What is claimed:
1. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits
Hsp90, wherein the agent has an 1C50 for cell survival of less than about 20 nM in MV-4-1 1 cells.
2. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits
Hsp90, wherein the agent is at least about 5 times more affective at killing MV -4- 1 1 cells than geldanamycin analogs.
3. The method of Claim 2, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
4. The method of Claim 2, wherein the agent is an antibiotic or derivative thereof.
5. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (T):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
OC(O)NR10RM, -SC(O)NR10R1I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNRI0Rn, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0Ri1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Ri 1, -
NR7C(NR8)NR1ORH, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R11, -SS(0)pNR,oRι i, -NR7S(O)pNR,0R|,, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)-OR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR1ORI ,, -
NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R| ,, -SC(S)NR10RM, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R71 -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10Rn, -NR7C(NR8)NR10R11,
-C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -OP(O)(OR7)2, or -SP(O)(OR7)2;
Rj is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rιo and RM, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rj0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
6. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (II):
(H) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR1OR1 1, -SC(O)NR10Ri i, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRιi, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1L -SS(O)PNR1ORn, -NR7S(O)11NR10R1 ,, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0Rι i, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RM, -SC(NR8)NR10R11, - NR7C(NR8)NR10RI 1, -OP(O)(ORT)2, Or -SP(O)(OR7^; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NRi0R1 I, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)11NR10R1,, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7) -OS(O)PNRI0R1 11 -SS(O)PNR10R1 1, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NRg)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R,,, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(ORT)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7) -S(O)POR7, - NRgS(O)pR7, or -S(O)pNR|0R,,, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -
S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NRgS(O)pR7, or -S(O)pNR|0Ru; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R1O and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R2O, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
7. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III): :
(IH) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)JDH, -S(CH2^SH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10RI I, -NR7C(O)NR10RU, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1U -SS(O)PNR10Rn, -NR7S(O)PNR10R11, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R| ,, -SS(O)pNR10Rn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10R,i, -SS(O)pNR10Rπ, - NR7S(O)pNR,0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1,, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR«)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORH, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, ■ S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R)0 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyt, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rιs is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substitυents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7,
-OS(O)pR7, -S(O)pOR7, -NR8S(O)pR7, or -S(0)pNR,oRιι;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
8. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
(VI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR|0Rιi, -SC(O)NR,0Rιi, -NR7C(O)NRI0RI I, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNRI0R1 L -SS(O)PNRI0R11, -NR7S(O)PNR10R1I, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn3 -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10R1 1, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1), -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)PNR10R1 ,, -NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rn, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri 1, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORn, -SC(NR8)NR1ORn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
9. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Rn, -SC(O)NRi0Ri 1, -NR7C(O)NR10RU, -OC(O)R7, -SC(O)R7, ■ NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rii, -SS(O)pNR,0Rn, -NR7S(O)pNR10Rn, -
OS(0)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10RM, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NRg)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NRe)OR7, -OC(NR8)NR1ORiU -SC(NR8)NR10R11, - NR7C(NR8)NR10R1I, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - OCCHjλ.SH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1I, -SC(O)NR10Ri i, -NR7C(O)NR10RU, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R11, -SS(O)PNR10R11, -NR7S(O)pNR,0RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, -
NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10R1 ,, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R,,, -SC(NR8)NRi0Rn, -
NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R,o and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
10. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
I0Rιi, -SC(O)NR
10Ri
I, -NR
7C(O)NR
10R
H, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRiORi 1, -SCH2C(O)NR10Ru, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)pNR10Rπ, -
OS(O)pOR7> -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10R1 1, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NRj)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SCCNR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR
7CH
2C(O)OR
7, -OCH
2C(O)NR
10R
n, -SCH
2C(O)NR
1OR
11, -
NR
7CH
2C(O)NR
10R
n, -OS(O)
PR
7, -SS(O)
PR
7, -S(O)
POR
7> -NR
7S(O)
PR
7, - OS(O)pNR
10Rii, -SS(O)
pNR
l0R,,, -NR
7S(O)
pNR,
0Rπ, -OS(O)
POR
7, -SS(O)
pOR
7l -NR
7S(O)pOR
7, -NR
7S(O)
PR
7, -OS(0)
pNR,oRu,
- NR
7S(0)
pNR,oRn, -OS(O)
POR
7, -SS(O)
POR
7, -NR
7S(O)
pOR
7) -OC(S)R
7, - 5 SC(S)R
7, -NR
7C(S)R
7, -OC(S)OR
7, -SC(S)OR
7, -
NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ru, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR1ORn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
10 S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(ORT)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
I S an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted 0 cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 5 R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally 0 substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRI0RH, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(OpR7, or -S(O)pNR10Rπ; R26 is a lower alkyl; 5 p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
1. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (DC):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR,0RM, -NR7C(O)NR10RiI, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR,0Rn, -NR7S(O)pNRI0R,i, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)11OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CHj)nOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0Rn, -SS(O)pNR10Rn, -NR7S(O)pNRl0Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rn, -
NR7S(O)PNR10R1 1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR, ,, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-OP(0)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted hetβroaryl or an optionally substituted 8 to 14-membered aryl; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
12. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ky, R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CHz)1nSH, -S(CH2)mNR7H, - OC(0)NR,oRu, -SC(O)NR10RH, -NR7C(O)NR10Rn, . -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri i, -
NR7CH2C(O)NR1ORM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1L -SS(O)PNR1ORI 1, -NR7S(O)PNR10R11, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7J2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR25, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, -
OC(O)NR10R11, -SC(O)NR10Rii, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR|oRπ, -SCH2C(O)NR,0Rι i, - NR7CH2C(0)NR,oRi ι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> -
OS(O)PNR10R1 I, -SS(O)PNR10R11, -NR7S(O)pNR10Rιi, -OS(O)POR7> -SS(O)POR7> -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR)0Rι., -SS(O)PNR1OR1., - NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, • S(O)NHR8, -S(O)2NHR85-OP(O)(OR7),, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
13. A method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)π,SH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORn1 -SS(O)PNR1ORiI, -NR7S(O)PNR10R,,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7) -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R, ,, -SC(S)NR10R,,, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR1,, -SC(NR8)NR10R1 ,, -
NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)raSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0R,,, -SS(O)pNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR1OR11, -
NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NRi0Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI I, -SC(NR8)NR10Rn, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Ru. -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)PNRI0RM; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
14. The method of any one of Claims 1-13, wherein the compound is administered with an additional therapeutic agent.
15. The method of Claim 14, wherein the additional therapeutic agent is an anticancer agent.
16. A method of inducing degradation of a FLT3 kinase in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 20 nM in MV-4-1 1 cells.
17. A method of inducing degradation of a FLT3 kinase in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing MV-4- 1 1 cells than geldanamycin analogs.
