.sup.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.sup.24A and R.sup.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.sup.25A and R.sup.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.sup.26A and R.sup.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.sup.27A and R.sup.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.sup.28A and R.sup.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.sup.29A and R.sup.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.sup.30A and R.sup.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 m1, m3, m4, m6, m7, m9, m10, m11, m17, m18, m19, m20, m21, m22, m23, m24, m25, m26, m27, m28, m29, m30, m31, m32, m33, m34 and m35 is independently 1 or 2; Each v1, v3, v4, v6, v7, v9, v10, v11, v17, v18, v19, v20, v21, v22, v23, v24, v25, v26, v27, v28, v29, v30, v31, v32, v33, v34 and v35 is independently 1 or 2; Each n1, n3, n4, n6, n7, n9, n10, n11, n17, n18, n19, 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 Each X.sup.1, X.sup.3, X.sup.4, X.sup.6, X.sup.7, X.sup.9, X.sup.10, X.sup.11, X.sup.17, X.sup.18, X.sup.19, X.sup.20, X.sup.21, X.sup.22, X.sup.23, X.sup.24, X.sup.25, X.sup.26, X.sup.27, X.sup.28, X.sup.29, X.sup.30, X.sup.31, X.sup.32, X.sup.33, X.sup.34, and X.sup.35 is independently —Cl, —Br, —I or —F.
29. Compound of claim 28 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, midazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein Ring B is optionally substituted with one or more substituents.
30. Compound of claim 28 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.
31. Compound of claim 28 wherein ring B is selected from selected from ##STR00517##
32. Compound of claim 28 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.
33. Compound of claim 28 wherein ring B is selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl, wherein ring B is optionally substituted with one or more substituent groups.
34. Compound of any one of claims 28-33 wherein E is selected from —C(═O)CH═CH.sub.2, —C(═O)-ethynyl, —C(═O)CH═CHCF.sub.3, —C(═O)CH═CHCHF.sub.2, —C(═O)CH═CHCH.sub.2F, and —C(═O)CH.sub.2Br.
35. Compound of any one of claims 28-34 wherein W is S.
36. Compound of any one of claims 28-35 wherein R.sup.10 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl; and R.sup.11 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl.
37. A pharmaceutical composition, comprising the compound of any one of claims 1-36 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
38. A method of inhibiting E1 in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 1-36 or a composition of claim 37.
39. The method of claim 38 wherein said compound is administered at a rate approximately equal to the half life of an E1 enzyme.
40. The method of claim 38, wherein said compound is covalently attached to an E1 cysteine amino acid corresponding to Cys30 of Uba2 subunit 2.
41. The method of one of claims 38-40, wherein E comprises an electrophilic moiety.
42. The method of one of claims 38-41, wherein E contains a moiety that is at least sufficiently electron withdrawing to allow said compound to covalently bind to an E1 cysteine amino acid corresponding to Cys30 of Uba2 subunit 2, wherein said E1 cysteine amino acid is bound to carbon attached to R.sup.17 and R.sup.19.
43. The method of one of claims 38-42, wherein said compound covalently binds to an E1 cysteine amino acid corresponding to Cys30 of Uba2 subunit 2; and forms a complex of formula: ##STR00518##
44. A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 1-36 or a composition of claim 37.
45. A method of inhibiting cell proliferation in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims claims 1-36 or a composition of claim 37.
46. The method of claim 45 wherein the cancer is selected from multiple myeloma, head and neck cancer, stomach cancer, renal cancer, prostate cancer, melanoma or endometrial cancer.
47. The method of claim 45 wherein the cancer is NHL.
48. A method of identifying novel druggable sites in therapeutic target 6 proteins, said method comprising contacting a protein with a compound of one of claims 1 to 36.
49. A method of treating cancer in a mammal comprising administering to said mammal an effective amount of a dual SUMO E1/atg7 inhibitor; or a dual SUMO E1/Nedd8 inhibitor.
50. The method of claim 38, wherein said compound is covalently attached to a cysteine amino acid in an E1 corresponding to Uba1, Uba2, Uba3, Uba4, Uba7 or Atg7.
Description
EXAMPLES
Example 1
[0637] ##STR00218##
1-(6-bromo-4-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
Step A—Preparation of 2-((4-bromobenzyl)amino)-1-(2-chlorophenyl)ethan-1-one
[0638] ##STR00219##
[0639] To a mixture of (4-bromophenyl)methanamine (20 mmol), potassium carbonate (60 mmol) in acetonitrile (50 mL) was added 2-bromo-1-(2-chlorophenyl)ethan-1-one (20 mmol) under argon. After two hours, the mixture was filtered and the filtrate was concentrated in vacuo to give a crude mixture that was used directly for next step without further purification. MS (ES+): 338.0, 339.9 (M+H).
Step B—Preparation of 2-((4-bromobenzyl)amino)-1-(2-chlorophenyl)ethan-1-ol
[0640] ##STR00220##
[0641] To a mixture of 2-((4-bromobenzyl)amino)-1-(2-chlorophenyl)ethan-1-one (20 mmol) in methanol (50 mL) was added sodium borohydride (20 mmol). After one hour, the mixture was concentrated in vacuo and the residue was extracted between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified via flash chromatography to give 2.3 g (7.1 mmol) of the desired product. MS (ES+): 339.7, 341.7 (M+H).
Step C—Preparation of 6-bromo-4-(2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline
[0642] ##STR00221##
[0643] To a mixture of 2-((4-bromobenzyl)amino)-1-(2-chlorophenyl)ethan-1-ol (7 mmol) in dichloromethane (30 mL) was added methanesulfonic acid (35 mmol), and the mixture was heated at 70° C. for two hours. The mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate aqueous solution saturated until pH>8. The mixture then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified via flash chromatography to give 0.6 g (7.1 mmol) of the desired product. MS (ES+): 321.8, 323.8 (M+H).
Step D—Preparation of 1-(6-bromo-4-(2-chlorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
[0644] To a mixture of 6-bromo-4-(2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.25 mmol), NN-diisopropylethylamine (0.75 mmol) in dichloromethane (3 mL) was added acryloyl chloride (0.25 mmol). After 5 min, the mixture was quenched with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified with preparative thin-layer chromatography to give 80 mg (0.21 mmol) of the desired product. MS (ES+): 375.8, 377.8 (M+H).
Example 2
[0645] ##STR00222##
1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
Step A—Preparation of (E)-2-(((5-chlorothiophen-2-yl)methyl)imino)-1-(o-tolyl)ethan-1-ol
[0646] ##STR00223##
[0647] To a mixture of 5-chlorothiophene-2-carbaldehyde (1.65 mmol), 2-amino-1-(o-tolyl)ethan-1-ol (1.65 mmol) in dichloromethane (20 mL) was added anhydrous magnesium sulfate (6 mmol). The mixture was heated at 50° C. under argon for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a crude mixture that was used directly for next step without further purification. MS (ES+): 279.8, 281.8 (M+H).
Step B—Preparation of 2-(((5-chlorothiophen-2-yl)methyl)amino)-1-(o-tolyl)ethan-1-ol
[0648] ##STR00224##
[0649] To a mixture of (E)-2-(((5-chlorothiophen-2-yl)methyl)imino)-1-(o-tolyl)ethan-1-ol (1.65 mmol) in methanol (30 mL) was added sodium borohydride (1.65 mmol). After one hour, the mixture was concentrated in vacuo and the residue was extracted between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified via flash chromatography to give 400 mg (1.42 mmol) of the desired product. MS (ES+): 282.0, 284.0 (M+H).
Step C—Preparation of 2-chloro-4-(o-tolyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
[0650] ##STR00225##
[0651] To a mixture of 2-(((5-chlorothiophen-2-yl)methyl)amino)-1-(o-tolyl)ethan-1-ol (1.42 mmol) in dichloromethane (10 mL) was added methanesulfonic acid (10 mmol), and the mixture was heated at 90° C. for two hours. The mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate aqueous solution saturated until pH>8. The mixture then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified via flash chromatography to give 0.16 g (0.6 mmol) of the desired product. MS (ES+): 263.8, 265.8 (M+H).
Step D—Preparation of 1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
[0652] To a mixture of 2-chloro-4-(o-tolyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.38 mmol), N,N-diisopropylethylamine (0.114 mmol) in dichloromethane (3 mL) was added acryloyl chloride (0.38 mmol). After 5 min, the mixture was quenched with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified by preparative thin-layer chromatography to give 30 mg (0.1 mmol) of the desired product. MS (ES+): 318.0, 320.0 (M+H).
Example 3
[0653] ##STR00226##
(E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4,4,4-trifluorobut-2-en-1-one
[0654] 4,4,4-Trifluorocrotonic acid (11.0 mg, 0.08 mmol), DIPEA (0.26 mL, 0.15 mmol), and HATU (43.0 mg, 0.11 mmol) was added to a round bottom flask and dissolved in dichloromethane (2 mL). The mixture was stirred at r.t. for 15 min. 2-chloro-4-(o-tolyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (20.0 mg, 0.08 mmol) was added to the mixture and stirred for 3 h. The mixture was diluted with dichloromethane (5 mL) and was then washed with sat. NH.sub.4Cl solution (5 mL) and the organic layer was separated. The organic liquor was then washed with sat. NaHCO.sub.3 solution (5 mL), separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude oil was then dissolved in dichloromethane (1 mL) and purified by prep TLC (30% ethyl acetate/hexanes) to give the final product as a white solid (19 mg). LC-MS Calcd for C.sub.18H.sub.16ClF.sub.3NOS 386.84 [M+H].sup.+, found 386.1 [M+H].sup.+.
Example 4
[0655] ##STR00227##
2-chloro-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1-one
[0656] 2-Chloro-4-(o-tolyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (20 mg, 0.08 mmol) and DIPEA (0.26 mL, 0.19 mmol) was dissolved in dichloromethane (2 mL) and stirred at 0° C. Chloroacetylchloride (0.07 mL, 0.152 mmol) was added to the mixture dropwise and stirred for 10 min. The mixture was then diluted with ethyl acetate (5 mL) and washed with sat. NaHCO.sub.3 solution (5 mL). The organic layer was then separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude oil was diluted in dichloromethane (1 mL) and purified by prep TLC (40% ethyl acetate/Hexanes) to give the final product as a yellow oil (45 mg). LC-MS Calcd for C.sub.16H.sub.15Cl.sub.2NOSNa 363.26 [M+Na].sup.+, found 363.7 [M+Na].sup.+.
Example 5
[0657] ##STR00228##
Step A—Preparation of (E)-4,4-difluorobut-2-enoic Acid
[0658] ##STR00229##
[0659] Ethyl (E)-4,4-difluorobut-2-enoate (258 mg, 2.11 mmol) was stirred in a 10% NaOH solution (3 mL) at 50° C. for 16 h. 0.5 N HCl solution was added the mixture until a pH of 1 was achieved. The mixture was then extracted with ethyl acetate (5×5 mL). The organic liquor was dried over MgSO.sub.4 and concentrated in vacuo to give a yellow oil, (227 mg). The crude product was then used in the next reaction without purification.
Step B—Preparation of (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4,4-difluorobut-2-en-1-one
[0660] (E)-4,4-difluorobut-2-enoic acid (10.0 mg, 0.08 mmol), HATU (43.0, 0.11 mmol), and DIPEA (0.26 mL, 1.49 mmol) was dissolved in 2 mL of dichloromethane. The mixture was stirred at r.t. for 15 min. The amine 17-117 was added to the mixture and stirred at r.t. for 2 h. Upon completion, the mixture was diluted with ethyl acetate (5 mL) washed with 0.5 N HCl (5 mL) and separated. The organic layer was then dried over MgSO.sub.4 and concentrated in vacuo. The crude oil was then dissolved in dichloromethane (1 mL) and purified by prep TLC (40% ethyl acetate/hexanes) to give the final product as a clear oil (18 mg). LC-MS Calcd for C.sub.18H.sub.16ClF.sub.2NOSNa 390.84 [M+Na].sup.+, found 389.8 [M+Na].sup.+.
Example 6
[0661] ##STR00230##
(E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-fluorobut-2-en-1-one
Step A—Preparation of ethyl (E)-4-fluorobut-2-enoate
[0662] ##STR00231##
[0663] Ethyl-4-bromocrotonate (500 mg, 2.59 mmol) and AgF (990 mg, 7.77 mmol) was dissolved in MeCN (5 mL) and stirred in the dark at RT for 24 h. The mixture was filtered through a Celite pad and washed with dichloromethane. The organic liquor was concentrated in vacuo and used in the next reaction without further purification.
Step B—Preparation of (E)-4-fluorobut-2-enoic Acid
[0664] ##STR00232##
[0665] The crude ethyl (E)-4-fluorobut-2-enoate was dissolved in methanol (5 mL) and KOH (290 mg, 5.18 mmol) was added to the mixture and stirred for 16 h. 0.5 N HCl was added to the mixture until a pH of 3 was achieved. The mixture was then extracted with ethyl acetate (5×10 mL), separated, and dried over MgSO.sub.4. The organic liquor was then concentrated in vacuo to give the crude product as a yellow oil (380 mg). The product was used in the next reaction without further purification.