18. The method of Claim 17, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
19. The method of Claim 17, wherein the agent is an antibiotic or derivative thereof.
20. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR,0Rii, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7> -NR7S(O)-R7, - OS(O)PNR1ORn5 -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, - OS(O)POR7, -SS(O)pOR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRIORI I, - NR7C(NR8)NR10Ri 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rι ι, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rii, -SS(O)pNR10Rιi, -NR7S(O)-NR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNRI0Rπ, -SS(O)pNRI0R,,, - NR7S(O)pNR10Rπ, -OS(O)POR7> -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI I, -SC(S)NR10RI I, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NR8)NR10Rn, - NR7C(NR8)NRIORI I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R; is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
21. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (II):
(II) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri i, - NR7CH2C(0)NR,oRn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 I5 -SS(O)PNR10R1 1, -NR7S(O)pNR10R,,, - OS(O)POR7, -SS(O)11OR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, •
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SCCNR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NR8)NR10R1 1, - NR7C(NR8)NR1ORM, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri ,, -SCH2C(O)NR10RM, -
NR7CH2C(O)NRi0R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10RM, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR115 -SS(O)PNR10R11, - NR7S(O)PNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0Rn, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR^)OR7, -NR7C(NR8)OR7, -OC(NRe)NR10Rn, -SC(NR8)NR1ORH, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2; R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxy IaI kyl, alkoxyalkyl, guanadino, -NR10R11, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)PR7, or -S(O)pNR10Ru, or two to five sυbstituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri i, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R7, or -S(O)pNR10Rπ; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R2O, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
22. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NRi0Ri i, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCHJC(O)NR10RI 1 , - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10Ru, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR4)OR7, -NR7C(NR8)OR7, -OC(NRe)NR10Rn, -SC(NRe)NRi0RIi, - NR7C(NR8)NR10RI 1, -OP(O)(ORT)2, or -SP(O)(ORT)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0Rπ, -SS(O)pNR10Rt l, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)11NR10RI I5 -SS(O)PNR1ORI 1, - NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10Ri1, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Ri1, -SC(NR8)NRI0RI 1, - NR7C(NR8)NRi0R1 1, -C(O)OH, -C(O)NHR*, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted aikyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri u -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7 , -S(O)POR7, -NR8S(O)PR7, or -S(O)pNRI0Rπ;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
23. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RI I, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7* -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1,, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1OR1 I1 -SS(O)PNR10R1 ,, -NR7S(O)PNR10R11, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORu, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(0)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)inSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)(nSH, -S(CH2)mNR7H, - OC(O)NR10Rιi, -SC(O)NR10Rn, -NR7C(O)NR10Ri 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ru, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R,,, -SS(O)pNR10Ri i, -NR7S(0)pNR,oRi,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1L -SS(O)PNR1ORn, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR4)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Ri1, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R] is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
24. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR10Ri1, -NR7C(O)NR10RM , -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)pNR10Rπ, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR,0R, ,, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NRi0R,,, -SC(NR8)NR10RI 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, -
OC(O)NR10R11, -SC(O)NR10R1,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(0)NR,oR, ι, -OS(O)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 ,, -SS(O)PNR10R11, -NR7S(O)pNR10R, ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7) -NR7S(O)PR7> -OS(O)pNR,0Rii, -SS(O)pNR,0R,,, - NR7S(O)PNR10R11, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI 1, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rj1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
25. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VIH):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substiruents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Ri 1, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1,, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10R, 1 , -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10R1 1, -
NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R.., -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rl l5 -SS(O)pNR10Ru, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, -
NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NRi0R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NRi0R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRgS(O)11R7, or -S(O)PNR10RM ; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
26. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (EX):
(EX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH
5 -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10RM, -SC(O)NR
10R
11, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri u - NR7CH2C(O)NR10R11, -0S(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10Rι., - OS(O)POR7, -SS(0)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NRg)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1 , -SC(NR8)NRI0R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7^;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CHz)1nNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NRi0Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR,0Rn, -NR7S(O)pNRl0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNR)0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)J, or -SP(O)(OR7)2; • Rj is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
27. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (X): [
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
πiSH, -0(CH
2)
H1NR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)JMR
7H, - OC(O)NR
10R
1., -SC(O)NR
10RiI, -NR
7C(O)NR
10R
n, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 11 -SS(O)PNR10R11, -NR7S(O)PNR10RU, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR^)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiU -SC(NR8)NR10Rn, - NR7C(NR8)NR1ORi,, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
0(CH2J111SH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RiI, -SC(O)NR10R11, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10Riι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)PNRi0R1., -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R119 -SS(O)PNR10R11, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)11OR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10RM, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8)-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
28. A method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10RiI, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR|0Rιi, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 I1 -SS(O)-NR10R11, -NR7S(O)PNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NRa)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -OP(O)(ORT)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)roOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, -
OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)
pNR
l0R
n, -SS(O)
pNR
10R
n, -NR
7S(O)
pNR
10R
n> -OS(O)
POR
7, -SS(O)
POR
7,
-NR
7S(O)
POR
7, -NR
7S(O)
PR
7,
- NR
7S(O)pNR
10Ri,, -OS(O)
POR
7, -SS(O)
POR
7, -NR
7S(O)
POR
7, -OC(S)R
7, - SC(S)R
7, -NR
7C(S)R
7, -OC(S)OR
7, -SC(S)OR
7, - NR
7C(S)OR
7, -OC(S)NR
10R
I 1, -SC(S)NR
10R
11, - NR
7C(S)NR
10R
U, -OC(NR
8)R
7, -SC(NR
8)R
7, -NR
7C(NR
8)R
7, -OC(NR
8)OR
7, -
SC(NR
8)OR
7, -NR
7C(NR
8)OR
7, -OC(NR
8)NR
10R
11, -SC(NR
8)NR
10R
11, - NR
7C(NR
3)NR
10R
11, -C(O)OH, -C(O)NHR
8, -C(O)SH, -S(O)OH, -S(O)
2OH, - S(O)NHR
8,
or -SP(O)(OR
7)Z;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NR8S(OpR71 Or -S(O)pNR10Rπ;
R26 is a lower alkyl; ς p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
29. The method of any one of Claims 20-28, wherein the compound is administered with an additional therapeutic agent.
30. The method of Claim 29, wherein the additional therapeutic agent is an anticancer agent.
31. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 20 nM in MV -4-1 1 cells.
32. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing MV-4-1 1 cells than geldanamycin analogs.
33. The pharmaceutical composition of Claim 31 or 32, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
34. The pharmaceutical composition of Claim 31 or 32, wherein the agent is an antibiotic or derivative thereof.
35. The pharmaceutical composition of any one of Claims 3 1 -34, further comprising one or more additional therapeutic agents.