Step C—Preparation of (E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-fluorobut-2-en-1-one
[0666] The crude (E)-4-fluorobut-2-enoic acid (7.99 mg, 0.08 mmol), DIPEA (0.26 mL, 0.15 mmol), and HATU (43.0 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and stirred for 10 min. The amine 17-117 (20.0 mg, 0.08 mmol) was added to the mixture and stirred at r.t. for 3 h. The mixture was diluted with dichloromethane (5 mL) and washed with 0.5 N HCl (5 mL). The organic layer was separated and then washed with sat. NaHCO.sub.3 solution (5 mL). The organic layer was separated, dried over MgSO.sub.4 and concentrated in vacuo. The crude product was then dissolved in dichloromethane (1 mL) and purified by prep TLC (40% ethyl acetate/hexanes) to give both the product (6.34 mg). LC-MS Calcd for C.sub.18H.sub.17ClFNOS 349.85 [M].sup.+, found 349.8 [M].sup.+.
Example 7
[0667] ##STR00233##
N-(4-(o-tolyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)acrylamide
Step A—Preparation of 1-(thiophen-2-yl)propan-2-one
[0668] ##STR00234##
[0669] 2-(Thiophen-2-yl)acetic acid (1.00 g, 9.79), Ac.sub.2O (5.15 mL, 39.2 mmol), and N-methylimidazole (0.78 mL, 9.79 mmol), was stirred at 50° C. for 1 h. Upon completion, 10% KOH solution was added to the mixture. The mixture was extracted with ethyl acetate (15 mL) and separated. The organic layer was then washed with sat. NH.sub.4Cl solution (20 mL) and separated. The organic layer was then washed with sat. NaHCO.sub.3 solution (20 mL), separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude oil was used in the next reaction without further purification.
Step B—Preparation of (E)-1-(thiophen-2-yl)-4-(o-tolyl)but-3-en-2-one
[0670] ##STR00235##
[0671] 2-methylbenzaldehyde (1.25 mL, 10.8 mmol) and KOH (82.0 mg, 1.47 mmol) was added to 40 mL of water and heated to 60° C. 1-(thiophen-2-yl)propan-2-one was added to the mixture dropwise and stirred for 16 h. The reaction was then quenched with sat. NH.sub.4Cl solution (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was separated and washed with sat. NaHCO.sub.3 solution (10 mL). The organic layer was separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude product was purified by silica flash column chromatography (0-20% ethyl acetate/hexanes) to give the product as a yellow oil (504 mg). LC-MS Calcd for C.sub.15H.sub.14OSNa 265.34 [M+Na].sup.+, found 264.9 [M+Na].sup.+.
Step C—Preparation of 4-(o-tolyl)-4,7-dihydrobenzo[b]thiophen-6(5H-one
[0672] ##STR00236##
[0673] (E)-1-(Thiophen-2-yl)-4-(o-tolyl)but-3-en-2-one (0.83 g, 3.40 mmol) was dissolved in dichloromethane (150 mL). AlCl.sub.3 (6.00 g, 44.9 mmol) was added to the mixture and stirred for 2 h. The mixture was then quenched with sat. Rochelle's salt solution. The mixture was separated, further extracted with dichloromethane (2×50 mL) and dried over MgSO.sub.4. The organic layer was concentrated in vacuo and purified by silica column flash chromatography (0-40% ethyl acetate/hexanes) to give the product as a yellow solid. LC-MS Calcd for C.sub.15H.sub.14OSNa 265.34 [M+Na].sup.+, found 267.0 [M+Na].sup.+.
Step D—Preparation of 4-(o-tolyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-amine
[0674] ##STR00237##
[0675] 4-(o-Tolyl)-4,7-dihydrobenzo[b]thiophen-6(5H)-one (177 mg, 0.73 mmol) was dissolved in a dichloromethane:methanol mixture (2:1, 15 mL). Ammonium formate (164 mg, 2.92 mmol), p-TsOH (12.5 mg, 0.07 mmol), and mol sieves were added to the mixture and stirred for 14 h. NaBH.sub.4 (55.3 mg, 1.46 mmol) was added to the mixture slowly and stirred for 1 h. 1 N HCl (3 mL) was added the mixture. The mixture was then extracted with ethyl acetate (20 mL) and separated. The organic layer was then washed with a sat. NaHCO.sub.3 solution (20 mL), separated, and dried over MgSO.sub.4. The organic liquor was then concentrated in vacuo and purified by silica flash column chromatography to give the product as a yellow oil (72 mg). LC-MS Calcd for C.sub.15H.sub.17NSNa 266.37 [M+Na].sup.+, found 266.9 [M+Na].sup.+.
Step E—Preparation ofN-(4-(o-tolyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)acrylamide
[0676] 4-(o-Tolyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-amine (20 mg, 0.08 mmol) and DIPEA (0.04 mL, 0.25 mmol) was dissolved in dichloromethane (1 mL). Acryloyl chloride (0.01 mL, 0.12 mmol) was added to the mixture dropwise and stirred for 10 min. The mixture was then diluted with dichloromethane (5 mL) and washed with sat. NaHCO.sub.3 solution (5 mL). The organic layer was then separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude oil was diluted in dichloromethane (1 mL) and purified by prep TLC (50% ethyl acetate/hexanes) to give the final product as a yellow oil (3.5 mg). LC-MS Calcd for C.sub.18H.sub.19NOS 297.42 [M].sup.+, found 297.2 [M].sup.+.
Example 8
[0677] ##STR00238##
1-(4-([1,1′-biphenyl]-2-yl)-2-chloro-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
Step A—Preparation of Boc-protected 2-amino-1-(2-bromophenyl)ethan-1-one
[0678] ##STR00239##
[0679] To a mixture of di-tert-butyl iminodicarboxylate (3.9 g, 18 mmol) in dry DMF (25 mL) was added NaH (1 g, 60% oil suspension) and the resulting mixture was stirred under argon for 2 hours. 2-bromo-1-(2-bromophenyl)ethan-1-one (5 g, 18 mmol) in DMF (25 mL) was added and the mixture was stirred under argon overnight. The mixture was quenched with 200 mL saturated NH.sub.4Cl solution (aq.) and then extracted with ethyl acetate (200 mL). The organic layer was washed with brine, then dried over MgSO.sub.4. After concentration in vacuo, flash chromatography was used to isolate 4.4 g of the desired product.
Step B—Preparation of Boc-protected 1-([1,1′-biphenyl]-2-yl)-2-aminoethan-1-one
[0680] ##STR00240##
[0681] Boc-protected 2-amino-1-(2-bromophenyl)ethan-1-one (828 mg, 2 mmol), phenylboronic acid (268 mg, 2.2 mmol), K.sub.3PO.sub.4 (1.4 g, 6.6 mmol) and PdCl.sub.2(dppf) (74 mg, 0.1 mmol) were mixed in dioxane (30 mL) and DI water (10 mL) and the mixture was heated at 90° C. under argon overnight. The mixture was then concentrated and purified by flash chromatography to give 690 mg yellow oil.
Step C—Preparation of 1-([1,1′-biphenyl]-2-yl)-2-aminoethan-1-one
[0682] ##STR00241##
[0683] Boc-protected 1-([1,1′-biphenyl]-2-yl)-2-aminoethan-1-one (690 mg, 3.3 mmol) was dissolved in 14 mL dichloromethane, then 6 mL TFA was added and the mixture was stirred at room temperature for 10 min. The mixture was concentrated under high vacuum and the resulting crude product was used directly for next step.