36. The pharmaceutical composition of Claim 35, wherein the additional therapeutic agent is an anticancer agent.
37. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (I):
(D or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ky, R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)nOR7, -NR7S(O)PR7, - OS(O)PNR1ORn5 -SS(O)PNR10R11, -NR7S(O)PNR10R11, - OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RU, -SC(S)NR10R11, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 I, -OP(O)(OR7)2, or -SP(O)(OR7)2; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10RU, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ru, -SCH2C(O)NR10R1 1, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)-R7, - OS(O)11NR10R1 ,, -SS(O)pNR10Rn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rιι, -SS(O)pNRl0R,,, - NR7S(0)pNR,oRu, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORH, - NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; Rs is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R.26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
38. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (II):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR,0Riι, -SC(O)NR,0Rii, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R1 ,, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10RU, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 ,, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR|0Rπ, - NR7CH2C(O)NR10R11, -OS(O)-R7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNRi0R11, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R1 U -SS(O)PNR10R11, - NR7S(O)pNRl0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR,0Ri,, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7) -S(O)POR7, -
NRgS(O)pR7, or -S(O)pNR,0R,,, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0R1 1, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10R,,, -NR8C(O)R7, -SR7, - S(O)PR7? -OS(O)PR7, -S(O)POR7, -NR8S(O)11R^ Or -S(O)11NR1OR11; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R,o and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
39. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (III):
(I") or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ry, R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Ri 1, -SC(O)NR,0Rιi, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R, 1, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10RI , , -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI U -SSCO)11NR1ORI 1, -NR7S(O)11NR10R1 ,, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 I, -SC(S)NR10Ri 1, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RI 1, -
NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -S P(O)(OR7 )2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NRi0R1., -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R, ,, -SCH2C(O)NR10Ri ,, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn, -SS(O)pNR10R, ,, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR1 U -SS(O)PNR10R1 1, - NR7S(O)pNR,0R,i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10R11, -
NR7C(S)NR10Ri1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, - NR7C(NR8)NRi0R1 I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R1O and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7 , -S(O)POR7, -NR8S(O)PR7, or -S(O)pNRl0Rl ι ; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
40. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR,0Rι i, -SC(O)NR10RiI, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)pOR7, -NR7S(O)PR7, - OS(O)PNR10R1^ -SS(O)PNR10R1 1, -NR7S(O)pNRI0R,,, - OS(O)POR7, -SS(O)pOR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 I, -SC(S)NR10R1 I, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RM, - NR7C(NR8)NR10R1 I, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R1 1, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(COpR7, -OS(O)pNR10Rιi, -SS(O)PNRI0RM, - NR7S(O)pNR10R,i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7j -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI I, -SC(S)NR10RI i, - NR7C(S)NR10R1,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi 1, -SC(NR8)NRiOR1,, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl ;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyciyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R| 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyciyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyciyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
41. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI I, -SC(O)NR10RI 1, -NR7C(O)NR10RI 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R,,, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn1 -SS(O)PNR1ORH, -NR7S(O)pNR10Rn, - OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NRi0Rn, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0Rn, -SS(O)PNR10R1 ,, -NR7S(O)PNR,0RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR1 N -SS(O)PNR10R1 ,, - NR7S(O)PNR10Rn, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R?, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORM, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
42. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Rn, -SC(O)NR
10RI I, -NR
7C(O)NR
10RU, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(0)NR,oRn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR1OR1 I, -NR7S(O)PNR10RΠ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R, ,, -
NR7C(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri,, -SC(NR8)NR10R11, - NR7C(NR8)NR10Ri1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CHz)111SH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 ,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10RM, -SS(O)pNR,0Rπ, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally
substitutβd alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7) -NR8S(OpR7, or -S(O)pNR10R,,; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
43. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (IX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, •
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10RI i, - NR7CH2C(O)NR10R,,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)11R7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNR10R, i, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ru, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10RM, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rii, -SS(O)pNRI0Rii, -NR7S(O)pNR,0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(0)pNRιoRι ι, -SS(O)pNRl0Rn, - NR7S(O)11NR10Ri1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NRi0R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
44. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; Ri is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10Ri i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)11NR10R1 I1 -SS(O)PNR10R11, -NR7S(O)11NRi0R1 1, - OS(O)POR7, -SS(O)nOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SCCNR8)NR10R1I, -
NR7C(NR8)NR10R1 ,, -OP(0)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10RM, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R1I? -SS(O)PNR10R11, -NR7S(O)pNR,0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNR10Rιi, -
NR7S(0)pNR,oRi ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1I, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
RIQ and R1 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R1), taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
45. A pharmaceutical composition for treating a FLT3 associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
S or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0 O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R,,, -SC(O)NR10R, 1, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - 5 NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1OR1 11 -SS(O)PNR10R1 1, -NR7S(O)PNRI0RU, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R, ,, -SC(S)NR10Ri1, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NRJ)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - 0 SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rι ι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R11, -SS(O)PNR10R11, -NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, 0 -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNRl0Rπ, -
NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10Ri i, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRIORI 1, -
5 NR7C(NR8)NR10R1 I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR81-OP(O)(OR7):, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
10 cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted I S alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R1], taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or 0 an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alky], wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally 5 substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRI0R1 ,, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)-OR7, -NR8S(O)11R7, or -S(O)pNR10Ru; 30 R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
46. The pharmaceutical composition of any one of Claims 37-45, wherein the 35 pharmaceutical composition comprises an additional therapeutic agent.
47. The pharmaceutical composition of Claim 46, wherein the additional therapeutic agent is an anticancer agent.
48. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 50 nM in AML cell line K.asumi-1, provided that the isolated agent is not a compound disclosed in U.S. Patent Application Serial No. 1 1/282,1 19.
49. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing AML cell line Kasumi-1 than geldanamycin analogs, provided that the isolated agent is not a compound disclosed in U.S. Patent Application Serial No. 1 1/282,1 19.
50. The method of Claim 49, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
51. The method of Claim 49, wherein the agent is an antibiotic or derivative thereof.
52. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
(VI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CH
2)JMR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Rii, -SC(O)NR
10R
11, -NR
7C(O)NR
10RM, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(0)NR,oRi,, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Ri1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn1 -SS(O)11NR10R11, -NR7S(O)PNR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri,, -SC(NR8)NR10Ri 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7).;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, -
OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 1, -SS(O)PNR10R11, -NR7S(O)PNR10R1 1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR1 U -SS(O)PNR10R11, - NR7S(O)pNR10RM, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10RH, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7),, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
53. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(0)NR,oR|,, -SC(O)NR
10R
11, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri ,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR1OR11, -NR7S(O)PNR10RU, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RH, -SC(NR8)NR10RI i, - NR7C(NR8)NR10Ri 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R1 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)PNR10R1., -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNRl0R, ι, -OS(O)POR7, -SS(O)POR7, -NR7S(O)15OR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHRg,-OP(0)(OR7)2, or -SP(0)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ri 1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
54. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substiruents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI I, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)-R7, -SS(O)PR7, -S(O)POR7> -NR7S(O)PR7, - OS(O)PNR1OR1 N -SS(O)PNR10R1 1, -NR7S(O)13NR10R11, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R, ,, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RM, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R1 1, -SC(O)NR10R1 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10Ri1, -SS(O)pNR10Rπ, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)pNR,0Rπ, -SS(O)pNR,0Ru, - NR7S(0)pNR,oRu, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri i, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NRI0RU, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRa,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkeπyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)-R7, -
S(O)POR7, -NR8S(O)11R7, or -S(O)pNR10Rn;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
55. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (DC):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
roOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR,0Rii, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1,, - NR7CH2C(O)NRiORi !, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R,,, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R]1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NRIORI I, -
NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRιi, -SC(O)NRi0R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Ri 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0RM, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)nR7, -OS(O)PNR10R1 U -SS(O)11NR10R11, -
NR7S(O)pNRl0R|,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI I, -SC(S)NR10RI 1, -
NR7C(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R1., - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted hetcroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
56. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI L -SS(O)PNR1ORM, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NRi0Ri1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, ■ SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10RI 1, -
NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR)0R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)PNR10R1 ,, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)pR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNRi0RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Ri 1, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, ■ S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally S substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the 0 nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. 5
57. A method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
0 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - 5 O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(0)NR,oRιi, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, • NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - 0 NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)11NR10R11, -NR7S(O)11NR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7) -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10R11, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI i, -SC(NR8)NR10RM, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR|0Rn, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NRi0R1 1, -OS(O)PR7, -SS(O)PR7, -S(0)POR7, -NR7S(O)PR7, - OS(O)PNR10RM, -SS(O)11NR10R11, -NR7S(O)pNRI0Rn, -OS(0)POR7> -SS(O)POR7) -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)pNRl0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted
cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRgS(O)pR7, or -S(O)PNR10R11 ;
Rj6 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
58. The method of any one of Claims 48-57, wherein the compound is administered with an additional therapeutic agent.
59. The method of Claim 48, wherein the additional therapeutic agent is an anticancer agent.
60. A method of inducing degradation of a c-kit kinase in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits
Hsp90, wherein the agent has an IC50 for cell survival of less than about 50 nM in AML cell line Kasume-1 , provided that the isolated agent is not a compound disclosed in U.S. Patent Application Serial No. 1 1/282,1 19.