Step D—Preparation of 1-([1,1′-biphenyl]-2-yl)-2-aminoethan-1-ol
[0684] ##STR00242##
[0685] 1-([1,1′-Biphenyl]-2-yl)-2-aminoethan-1-one (3.3 mol) was dissolved in methanol (5 mL), then NaBH.sub.4 (123 mg, 3.3 mol) was added and the mixture was left at room temperature for 30 min. After removal of the solvent, the mixture was partitioned between ethyl acetate (30 mL) and saturated NaHCO.sub.3 solution (30 mL, aq.). The organic phase was dried over MgSO.sub.4 and then concentrated. Flash chromatography on silica gel yielded 100 mg of the title compound as a light yellow oil. MS (ES+): 214.0, 215.1 (M+H).
Step E—Preparation of (E)-1-([1,1′-biphenyl]-2-yl)-2-(((5-chlorothiophen-2-yl)methylene)amino)ethan-1-ol
[0686] ##STR00243##
[0687] 1-([1,1′-Biphenyl]-2-yl)-2-aminoethan-1-ol (100 mg, 0.47 mmol), 5-chlorothiophene-2-carbaldehyde (70 mg, 0.47 mmol), MgSO.sub.4 (240 mg, 2 mmol) were mixed in dichloromethane and heated at 50° C. for 3 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to give a crude product.
Step F—Preparation of 1-([1,1′-biphenyl]-2-yl)-2-(((5-chlorothiophen-2-yl)methyl)amino)ethan-1-ol
[0688] ##STR00244##
[0689] (E)-1-([1,1′-Biphenyl]-2-yl)-2-(((5-chlorothiophen-2-yl)methylene)amino)ethan-1-ol (0.47 mmol) was dissolved in methanol (20 mL), then sodium borohydride (0.47 mmol) was added, and the mixture was left at room temperature for 30 min. After removal of the solvent, the mixture was partitioned between ethyl acetate (30 mL) and saturated NaHCO.sub.3 solution (30 mL, aq.). The organic phase was dried over MgSO.sub.4 and then concentrated. Flash chromatography on silica gel yielded 22 mg of the title as white solid. MS (ES+): 343.9, 346.0 (M+H).
Step G—Preparation of 4-([1,1′-biphenyl]-2-yl)-2-chloro-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
[0690] ##STR00245##
[0691] 1-([1,1′-Biphenyl]-2-yl)-2-(((5-chlorothiophen-2-yl)methyl)amino)ethan-1-ol (0.064 mmol) was mixed with methanesulfonic acid (0.45 mmol), and the mixture was heated at 80° C. for two hours. The mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate aqueous solution saturated until pH>8. The mixture then extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified with preparative TLC to give 8 mg (0.025 mmol) of the desired product. MS (ES+): 325.8, 327.8 (M+H).
Step H—Preparation of 1-(4-([1,1′-biphenyl]-2-yl)-2-chloro-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
[0692] To a mixture of 4-([1,1′-biphenyl]-2-yl)-2-chloro-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (6 mg, 0.018 mmol), N,N-diisopropylethylamine (7 mg, 0.055 mmol) in dichloromethane (3 mL) was added acryloyl chloride (1.6 mg, 0.018 mmol). After 5 min, the mixture was quenched with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The crude mixture was purified via preparative thin-layer chromatography to give 2 mg (0.005 mmol) of the desired product. MS (ES+): 379.8, 381.8 (M+H).
Example 9
[0693] ##STR00246##
(E)-4-bromo-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)but-2-en-1-one
Step A—Preparation of (E)-4-bromobut-2-enoic Acid
[0694] ##STR00247##
[0695] At 0° C., ethyl-4-bromocrotonate (300 m g, 1.55 mmol) and LiOH—H.sub.2O (65 mg, 1.55 mmol) was mixed in THF (10 mL) and DI water (10 mL) for 2 hours, then 1N HCl was added to the mixture until a pH of 1 was achieved. The mixture was then extracted with ethyl acetate (5×10 mL), separated, and dried over MgSO.sub.4. The organic liquor was then concentrated in vacuo to give the crude product as a yellow oil (200 mg, 1.2 mmol). The product was used in the next reaction without further purification. MS (ES−): 163.0, 165.0 (M−H).
Step B—Preparation of (E)-4-bromobut-2-enoyl Chloride
[0696] ##STR00248##
[0697] The crude of (E)-4-bromobut-2-enoic acid (200 mg, 1.2 mmol), was dissolved in SOCl.sub.2 (5 mL) heated to reflux for 2 hours. The mixture was concentrated in vacuo and the crude product was used directly for next step.
Step C—Preparation of (E)-4-bromo-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)but-2-en-1-one
[0698] At 0° C., the crude (E)-4-bromobut-2-enoyl chloride (1.2 mmol) was added to a mixture of 2-chloro-4-(o-tolyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (30 mg, 0.114 mmol), DIPEA (88 mg, 0.684 mmol) in dichloromethane (3 mL) and DMF (2 mL). The mixture was sonicated for 20 min and then partitioned between ethyl acetate (25 mL) and brine (25 mL). The organic layer was dried over MgSO.sub.4 and then concentrated. Preparative TLC was used to isolate 10 mg of desired product.
Example 10
[0699] ##STR00249##
(E)-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-4-(dimethylamino)but-2-en-1-one
[0700] At 0° C., (E)-4-bromo-1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)but-2-en-1-one (10 m g, 0.024 mmol) was mixed with THF (1 mL), then 1 mL of 2 M dimethylamine in THF was added. After 30 min, the mixture was concentrated in vacuo to give the crude product, which was purified by preparative-TLC to give 6 mg of desired product. The product was used in the next reaction without further purification. MS (ES+): 374.8, 376.8 (M+H).
Example 11
[0701] ##STR00250##
1-(7-chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
Step A—Preparation of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile
[0702] ##STR00251##
[0703] Potassium tert-butoxide (2.94 g, 26.2 mmol) was added in one portion to a solution of 2-(4-chlorophenyl)acetonitrile (3.97 g, 26.2 mmol) in DMSO (15 mL). Next, 2-Bromopyridine (1 mL, 10.5 mmol) was added and the vial sealed and heated in a 94° C. heat block for 16 hours. After cooling to room temperature, the reaction was poured into water. The pH of the solution was adjusted to pH=7 with the addition of 10% HCl aq. solution and was extracted with ethyl acetate. The combined organics were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified via column chromatography with 4:1 hexanes/ethyl acetate as eluent to provide the title compound. MS (ES+): 229.1 (M+H).