61. A method of inducing degradation of a c-kit kinase in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing AML cell line Kasumi-1 than geldanamycin analogs, provided that the isolated agent is not a compound disclosed in U.S. Patent Application Serial No. 1 1/282,1 19.
62. The method of Claim 61 , wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
63. The method of Claim 61 , wherein the agent is an antibiotic or derivative thereof.
64. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VO:
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR,0Riι, -SC(O)NRi0Ri i, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR
7CH
2C(O)OR
7, -OCH
2C(O)NR
10Rn, -SCH
2C(O)NR
10Ri ,, - NR
7CH
2C(O)NR
10Ri i, -OS(O)
PR
7, -SS(O)
PR
7, -S(0)
POR
7, -NR
7S(O)
PR
7, -
-SS(O)
PNR
10R
1,, -NR
7S(O)
pNR,
0R
π, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10R1 I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Ru, -SS(O)pNR10Rπ, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR1ORIi5 -SS(O)PNR10Rn, - NR7S(O)pNR10Rii, -OS(O)POR7, -SS(O)POR7) -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10Ri 1, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R1 I, - NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered ary 1;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
65. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R1 1, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 11 -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10RM, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR1ORM, - NR7C(NR8)NRi0R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R1 1, -NR7C(O)NRi0R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R1 1, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10Rn, -SS(O)PNR10RM, -NR7S(O)PNR|0RU, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 U -SS(O)PNR10R11, - NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR,,, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(ORv)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyny), an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and R,,, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
66. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Rj;
R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
inSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR,
0Rii, -SC(O)NR
10R
I I, -NR
7C(O)NR
10RH, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7> -S(O)POR7> -NR7S(O)PR7, - OS(O)PNR1ORI 11 -SS(O)PNR10R1 ,, -NR7S(O)PNR10RΠ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R1,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 ,, -SC(NR8)NR1ORH, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)roSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10RI 11 -SS(O)PNR1ORI I, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(0)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R1 1, for each occurrence, are independently -H, an optionally
substituted alky], an optionally substituted alkenyi, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NRjC(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NR8S(OpR71 Or -S(O)pNR,0R,,; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
67. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (DC):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R1 1, -SC(O)NR10Rii, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, •
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NRioRi i, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10Ri u -OS(O)PR7, -SS(0)pR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 I1 -SS(O)PNR1ORI I, -NR7S(O)PNR10R1 ,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Ri i, - NR7C(S)NRi0R1 ,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiOR11. -SC(NR8)NRi0R11, - NR7C(NR8)NR1ORH, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0R1 I, -SC(O)NR10Ri1, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10RI ., - NR7CH2C(O)NR10RH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0R, ,, -SS(O)pNR,0Rπ, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR,0RM, -SS(O)pNR10R, i, - NR7S(O)PNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR,0R,,, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R1 I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alky I; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
68. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH,
-S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RM, -SC(O)NR10R11, -NR7C(O)NRI0R1 I, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10RI ,, - NR7CH2C(O)NRl0Riι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1OR115 -SS(O)PNR1OR1 ,, -NR7S(O)PNR10R, ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RI 1, -SC(S)NR10R11, - NR7C(S)NR10Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10R11, -
NR7CCNR8)NR,oRι i, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)roNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI I, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 1, -SS(O)-NR10R1 1, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR1OR1 I, -
NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1,, -
NR7C(S)NRi0R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R,,, -SC(NR8)NRi0R11, -
NR7C(NR8)NRIORI I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkβnyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R1,, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryi; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
69. A method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Rn, -SC(O)NR10Ri ,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI L -SS(O)PNR10RII, -NR7S(O)pNRI0Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR,0Rn, -SC(S)NRi0Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRI0Rπ, -SS(O)pNRl0R.i, -NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNII10R1 11 -SS(O)PNR10RU , -
NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10RI , , -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(0)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)pOR7, -NR8S(O)PR75 Or -S(O)PNR10R11; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
70. The method of any one of Claims 60-69, wherein the compound is administered with an additional therapeutic agent.
71. The method of Claim 70, wherein the additional therapeutic agent is an anticancer agent.
S 72. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 50 nM in AML cell line Kasume-1, provided that the isolated agent is not a compound disclosed in U.S. Patent Application Serial No. 1 1/282,1 19. 0
73. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing AML cell line Kasumi-1 than geldanamycin analogs, provided that the isolated agent is not a compound disclosed in U.S. 5 Patent Application Serial No. 1 1 /282, 1 19.
74. The pharmaceutical composition of Claim 72 or 73, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
0 75. The pharmaceutical composition of Claim 72 or 73, wherein the agent is an antibiotic or derivative thereof.
76. The pharmaceutical composition of any one of Claims 72-75, further comprising one or more additional therapeutic agents. 5
77. The pharmaceutical composition of Claim 76, wherein the additional therapeutic agent is an anticancer agent.
78. A pharmaceutical composition for treating a c-kit associated cancer in a subject, 0 comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)inSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri I, -SC(O)NR10RI i, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)-R7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 15 -SS(O)PNR10R1 1, -NR7S(O)11NR10R11, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Ru, -SC(S)NR10R1 1, -
NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R1 I, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R1 1, -SC(O)NR10R1 1, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R73 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR|0Rn, -SS(O)PNR10R1 1, -NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)POR7> -NR7S(O)pOR7, -NR7S(O)pR7, -OS(O)PNR10R1 15 -SS(O)PNR10R11, - NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R1 1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RH, -SC(NR8)NR10R1I, - NR7C(NR8)NR10R,,, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(0R7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and Rs, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rj0 and Rj1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
79. A pharmaceutical composition for treating a c-kit associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
25, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
11, -SC(O)NR
10R
11, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
71 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 U -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7^; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10Ri i, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, - OS(O)PNR10Ri1, -SS(O)pNRl0Rπ, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1W -SS(O)11NR1OR1I, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR1C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRJ)NR10R, ,, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Riσ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyi, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
80. A pharmaceutical composition for treating a c-kit associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VlIl):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0(CHz)1nSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRn, -SS(O)pNR10RM, -NR7S(O)pNR10Rn, - OS(O)POR7, -SS(O)pOR7, -NR7S(O)15OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NRe)OR7, -NR7C(NRe)OR7, -OC(NRe)NRi0Ri i, -SC(NRe)NR10Rn, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, Or -SP(O)(OR7^;
Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)raNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1I, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R,,, - NR7CH2C(O)NR10R,,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR, i, -SS(O)PNR10R1 ,, -NR7S(O)pNR)0R, i, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 ,, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRe,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aikynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyi, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aikynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyi, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyi or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted aikynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(0)pNR,oR]i;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
81. A pharmaceutical composition for treating a c-kit associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (EX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ri i, -SC(O)NR
10R
M, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,ORM, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR1ORH, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri 1, -SC(NR8)NR1ORu, - NR7C(NR8)NR10R11, -OP(O)(OR7)2) or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRιi, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0Rn, -SS(O)pNR10Rn, -NR7S(O)pNR,0R,,, -OS(O)POR7, -SS(O)POR7> -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rn, - NR7S(O)pNR10Rn, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NRi0Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)J, or -SP(θχθR7)2;
R3 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
A pharmaceutical composition for treating a c-kit associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
roSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10RM, -SCH2C(O)NR10RM , - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)PNRI0R1 1, -NR7S(O)pNR10R,,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NR10R11, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NRi0Rn, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)raNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0R, ,, -SS(O)pNR10R, ,, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR,0Rn, -SS(O)pNR10Rn, -
NR7S(O)PNR10R1 1, -OS(O)POR7> -SS<O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OCCNR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORM, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ru, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
83. A pharmaceutical composition for treating a c-kit associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ry, R, is -OH, -SH, -NR
7H, -OR
26, -SR
25, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10RH, -SC(O)NR,
0RI I, -NR
7C(O)NR
10RH, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rπ, -SCH2C(O)NR10Rπ, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRi,, -SS(0)pNRIORii, -NR7S(O)pNR10Rιi, -
OS(O)p0R7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRj1)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(ORj)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR10Rπ, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rπ, - NR7S(O)pNR10Rπs -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R|8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR,0Ru, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRβS(O)pR7, or -S(O)pNR10Rπ; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
84. The pharmaceutical composition of any one of Claims 78-83, wherein the pharmaceutical composition comprises an additional therapeutic agent.