Step B—Preparation of 2-(4-chlorophenyl)-2-(pyridin-2-yl)ethan-1-amine
[0704] ##STR00252##
[0705] Cobalt(II) chloride hexahydrate (2.62 g, 11.0 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile (4.2 g, 18.4 mmol) in 2:1 THF/water (90 mL) in one portion. The resulting clear solution was cooled in an ice bath for 15 minutes before sodium borohydride (695 mg, 18.4 mmol) was added in one portion. After the initial vigorous reaction, the ice bath was removed and stirred at room temperature. After 20 minutes, an additional portion of sodium borohydride (695 mg, 18.4 mmol) was added and the reaction stirred 20 additional minutes until complete as judged by LC/MS analysis. The reaction was placed in an ice bath and quenched by careful addition of 10% HCl until pH<3. After stirring at room temperature 1 hr., the solution was washed 1× with ethyl acetate and the separated organic layer back extracted 1×10% HCl. The pH of the combined aqueous solutions was adjusted to pH>10 with the addition of solid sodium carbonate and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the intermediate amine titled above. MS (ES+): 232.9 (M+H).
Step C—Preparation of methyl (2-(4-chlorophenyl)-2-(pyridin-2-yl)ethyl)carbamate
[0706] ##STR00253##
[0707] The crude amine product from STEP B above was dissolved in 100 mL of dichloromethane and cooled in an ice bath for 10 minutes before DIPEA (6.4 mL, 36.7 mmol) was added followed by methyl chloroformate (1.4 mL, 18.1 mmol). After 15 min., the reaction was quenched by the addition of saturated NaHCO.sub.3 (aq) and diluted with ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate. The combined organic extracts were washed with saturated NH.sub.4Cl.sub.(aq), brine, dried over sodium sulfate, filtered, and concentrated. The product was purified by filtering through a plug of silica gel with ethyl acetate to afford the titled compound.
Step D—Preparation of methyl 7-chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0708] ##STR00254##
[0709] A screw cap vial was charged with methyl (2-(4-chlorophenyl)-2-(pyridin-2-yl)ethyl)carbamate (300 mg, 1.03 mmol), paraformaldehyde (235 mg, 7.83 mmol), sulfuric acid (0.78 mL) and acetic acid (3.1 mL). The resulting solution was stirred over 48 h before being poured into ice water. The solution was neutralized with solid sodium carbonate and extracted with 2× ethyl acetate and 1× dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography with 1:1 ethyl acetate/hexanes to 2:1 ethyl acetate/hexanes to afford the desired product methyl 7-chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): 303.2 (M+H).
Step E—Preparation of 1-(7-Chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
[0710] ##STR00255##
[0711] Methyl 7-chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (208 mg, 0.69 mmol) was refluxed in 6 N HCl.sub.(aq) 5 mL for 14 hours. Concentrated HCl (2 mL) was added and the reaction refluxed 5 additional hours. The reaction was allowed to cool to room temperature, neutralized by the addition of solid sodium carbonate, and extracted 2× ethyl acetate and 1× dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was taken up in dichloromethane (3 mL) and cooled in an ice bath. DIPEA (0.30 mL, 1.7 mmol) and acryloyl chloride (0.060 mL, 0.74 mmol) were added and the reaction was stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified twice by PTLC with 5% methanol in ethyl acetate as the eluent followed by 5% methanol in dichloromethane as the eluent for the second purification to afford the titled product 1-(7-Chloro-4-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one. MS (ES+): 298.9 (M+H).
Example 12
[0712] ##STR00256##
1-(3-bromo-8-phenyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one
Step A—Preparation of 5-Bromo-2-(cyano(phenyl)methyl)nicotinonitrile
[0713] ##STR00257##
[0714] A screw cap vial was charged with 5-bromo-2-chloronicotinonitrile (0.5 g, 2.30 mmol), 2-phenylacetonitrile (0.650 mL, 5.63 mmol), and cesium carbonate (1.5 g, 4.60 mmol). MeCN was added (10 mL) and the vial was sealed and heated in a heat block set at 60° C. overnight. After cooling to room temperature, the reaction was poured into water and neutralized with 10% HCl.sub.(aq) to a pH of 7 and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography with a 0-25% gradient of ethyl acetate/hexanes. The product was further recrystallized with ethyl acetate and hexanes to afford the title product was a white crystalline product. MS (ES+): 297.9, 299.9 (M+H).
Step B—Preparation of 3-Bromo-8-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine
[0715] ##STR00258##
[0716] To a solution of 5-bromo-2-(cyano(phenyl)methyl)nicotinonitrile (0.200 g, 0.67 mmol) in THF (3.4 mL) cooled to 0° C. in an ice bath was added diisobutylaluminium hydride as a 1.0 M solution in THF (2.7 mL, 2.7 mmol). The reaction was allowed to warm to room temperature and stirred. An additional portion of diisobutylaluminium hydride solution was added (2.0 mL, 2.0 mmol) and the reaction was stirred. The reaction was quenched by the addition of a saturated aqueous solution of Rochelle salt. Solid NaOH was added to adjust the pH to >11 followed by dilution with ethyl acetate and the biphasic mixture was stirred until two clear solutions were observed. The layers were separated, and the aqueous layer extracted 3× ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was used directly for the next reaction. MS (ES+): 301.9, 303.8 (M+H).
Step C—Preparation of 1-(3-bromo-8-phenyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one
[0717] The crude product from STEP B above was taken up in dichloromethane (3 mL) and cooled to 0° C. DIPEA (0.250 mL, 1.44 mmol) followed by acryloyl chloride (0.053 ml, 6.7 mmol) were added and the solution stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC with a 2:1 ethyl acetate/Hexanes mixture as eluent. The product was then further purified by PTLC with 20:1 dichloromethane/methanol as eluent to afford the title product 1-(3-bromo-8-phenyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)prop-2-en-1-one. MS (ES+): 342.7, 344.7 (M+H).
Example 13
[0718] ##STR00259##
1-(2-chloro-4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
Step A—Preparation of 2-cyclohexyl-2-(thiophen-3-yl)acetonitrile
[0719] ##STR00260##
[0720] A solution of 3-thiopheneacetonitrile (1 mL, 9.4 mmol) in THF (40 mL) was cooled for 15 minutes in a −78° C. acetone/dry ice bath before a 1 M solution of NaHMDS in THF (9.4 mL, 9.4 mmol) was slowly added. The resulting solution was stirred 45 minutes before iodocyclohexane (1.5 mL, 11.6 mmol) was added to the dark orange solution. The reaction was stirred 10 minutes before allowing to warm to 0° C. After 1 hr. at this temperature the reaction was quenched with saturated aqueous ammonium chloride and diluted with water and ethyl acetate. The layers were separated, and the aqueous layer extracted 3× ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using 0-15% ethyl acetate in hexanes gradient to afford the titled product 2-cyclohexyl-2-(thiophen-3-yl)acetonitrile.