85. The pharmaceutical composition of Claim 84, wherein the additional therapeutic agent is an anticancer agent.
86. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits
Hsp90, wherein the agent has an IC50 for cell survival of less than about 50 nM in NCI-H1975 human lung cancer cell line.
87. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits
Hsp90, wherein the agent is at least about S times more affective at killing NCI- HI 975 human lung cancer cell line than geldanamycin analogs.
88. The method of Claim 87, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
89. The method of Claim 87, wherein the agent is an antibiotic or derivative thereof.
90. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Rj; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)KR10R,,, -SC(O)NR10RH, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1I, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNRI0RM , -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NTl10R1 I, -SC(S)NR10R1 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NRI0RH, -
NR7C(NR8)NR10RH, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)JS[R7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ru, -SC(O)NR10R1 1, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NRI0R1 1, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10Ri i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRι i, -SS(0)pNR,oRn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1ORI L -SS(O)PNR10R1 1, - NR7S(O)PNR10R1 1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NRi0R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NRIORI I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR,,,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (II):
(II) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R^; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)mOH, - O(CH2)mSH, -O(CH2)roNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)PR7, - OS(O)PNR1ORM5 -SS(O)PNR10R11, -NR7S(O)PNR10R1 ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR*)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORu, -SC(NR8)NR10R11, - NR7C(NR8)NR10RM, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR,0Rn, -SCH2C(O)NRi0R11, -
NR7CH2C(O)NRi0Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1OR,,, -SS(0)pNR,oRn, -NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)pOR7j -NR7S(O)pR7> -OS(O)pNR10R,,, -SS(O)pNR10Rn, - NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10R11, -
NR7C(S)NR10Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR«, -S(O)2NHR«,-OP(O)(OR7)2, or -SP(O)(OR7)2; R2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraraikyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NRi0Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)PR71 Or -S(O)PNR10R111 Or ii) two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraraikyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNRl0Rn; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraraikyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or S an optionally substituted heteroaryl;
R2O, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted 0 heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4. 5
92. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
(HI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are 5 optionally further substituted with one or more substituents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, OC(O)NRi0R11, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - 0 SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR1OR1,, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7) -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)PNR1OR11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7> -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10RM, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR3)OR7, -OC(NR8)NRiOR11, -SC(NR8)NR10Ri1, - NR7C(NR8)NR10RM, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NRi0Rn, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NRi0Rii, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)pOR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rn, - NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NR10RI i, - NR7C(S)NR10Ri 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRs)NRi0Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the
nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR|0Rn, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7
, -S(O)POR7> -NRsS(O)11R7, or -S^NR.oR. ,;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
93. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Rj; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
roOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RH, -SC(O)NR10Ri,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, • NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri ,, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNRI0R,,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10RI I, - NR7C(S)NRi0R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R1 I, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR| i, -SS(O)pNR10R| ,, -NR7S(O)pNR10R|i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)pR7, -OS(O)PNR10R1 U -SS(O)PNR1OR1 1, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7) -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 u -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R,,, -SC(NR8)NRiORi i, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8^OP(O)(OR7),, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R1 I, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and R1 1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or
an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; Ri is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Ri 1, -SC(O)NR10RiI5 -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> -
OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)11OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10RM, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R73 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NR10RI i, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, - OS(O)11NR1OR11, -SS(O)pNR10RM, -NR7S(O)PNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(OpR7, -OS(O)pNR10Rιi, -SS(O)pNRl0Rn, -
NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i. -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R11, -
NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR3, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7), ;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
95. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI . , -SC(O)NR10RU, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)11R7, - OS(O)PNR10R1 ^ -SS(O)PNR1OR1 I, -NR7S(O)PNRI0RM, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NR10R11, - NR7C(NR8)NR10RI ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(0)pNRioRιi, -SS(O)pNRl0Rn, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7CCNR8)OR7, -OC(NR8)NR1ORi I, -SC(NR8)NR1ORn, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH5 - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)I, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an ' optionally substituted heteraralkyl; or R]0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRioRn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NR8S(O)11R^ Or -S(O)pNR,βRn; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
96. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (EX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryi or the heteroaryl are optionally further substituted with one or more substituents in addition to Ky,
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ru, -SC(O)NR10R1 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR71 -S(O)11OR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)pNR10RM, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi I, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10Rii, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10RM, - NR7CH2C(O)NRi0Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R|,, -SS(O)pNR10Ri,, -NR7S(O)pNRl0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR|0Rn, -SS(O)pNR10Riι, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7CChIR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NRi0Rπ, - NR7C(NR8)NR10RI I, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
97. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R, ,, -SC(O)NR
10R
I I, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(0)NRioRιi, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn5 -SS(O)PNR10R1,, -NR7S(O)PNR10R1 ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R,,, -OP(O)(OR7)2, or -SP(O)(OR7)Z; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10RM, -SS(O)PNR10R1 ,, -NR7S(O)pNRI0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)pNRI0R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR4OOR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R,,, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z1 Or -SP(O)(OR7)Z;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyi, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
RiO and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, S an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R,o and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; 0 p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
98. A method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by 5 formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are 0 optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10RI I, -NR7C(O)NR,0RU, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - 5 SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR,0Rii, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn1 -SS(O)PNR1OR1I, -NR7S(O)pNR10R,,, - OS(0)pOR7, -SS(O)pOR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, 0 OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NRi0R11, -OC(NRe)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NRs)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1I, -SC(NR8)NRIORI U - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 1. - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)^R7, - OS(O)PNR10R1 ,, -SS(O)PNR10R11, -NR7S(O)pNR10Rn , -0S(O)pOR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(0)pNR,oRn, - NR7S(O)pNRl0RM, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NRm)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(0)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky!, an optionally substituted alkenyl, an optional Iy substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R11, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
sυbstituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Rιι, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)pNR,βRιι;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
99. The method of any one of Claims 86-98, wherein the compound is administered with an additional therapeutic agent.
100. The method of Claim 99, wherein the additional therapeutic agent is an anticancer agent.
101. A method of inducing degradation of EGFR in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 50 nM in NCI-Hl 975 human lung cancer cell line.