Step B—Preparation of 2-cyclohexyl-2-(thiophen-3-yl)ethan-1-amine
[0721] ##STR00261##
[0722] A 1 M solution of borane in THF (12 mL, 12 mmol) was added to a solution of 2-cyclohexyl-2-(thiophen-3-yl)acetonitrile (1.23 g, 6 mmol) in THF (30 mL) under argon atmosphere. The reaction was heated to 55° C. overnight before allowing to cool to room temperature. The reaction was placed in an ice bath for 10 minutes before 1 M KOH aqueous solution was slowly added. The mixture was stirred 15 minutes and then extracted with ethyl acetate. The combined organic layers were extracted with 10% aqueous HCl. The combined HCl aqueous extracts was adjusted to pH>10 with 1 N KOH aqueous solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product which was used without further purification. MS (ES+): 210.1 (M+H).
Step C—Preparation of 4-cyclohexyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
[0723] ##STR00262##
[0724] A mixture of 2-cyclohexyl-2-(thiophen-3-yl)ethan-1-amine (0.170 g, 0.83 mmol), 37% aqueous formaldehyde (0.528 mL, 7.1 mmol) acetic acid (0.3 mL) and conc. HCl (5 uL) were heated to 80° C. for 15 minutes. The solution was allowed to cool to room temperature before pouring into aqueous sodium carbonate solution and was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product which was used without further purification. MS (ES+): 221.9 (M+H).
Step D—Preparation of 1-(4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
[0725] ##STR00263##
[0726] The crude product from the previous reaction was taken up in dichloromethane (3 mL) and cooled to 0° C. DIPEA (0.300 mL, 1.73 mmol) followed by acryloyl chloride (0.080 ml, 1.01 mmol) were added and the solution stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-40% ethyl acetate in hexanes to afford the desired product 1-(4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one. MS (ES+): 275.9 (M+H).
Step E—Preparation of 1-(2-chloro-4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
[0727] A solution of 1-(4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one (26 mg, 0.094 mmol) and N-chlorosuccinimide (15 mg, 0.113 mmol) in DMF was heated in a 55° C. heat block for 15 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC with a 2.5:1 hexanes/ethyl acetate mixture as eluent to afford 1-(2-chloro-4-cyclohexyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one. MS (ES+): 309.9 (M+H).
Example 14
[0728] ##STR00264##
1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
Step A—Preparation of 2,2-diphenylpropanenitrile
[0729] ##STR00265##
[0730] A solution of diphenylacetonitrile (2 g, 10.4 mmol) in THF (50 mL) was cooled in an ice bath for 15 minutes. Next, 1 M solution of NaHMDS in THF (12.5 mL, 12.5 mmol) was added and the solution stirred 30 minutes before methyl iodide (0.777 mL, 12.5 mmol) was added and the solution was stirred overnight while coming to room temperature. The reaction was partitioned between ethyl acetate and water. The aqueous solution was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous ammonium chloride solution, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using an eluent of 1:20 ethyl acetate in hexane to afford the desired product 2,2-diphenylpropanenitrile.
Step B—Preparation of 2,2-diphenylpropan-1-amine
[0731] ##STR00266##
[0732] A 1 M solution of borane in THF (9.7 mL, 9.7 mmol) was added to a solution of 2,2-diphenylpropanenitrile (1.0 g, 4.82 mmol) in THF (24 mL) under argon atmosphere. The reaction was heated to 55° C. overnight before allowing to cool to room temperature. The reaction was placed in an ice bath for 10 minutes before 10% sodium carbonate aqueous solution was slowly added. The mixture was stirred 15 minutes and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product which was used without further purification. MS (ES+): 212.1 (M+H).
Step C—Preparation of N-(2,2-diphenylpropyl)-2,2,2-trifluoroacetamide
[0733] ##STR00267##
[0734] A solution of 2,2-diphenylpropan-1-amine (1.0 g, 4.82 mmol) as described above in dichloromethane (25 mL) was cooled to 0° C. Triethylamine (1.34 mL, 9.61 mmol) followed by trifluoroacetic anhydride (0.884 mL, 6.27 mmol) were added and the solution stirred 30 minutes at room temperature before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with saturated ammonium chloride aqueous solution, brine, dried over sodium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography with 20:1 hexanes/ethyl acetate as eluent to afford N-(2,2-diphenylpropyl)-2,2,2-trifluoroacetamide. MS (ES+): 307.9 (M+H).
Step D—Preparation of 2,2,2-trifluoro-1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
[0735] ##STR00268##
[0736] Paraformaldehyde (86 mg, 2.9 mmol) was added portion wise to a solution of N-(2,2-diphenylpropyl)-2,2,2-trifluoroacetamide (590 mg, 1.92 mmol) in a 4:1 mixture of AcOH and H.sub.2SO.sub.4 (7.5 mL). The solution was stirred at room temperature until complete as judged by LC/MS analysis. The reaction was poured into ice water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford the desired product 2,2,2-trifluoro-1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one. MS (ES+): 319.9 (M+H).
Step E—Preparation of 4-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline
[0737] ##STR00269##
[0738] Potassium hydroxide (0.215 g, 3.8 mmol) was added to a solution of 2,2,2-trifluoro-1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (0.340 g, 1.1 mmol) in methanol (7.5 mL) and water (1.5 mL) and the resulting solution stirred for 2 d. The methanol was removed in vacuo and the pH of the solution adjusted to pH<2 with 10% HCl aq solution. The aqueous solution was washed 1×MTBE and the organic layer was back extracted 1×10% aq HCl. The pH of the combined aqueous extracts was adjusted to pH of >11 with solid NaOH and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 4-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline. MS (ES+): 224.2 (M+H).
Step F—Preparation of 1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
[0739] ##STR00270##
[0740] To a solution of 4-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (202 mg, 0.90 mmol) in dichloromethane (4 mL) cooled in an ice bath was added DIPEA (0.30 mL, 1.7 mmol) and acryloyl chloride (0.060 mL, 0.74 mmol) and the reaction was stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC with 1.5/1 hexanes in ethyl acetate as the eluent to give the titled compound 1-(4-methyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one. MS (ES+): 277.9 (M+H).
Example 15
[0741] ##STR00271##
1-(6-ethyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
Step A—Preparation of benzyl 6-bromo-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0742] ##STR00272##
[0743] To a solution of 6-Bromo-4-phenyl-1,2,3,4-tetrahydroisoquinoline (7.5 g, 26.0 mmol), prepared according to methods described by Chennamanenia, N. K.; Arifb, J.; Frederick, S. B.; Gelb, M. H. Bioorganic & Medicinal Chemistry Letters 19 (2009) pp. 6582-6584 starting from 2-amino-1-phenylethan-1-ol and 4-bromobenzaldehyde, in dichloromethane (120 mL) was added triethylamine (7.25 mL, 52.0 mmol) and the solution was cooled in an ice bath for 15 minutes. CBz-Cl (3.67 mL, 26.0 mmol) was added slowly and the solution was stirred at 0° C. for 1 hr. before saturated aqueous sodium bicarbonate was added. The reaction was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford benzyl 6-bromo-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): 422.0, 423.9 (M+H).