102. A method of inducing degradation of EGFR in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing NCI- H 1975 human lung cancer cell line than geldanamycin analogs.
103. The method of Claim 102, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
104. The method of Claim 102, wherein the agent is an antibiotic or derivative thereof.
105. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (T):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ry, R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRn, -SC(0)NR,oRιi, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R, ,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 U -SS(O)PNR10R1 1 , -NR7S(O)PNR10RΠ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI I, -SC(NR8)NR10RI 1, - NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(ORi)2; Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NRi0R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR, 0R, i, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRn, -SS(O)pNR,0Ru, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNR10Ru, -SS(O)pNR10Rπ, - NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R, ,, -SC(S)NR10R1 1, -
NR7C(S)NR10RH , -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI I, -SC(NR8)NR1ORM, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R1 u for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R1O and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
106. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (II):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR1OR11, -NR7S(O)pNR10Rn, -
OS(0)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NRe)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0R1 1, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR,0Rn, -NR7S(O)pNR10Rii, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR|0RM, -SS(O)pNR10Rn, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR«,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10RM, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -
NRgS(O)pR7, or -S(O)pNR10Rii, or two to five substitυents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri1, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, - S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or .S(O)pNR10Rl i; and
R7 and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyi, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(0)NR,oRιi, -SC(O)NR10RI I, -NR7C(O)NR10RI ,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R73 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10RM, -SCH2C(O)NR10RI 1, - NR7CH2C(O)NR1ORH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10RI U -SS(O)PNR10RI 1, -NR7S(O)PNR10R1 1, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1., - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR4)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R, ,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri,, -SCH2C(O)NR10RM, - NR7CH2C(O)NR10R1 1, -OS(O)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Ri i, -SS(O)pNR10Ri i? -NR7S(O)11NR1OR11, -OS(O)POR7, -SS(O)POR7> -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 N -SS(O)PNR1OR1 1, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1 1, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR,,,-OP(O)(OR7)2, or -SP(O)(OR7), ;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0R11, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R71 Or -S(O)PNR10R1 ,; R_6 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rιi, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R1 I, - NR7CH2C(O)NR10Ri i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn1 -SS(O)PNR1ORn, -NR7S(O)pNR10Rι ι, -
OS(O)pOR7> -SS(O)POR7, -NR7S(O)-OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2J1nSH, -S(CH2)^NR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Ri 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7> -NR7S(O)PR7, -
OS(O)11NR10R1 ,, -SS(O)PNR10R1I, -NR7S(O)PNR10RH, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10R,,, -SS(O)pNR10R,,, - NR7S(0)pNRιoRιι, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R,., -SC(S)NR10R11, - NR7C(S)NR1OR11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OCCNR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Ri1, - NR7C(NR8)NR1OR11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
109. A method of inducing degradation of EGFR kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(0)NR,oRiι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R1 I, -NR7S(O)11NR10R1 ,, - OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR 10R, ,, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -OP(0)(OR7)2, or -SP(O)(0R7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)raNR7H, - OC(O)NRi0Rn, -SC(O)NR10R11, -NR7C(O)NR10R1,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)11NR10R1 ,, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR1 L -SS(O)11NRI0R1 ,, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NRioRn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi I, -SC(NR8)NR10Ri i, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(θχθR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, I or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
10. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VIIl):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
Ri is -OH, -SH, -NR
7H, -OR
26, -SR
26, -TsTHR
26, -O(CH
2)
raOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1 1, -SC(O)NR
10Rn, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
71 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10Ri i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1 1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)-NR10R11, -SS(O)PNR10R11, -NR7S(O)pNRI0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rπ, - NR7S(O)PNR10R11, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 I, -SC(S)NR,0Rπ> -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)Z, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally
substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and R\ i, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10R,,; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
1. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (IX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)JMR
7H, -
OC(O)NR10RM, -SC(O)NRI0R1 I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, ■
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(0)NRioRι i, - NR7CH2C(O)NR10Ri r, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR,i, -SS(0)pNR,oRiι, -NR7S(O)pNR,0Riι, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)11OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI 1, -SC(NR8)NRi0R1 I, - NR7C(NR8)NR1ORH, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)raOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR10Rn, -NR7C(O)NR10R,,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(0)NR,oR, i, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7? -SS(O)PR7) -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 ,, -SS(O)pNR10R,i, -NR7S(O)pNRl0Ri,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10RI L -SS(O)PNR10R1 1, - NR7S(O)pNR|0R,,, -OS(O)POR7, -SS(O)15OR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NRIORI U - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; RiQ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the
5 nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. 10
1 12. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (X):
I S or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0 O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10Ri 1, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10Ri1, - 5 NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10Rn5 -SS(O)PNR10R11, -NR7S(O)pNRl0Rπ, -
OS(O)POR7, -SS(O)POR7> -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, 0 SCCNR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRιi, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R1 I, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)PNR10Rn, -NR7S(O)PNR10RΠ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)pR7, -OS(O)PNR10R1U -SS(O)PNR10R11, -
NR7S(O)-NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri,, -SC(NR8)NR10R1 1, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
13. A method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)JMR
7H, -
OC(O)NR10Ri i, -SC(O)NR10R11, -NR7C(O)NRi0Ri ι, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR|0Rii, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)PNRI0R1 1, -NR7S(O)PNR10RM, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ru, - NR7C(S)NR10R1,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NRi0R,,, -
NR7C(NR8)NR10Ri1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR,0R,,, - NR7CH2C(O)NR1OR,,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0Ru, -SS(O)pNR,0R, ,, -NR7S(O)pNR,0RM> -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)pNR,0Rπ, -SS(O)PNR10R11, -
NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10RiI, -
NR7C(S)NR10Ri1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi I, -SC(NR8)NRI0R, ι, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
», Rio and R1,, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Ru, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRgS(O)pR7, or -S^pNR.oR,,; R∑6 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
14. The method of any one of Claims 101-1 13, wherein the compound is administered with an additional therapeutic agent.
1 15. The method of Claim 1 14, wherein the additional therapeutic agent is an anticancer agent.
1 16. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent has an ICs0 for cell survival of less than about 50 nM in NCI-Hl 975 human lung cancer cell line.
1 17. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing NCI-H1975 human lung cancer cell line than geldanamycin analogs.
1 18. The pharmaceutical composition of Claim 1 16 or 117, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
1 19. The pharmaceutical composition of Claim 116 or 1 17, wherein the agent is an antibiotic or derivative thereof.
120. The pharmaceutical composition of any one of Claims 1 16-1 19, further comprising one or more additional therapeutic agents.