Step B—Preparation of benzyl 6-ethyl-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0744] ##STR00273##
[0745] Ethylmagnesium bromide, 3 M solution in THF (0.474 mL, 1.42 mmol) was added to zinc chloride, 1.9 M solution in 2-MeTHF (1.25 mL, 2.38 mmol) and the solution was stirred 30 minutes at room temperature. In a separate vial, benzyl 6-bromo-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.200 mg, 0.47 mmol) and (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (17 mg, 0.023 mmol) were charged and the vial was evacuated and flushed with argon two times. THF was added and the vial was again evacuated and flushed with argon two times. Next, the ethyl zinc chloride solution prepared above was added and the vial was heated in a 90° C. heat block overnight. The reaction was allowed to cool to room temperature and partitioned between water and ethyl acetate and separated. The organic layer was washed with 10% aq HCl and the pH of the combined aqueous layers was adjusted to pH=7 with sodium carbonate. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford benzyl 6-ethyl-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate.
Step C—Preparation of 6-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline
[0746] ##STR00274##
[0747] Palladium hydroxide (4 mg, 0.03 mmol) was added to a solution of benzyl 6-ethyl-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (110 mg, 0.30 mmol) in 1:1 ethanol/ethyl acetate (1.5 mL). The reaction flask was evacuated and flushed with argon three times and then evacuated and flushed with a balloon of hydrogen gas. The reaction was stirred under a balloon of hydrogen until complete by LC/MS and then purged with argon. The reaction was filtered through a celite pad with ethyl acetate and concentrated to afford the desired product 6-ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline. MS (ES+): 238.1 (M+H).
Step D—Preparation of 1-(6-ethyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
[0748] The crude material from the previous reaction was taken up in dichloromethane (2 mL) and cooled in an ice bath. DIPEA (0.15 mL, 0.85 mmol) followed by acryloyl chloride (0.030 mL, 0.36 mmol) was added and the reaction was stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC to give the titled compound 1-(6-ethyl-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one. MS (ES+): 291.9 (M+H).
Example 16
[0749] ##STR00275##
3-(2-acryloyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-4-yl)pyridin-2(1H)-one
Step A—Preparation of 2-(4-chlorophenyl)-2-(2-methoxypyridin-3-yl)acetonitrile
[0750] ##STR00276##
[0751] A screw cap 20 m1 vial with a pressure relief cap was charged with 2-(4-chlorophenyl)acetonitrile (1 g, 6.60 mmol), 3-bromo-2-methoxypyridine (0.829 g, 4.41 mmol), sodium tert-butoxide (1.26 g, 13.1 mmol), palladium(II) acetate (49 mg, 0.22 mmol), and Xantphos (153 mg, 0.264 mmol). The vial was evacuated and flushed with argon three times. Dioxane (10 mL) was added and the vial was again evacuated and flushed with argon three times and then placed in a heat block preheated to 96° C. and stirred overnight. The reaction was allowed to cool to room temperature and poured into water. The pH of the solution was adjusted to pH=7 with 10% HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography with 0-25% ethyl acetate/hexanes as the gradient to afford the title compound. MS (ES+): 258.8 (M+H).
Step B—Preparation of 2-(4-chlorophenyl)-2-(2-methoxypyridin-3-yl)ethan-1-amine
[0752] ##STR00277##
[0753] Cobalt (II) chloride hexahydrate (1.27 g, 5.3 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(2-methoxypyridin-3-yl)acetonitrile (4.2 g, 8.9 mmol) in 2:1 THF/water (60 mL) in one portion. The resulting clear solution was cooled in an ice bath for 15 minutes before sodium borohydride (832 mg, 22.0 mmol) was added in one portion. After the initial vigorous reaction, the ice bath was removed and stirred at room temperature. After 20 minutes, an additional portion of sodium borohydride (832 mg, 22.0 mmol) was added and the reaction stirred 30 additional minutes until complete as judged by LC/MS analysis. The reaction was placed in an ice bath and quenched by careful addition of 10% HCl until pH<3. After stirring at room temperature 1 hr., the solution was washed 1× with ethyl acetate and the separated organic layer back extracted 1×10% HCl. The pH of the combined aqueous solutions was adjusted to pH>10 with the addition of solid sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. MS (ES+): 262.8 (M+H).
Step C—Preparation of methyl (2-(4-chlorophenyl)-2-(2-methoxypyridin-3-yl)ethyl)carbamate
[0754] ##STR00278##
[0755] The product from the previous step was taken up in dichloromethane (40 mL) and cooled in an ice bath for 10 minutes before DIPEA (3.8 mL, 21.8 mmol) was added followed by methyl chloroformate (1.4 mL, 8.80 mmol). After 15 min., the reaction was quenched by the addition of saturated NaHCO.sub.3(aq) and diluted with ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate. The combined organic extracts were washed with saturated NH.sub.4Cl.sub.(aq), brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography with 0-40% ethyl acetate/hexanes as the gradient to afford the title compound. MS (ES+): 320.9 (M+H).
Step D—Preparation of methyl 7-chloro-4-(2-methoxypyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0756] ##STR00279##
[0757] Paraformaldehyde (84 mg, 2.8 mmol) was added portion wise to a solution of methyl (2-(4-chlorophenyl)-2-(2-methoxypyridin-3-yl)ethyl)carbamate (893 mg, 2.78 mmol) in a 4:1 mixture of AcOH and H.sub.2SO.sub.4 (10 mL). The solution was stirred at room temperature overnight and then heated in a 55° C. heat block for 1 hr. until complete as judged by LC/MS analysis. The reaction was poured into ice water, neutralized to a pH=7 with solid sodium carbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford the desired product methyl 7-chloro-4-(2-methoxypyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): 332.9 (M+H).
Step E—Preparation of 3-(2-acryloyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-4-yl)pyridin-2(1H)-one
[0758] Methyl 7-chloro-4-(2-methoxypyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.20 g, 0.6 mmol) was refluxed in 48% aq. HBr (4 mL) overnight. The reaction was concentrated and dichloromethane (4 mL) and DIPEA (0.630 mL, 3.6 mmol) were added. The resulting solution was cooled in an ice bath for 10 minutes before acryloyl chloride (0.050 mL, 0.63 mmol) was added. The reaction was stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC with 5% methanol in ethyl acetate as the eluent to afford the titled product 3-(2-acryloyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-4-yl)pyridin-2(1H)-one. MS (ES+): 314.8 (M+H).