121. The pharmaceutical composition of Claim 120, wherein the additional therapeutic agent is an anticancer agent.
122. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)roSH, -S(CH2)mNR7H, - OC(O)NR1OR11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)15R7, - OS(O)PNR1OR1 L -SS(O)PNR1ORI I, -NR7S(O)pNR10Rπ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CHz)1nOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Ri1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ru, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)11NR10R1 ,, -SS(O)11NR10R1 ,, -NR7S(O)pNR10R,,, -OS(O)p0R7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7> -OS(O)PNR10R115 -SS(O)PNR10R11, - NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NRe)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI ,, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, • S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)2; Rs is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
123. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (II):
OD or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7,
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCHjC(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRii, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RI ,, -OS(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRu, -SS(0)pNR,oRn, -NR7S(O)PNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRj)R7, -NR7C(NRe)R7, -OC(NRe)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORM, -SC(NR8)NR10R11, - NR7C(NR8)NR10Ri i, -OP(O)(ORV)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rl t, -SS(O)PNR10R11, -NR7S(O)pNRi0RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10RM1 -SS(O)PNR10R11, - NR7S(O)pNRI0Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RM, -SC(NR8)NR10R11, - NR7C(NR8)NR10R,,, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)-R7, or -S(O)pNR10Rn, or
ii) two to five substituents selected from the group consisting of an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRJORM, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR4S(O)PR71 Or -S(O)pNRl0Rπ; and R7 and R%, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyi or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
124. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI ,, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -N R7S(O)11NR10R1 ,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI I, -SC(NR8)NRI0R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Ri1, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NRI0RM, - NR7CH2C(O)NRi0R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R,ι, -SS(O)pNR10R,ι, -NR7S(O)pNR|0Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNRi0R111 -SS(O)11NR10R11, - NR7S(O)11NR10R1,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rii, -SC(S)NR10Ri i, -
NR7C(S)NR10R, ,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RM, -SC(NR8)NR1ORU, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHRg,-OP(0)(OR7)2, or -SP(0)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R!0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R,8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR,0Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(OpR7^r -S(O)PNR10R11; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
125. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR25, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RM, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10RH, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR, ,, -SS(O)11NR10Rn, -NR7S(O)pNRI0Rπ, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10Ri I, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NRi0Rn, -SC(O)NR,0Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR,0Rn, -SS(O)pNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR10RH, - NR7S(O)-NR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7. -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2) or -SP(O)(OR7)2;
Rj is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R1O and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
126. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Rn, -SC(O)NR
10Ri i, -NR
7C(O)NR
10Rn, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NRiORi i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORI 11 -SS(O)PNR1ORM, -NR7S(O)PNR,0RM , - OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R, i, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRe)NR10R11, -SC(NR8)NR10Ri,, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(0R7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NRi0R11, -NR7C(O)NR,0Rπ, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 1, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNRl0R,,, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)-R7, -OS(O)pNR10Rn, -SS(O)pNR10Ri,, - NR7S(O)PNR10R11, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR,0R,i, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10R1I, - NR7C(NR8)NR1ORM, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rιo and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
127. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10RM, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10Rπ, - OS(O)p0R7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NRi0R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NRe)OR7, -NR7C(NR4)OR7, -OC(NR8)NR10RI i, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
.R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 ,, -SS(O)pNR10Rπ, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1OR1 W -SS(O)PNR10R1 1, - NR7S(O)pNRI0Rii, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10Ri,, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10RH, - NR7C(NR8)NR1ORU, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S^NHR^-OPtOXOR^, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Ri0 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7) -NRgS(O)pR7, or -S(O)pNR,0R, ,;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
128. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (EX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CHz)
1nNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
M, -SC(O)NR
10R
U, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR]0R11, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10RI b -SS(O)PNR10Ru, -NR7S(O)11NR10R11, -
OS(O)pOR7> -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RM, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> - OS(O)pNR10RM, -SS(O)pNR10RM, -NR7S(O)PNR10R1., -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNR,0Rπ, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-OP(0)(OR7)2, or -SP(OXOR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and Re, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
RIQ and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
129. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Rn1 -SC(O)NR10Ri 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R1 1, -NR7S(O)PNR10RU, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, -
NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0(CHj)1nSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NRi0Rn, -OS(O)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRI0Rn, -SS(O)pNR10Rn, -NR7S(O)-NR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10Rn, -
NR7S(0)pNR,oR,,, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR11, -SC(NR8)NRIORI I, -
NR7C(NRg)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR87-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rt0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
130. A pharmaceutical composition for treating an EGFR associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
raSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1,, -SC(O)NRi
0Ri ι, -NR
7C(O)NR
10RU, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10RM, -SCH2C(O)NR10RI ι, - NR7CH2C(O)NR10Ri ι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10RM1 -SS(O)PNR10R1 I, -NR7S(O)PNR,0R,, , -
OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI 1, -SC(S)NR10R11, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR^)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORu, -OP(O)(OR7)2, or -SP(O)(OR7).;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRi0Ri1, - NR7CH2C(O)NR10R, ,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> - OS(O)pNRi0Rπ, -SS(O)PNR10RM, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNRI0RM, - NR7S(O)pNR10RI l5 -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OCCNRg)NR10R1,, -SC(NR8)NR10R11, - NR7CCNR8)NR10Rπ, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and R)1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R]8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRgS(O)pR7, or -S(O)pNR,0R|.;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
131. The pharmaceutical composition of any one of Claims 122-130, further comprising one or more additional therapeutic agents.
132. The pharmaceutical composition of Claim 131, wherein the additional therapeutic agent is an anticancer agent.
133. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10Ri 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR1ORH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> - OS(O)PNR10R1 U -SS(O)PNR10R11, -NR7S(O)pNR10RM, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R1 1, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R1 1, -
NR7CH2C(O)NRiORi i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R,ι, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)11NR10R1 I 1 -SS(O)PNR10R1 I, - NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7) -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NR10R1 1, -
NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10RiI, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, Or -SP(O)(ORv)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
134. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (II):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substitueπts in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR,0Rii, -SCH2C(O)NR,0Rπ, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 11 -SS(O)PNR1OR1 ,, -NR7S(O)PNR10R, I, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11 , -OP(O)(OR7)2, or -SP(O)(OR7)2 ;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR,0Rπ, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Ru, -SS(O)pNR|0Ru, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNR|0Rπ, -SS(O)11NR10R1 ,, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, - NR7C(S)NRi0R1 I, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NRi0R11, -NReC(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -
NRgS(O)pR7, or -S(O)pNR,0R,,, or two to five substitυents selected from the group consisting of an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ru, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, - S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R7, or -S(O)pNR10R,,; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, I, 2, 3, or 4.