Example 17
[0759] ##STR00280##
1-(7-isobutoxy-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
Step A—Preparation of 2-((4-methoxybenzyl)amino)-1-phenylethan-1-ol
[0760] ##STR00281##
[0761] A mixture of 2-amino-1-phenylethan-1-ol (4.5 g, 32.8 mmol), p-anisaldehyde (4.4 mL, 36.2 mmol), and triethylamine (5.0 mL, 3.59 mmol) was stirred in methanol (125 mL) for 14 hours. The solution was cooled in an ice water bath and sodium borohydride (2.5 g, 6.61 mmol) was added and the reaction was stirred 3.5 hours while warming to room temperature. Saturated aqueous sodium bicarbonate was added and the reaction was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using 1:1 hexanes/ethyl acetate to 20% methanol in ethyl acetate as eluent to afford 2-((4-methoxybenzyl)amino)-1-phenylethan-1-ol. MS (ES+): 258.0 (M+H).
Step B—Preparation of 7-methoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline
[0762] ##STR00282##
[0763] A solution of 2-((4-methoxybenzyl)amino)-1-phenylethan-1-ol (3.0 g, 11.7 mmol) in dichloromethane (78 mL) was slowly added via an addition funnel to a slurry of aluminum trichloride (4.7 g, 35.0 mmol) in dichloromethane (78 mL) at room temperature. After 3 hours stirring an additional portion of aluminum trichloride (1.0 g, 7.5 mmol) was added and reaction was stirred. The reaction was poured into ice water and stirred, the pH of the aqueous layer was adjusted to pH>10 with 1 N NaOH. Solid Rochelle's salt was added, and the biphasic mixture was stirred until two clear layers were present. The layers were separated, and the aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 7-methoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline which was used directly in the next reaction.
Step C—Preparation of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-7-ol
[0764] ##STR00283##
[0765] Boron tribromide (1.67 mL, 1.67 mmol) as a 1 M solution in dichloromethane was added to a solution of 7-methoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.836 mmol) in dichloromethane (3 mL) cooled in an ice bath. The reaction was stirred for 2 hrs. before being quenched with ice water. The pH of the aqueous layer was adjusted to pH=7 with solid sodium carbonate and separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 4-phenyl-1,2,3,4-tetrahydroisoquinolin-7-ol. MS (ES+): 226.0 (M+H).
Step D—Preparation of tert-butyl 7-hydroxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0766] ##STR00284##
[0767] Boc-anhydride (3.1 g, 14.2 mmol) was added to a solution of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-7-ol (3.2 g, 14.2 mmol) in methanol (100 mL) with triethylamine (2.0 mL, 14.32 mmol) at room temperature and the solution was stirred 2 hours. Saturated aqueous ammonium chloride was added and the methanol was removed in vacuo. Ethyl acetate and water were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using 4:1 hexanes/ethyl acetate to afford tert-butyl 7-hydroxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white crystalline solid.
Step E—Preparation of tert-butyl 7-isobutoxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
[0768] ##STR00285##
[0769] A mixture of tert-butyl 7-hydroxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.31 mmol), 1-iodo-2-methylpropane (0.088 mL, 0.77 mmol), and cesium carbonate (300 mg, 0.92 mmol) was stirred at room temperature in MeCN (2 mL) and then heated overnight in a 60° C. heat block. The reaction was allowed to cool to room temperature, filtered, and concentrated. The crude residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography using 4:1 hexanes/ethyl acetate to afford tert-butyl 7-isobutoxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): 404.0 (M+Na).
Step F—Preparation of tert-butyl 7-isobutoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline
[0770] ##STR00286##
[0771] tert-Butyl 7-isobutoxy-4-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 0.18 mmol) was stirred in a 2:1 mixture of dichloromethane and TFA (3 mL) until the reaction was complete as judged by LC/MS. The reaction mixture was concentrated to afford the intermediate product 7-isobutoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline as the TFA salt which was used directly in the next reaction. MS (ES+): 282.0 (M+H).
Step G—Preparation of 1-(7-isobutoxy-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one
[0772] The crude product from the previous step was dissolved in dichloromethane (2 mL) and the solution was cooled in an ice water bath. Acryloyl chloride (0.015 mL, 0.19 mmol) and diisopropylethylamine (0.070 mL, 0.40 mol) were added and the reaction was stirred 30 minutes before being quenched with sat. NaHCO.sub.3 (aq) solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC with 2:1 hexanes in ethyl acetate as the eluent to afford the titled product 1-(7-isobutoxy-4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one. MS (ES+): 336.0 (M+H).
Example 18
[0773] ##STR00287##
1-(2-chloro-5-methyl-4-phenyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one
[0774] 1-(2-chloro-5-methyl-4-phenyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one was prepared as a single diastereomer according to the general procedure for the preparation of 1-(2-chloro-4-(o-tolyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)prop-2-en-1-one as described in EXAMPLE 2 starting from racemic 2-amino-1-phenylpropan-1-ol. MS (ES+): 318.0 (M+H).
Example 19
[0775] When incubating such compounds with the activating enzymes (E1) of ubiquitin, SUMO, Nedd8, Urm1, ISG15 or Atg7, it forms covalent adducts with the specific Cys residue as depicted below. For the compounds provided herein including embodiments thereof, a covalent adduct may be formed with a cysteine amino acid corresponding to a Cys residue highlighted and in bold from Uba1, Uba2, Uba3, Uba4, Uba7 or Atg7 as shown in the sequence alignment below.
TABLE-US-00002 Uba1 (ubiquitin) (SEQ ID NO: 1) LVGAGAIGCELLK Uba2 (SUMO) (SEQ ID NO: 2) VVGAGGIGCELLK Uba3 (Nedd8) (SEQ ID NO: 3) VIGAGGIGCELLK Uba4 (Urm1) (SEQ ID NO: 4) IVGCGGLGCPLAQ Uba7 (ISG15) (SEQ ID NO: 5) LVGAGAIGCELLK Atg7 (Atg8, Atg12) (SEQ ID NO: 6) LLGAGTLGCNVAR
[0776] Compounds are evaluated for their inhibitory effect on activating enzymes (E1) of ubiquitin, SUMO, Nedd8, Urm1, ISG15 or Atg7 using previously reported methods and protocols. One example is in: Allosteric inhibition of ubiquitin-like modifications by a class of inhibitor of SUMO-activating enzyme. Cell Chemical Biology, 26, 1-11, 2019. PMID: 28051857. The results are provided in Table 2.
[0777] Compounds are tested in the following manner. The compound and SUMO E1 are incubated for a predetermined amount of time. UBC9, SUMO1, and ATP are added to the E1-compound mixture and incubated at 37° C. The reaction is quenched with Laemmli Buffer. The UBC9-SUMO1 conjugation is analyzed via SDS gel electrophoresis. The percent inhibition is measured by the intensity of the UBC9-SUMO1 band compared to the no compound control. Activities are listed as compound concentration (uM), preincubation time of E1 with compound (min), and percent inhibition of adduct formation (%). Activities are listed as compound concentration (uM), preincubation time of E1 with compound (min), and percent inhibition of adduct formation (%).
TABLE-US-00003 TABLE 2 Compounds and Biological Activity. SUMO # Structure E1 Atg7 1
[0778] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.