A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Ri i, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 N -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(0)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ru, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRa)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, -
NR7C(NR8)NR10RH, -OP(O)(OR7)2, or -SP(O)(OR7J2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR1ORN, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RU, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn, -SS(O)pNR10Rn, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)15NR10Ru, -SS(O)pNRl0Rn, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ru, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0R11, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10Rn; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CHz)1nOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oR|i, -SC(O)NR10R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R1 1, -NR7S(O)pNR10Rπ, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NRi0Ri1, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)pNRi0Rπ, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)pNR10R,,, -SS(O)PNRI0RH, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Rn, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R?, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
137. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIl):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)riNR7H> - OC(O)NR10R11, -SC(O)NR10Ri1, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR10R11, -NR7S(O)PNR10R11, - OS(O)-OR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 1, -SS(O)pNR10Rπ, -NR7S(O)PNR10R11, -OS(O)POR7> -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)pNR10Rn, - NR7S(O)-NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -
NR7C(S)NR10Ri,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORi,, -SC(NRe)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRj,,-OP(O)(OR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R| ,, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
138. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroary I are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(0)NRioRn, -SC(O)NR
10R
n, -NR
7C(O)NRi
0R
n, -OC(O)R
7, .-SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
71 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR1OR11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, - OS(O)PNR10R1 N -SS(O)PNR10R1 1, -NR7S(O)pNR10Rn, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NRi0R1 1, -
NR7C(S)NR10R11, -OC(NR3)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NRj)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR1ORH, - NR7C(NR8)NR10Ri1, -OP(O)(OR7)2, or -SP(O)(OR7J2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NRi0R11, -SC(O)NR10Ri1, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ru, -SCH2C(O)NR10Rn, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)pNRl0Rιi, -OS(0)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNR10R,i, -SS(O)pNR,0Rn, - NR7S(O)pNR10Rn, -OS(O)POR7) -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri i, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -S P(O)(OR7)2 ; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R1 1, for each occurrence, are independently -H, an optionally
substitυted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR|0RM, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)pOR7> -NRgS(O)pR7, or -S(O)PNRI0RM; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
139. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (EX):
(EX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CH
2)JMR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RI I, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, •
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1., - NR7CH2C(O)NR1ORu, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRπ, -SS(O)pNR10Rii, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R1 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORn, -OP(O)(OR7)2, or -SP(O)(OR7^;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR1ORM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> - OS(O)pNR10Ri,, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)POR7) -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI I, -SC(S)NR10R,,, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRiOR1,, - NR7C(NR8)NR10RH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2N HRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
140. A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NRi0R11, -SC(O)NR10Rii, -NR7C(O)NRI0R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NRioR|i, -SCH2C(O)NR,0Rπ, - NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)11NRI0RI L -SS(O)PNR10R1 1, -NR7S(O)PNR10RM , -
OS(O)-OR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR|0Rπ, -SC(S)NR1ORi., - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1I, -SC(NR8)NR10R11, -
NR7C(NR8)NR10Ri1, -OP(O)(OR7)2, or -SP(O)(OR7J2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI ,, -SC(O)NR10RI ,, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ru, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)PNR10R11, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 U -SS(O)PNR10R1 1, -
NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NR10RM, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-OP(0)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
A method of treating a B-raf associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
(XI). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Ri i, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R79 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R1 1, -OS(0)PR7> -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10RI U -SS(O)PNR1ORM, -NR7S(O)PNR10R1 ,, -
OS(O)p0R7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8PR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 ,, -SC(NR8)NR10R1 1, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0Rn, -SC(O)NR10R1 1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)PNR10R11, -NR7S(O)-NR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNRl0Rn, -SS(O)pNR10Ru, -
NR7S(O)11NR10R1 1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ru, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NR8)NR10R11, - NR7C(NR8)NR10RI ,, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR81-OP(O)(ORv)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; s
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substitυents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)-R7, - S(O)-OR7, -NR8S(O)PR7, or -S(O)pNR10Ru; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
142. The method of any one of Claims 133-141, wherein the compound is administered with an additional therapeutic agent.
143. The method of Claim 142, wherein the additional therapeutic agent is an anticancer agent.
144. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Rπ, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R1 1, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RH, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0R11, -SC(O)NR10Rn, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR1ORH, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(0)pNR,oRii, -NR7S(O)pNR10R,ls -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7> -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, -
NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7( -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R1 N for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
145. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (II):
(ii) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CHz)1nNR7H, - OC(O)NR10RM, -SC(O)NR10RM, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri1, - NR7CH2C(O)NR10R1,, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR|0Rn, -SS(O)pNR10Rn, -NR7S(O)pNRl0Rπ, - 0S(O)p0R7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR, oRii, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRI0RI i, -SC(O)NR10R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10Ri 1, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR1OR1 L -SS(O)PNR10Rn, - NR7S(O),,NR,oRu, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORU, - NR7C(NRS)NR10RI 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10R11, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)PR7^r -S(O)pNR10R, i, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalky I, a heteroalkyl, -NRi0Ru, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10RM, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(OyI7, or -S(O)PNR10RM; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and RM, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R2O, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
146. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR25, -NHR26, -O(CH2)roOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRπ, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NRi0Ru, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R1L -SS(O)PNR1OR1., -NR7S(O)11NR10Rπ, - OS(O)POR7, -SS(O)-OR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NRg)NR10Ru, - NR7C(NR8)NR10RI I, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
RJ is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0(CH2)mSH, -O(CH2)raNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NRi0Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10RM, -SS(O)PNR10R1 ,, -NR7S(O)pNR10Rii, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNR10R, ,, - NR7S(O)pNR10Rn> -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7> -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NRgS(O)pR7, or -S(O)pNR10Rii;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
147. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VT):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CH
2)JMR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(0)NR,oRπ, -SC(O)NR
10RiI, -NR
7C(O)NR
10R
H, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R,,, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)nOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10R1 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRI0Rii, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Ri1, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Ru, -SS(O)PNR10Rn, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10Rn1 -SS(O)PNR10R11, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(0)2NHRg,-OP(0)(OR7)2, or -SP(O)(OR7)2;
R3 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Rj; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -0(CH2J1nNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JS[R7H, - OC(O)NR10R11, -SC(O)NR10RiI, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10RI 1, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 11 -SS(O)PNR10R1 1, -NR7S(0)PNR,ORI I , -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri 1, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NRx)OR7, -OC(NRg)NR10R11, -SC(NR4)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7^; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR10RH, - NR7S(0)PNR,ORM, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7) -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RI 1, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
149. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VIII):
(VIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)pR7, -
OS(O)pNR10Rπ, -SS(O)11NR10R1 ,, -NR7S(O)11NR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SPCOXORT)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NRiORi 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)pNRI0Rn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 15 -SS(O)PNRIOR1 1, -
NR7S(O)PNR10R11, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)11OR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri ι, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)PN R10Rn; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
150. A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (IX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
irSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1 I, -SC(O)NR
10R
11, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNRI0R1 ,, -NR7S(O)PNR10RM, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10Rn, - NR7C(NR8)NR1ORiI, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Ri i, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)PNRi0R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNR,0Rπ, -SS(O)pNR,0Rn, - NR7S(0)pNR,oR| i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
S cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 0 R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
151. A method of inducing degradation ofB-raf in a mammal, comprising 5 administering to the mammal an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: 0 ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substiruents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
11, -SC(O)NRi
0R
11, -NR
7C(O)NR
10R
H, -OC(O)R
7, -SC(O)R
7, - 5 NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR1ORu, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10Rn, - 0 OS(O)POR7> -SS(O)POR7> -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI i, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 I, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R1,, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0Rπ, -SS(O)pNR10Rπ, -NR7S(O)PNRi0R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10RI I, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NRi0Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(OXOR7)2, or -SP(O)(OR7)Z;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substitueπts in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(0)NR,oRιi, -SC(O)NR10Ri 1, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10Rn1 -SS(O)PNR10R11, -NR7S(O)11NR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CHz)1nSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRi0R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7)
-NR7S(O)pOR7( -NR7S(O)PR7, -OS(O)pNR10Riι, -SS(O)pNR,0Ru, - NR7S(O)pNRI0RI ls -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRβ,-OP(O)(OR7)2, Or -SP(O)(OR7^;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R1O and R)1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R1], -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NR8S(O)15R71 Or -S(O)pNR10R, , ;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
153. The method of any one of Claims 144-152, wherein the compound is administered with an additional therapeutic agent.
154. The method of Claim 153, wherein the additional therapeutic agent is an anticancer agent.
155. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (T):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R11, -SC(O)NR10RI I, -NR7C(O)NR10RI1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR,0Rii, -SCH2C(O)NRi0Ri,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)pNR10Rπ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)H1NR7H, -
OC(O)NR10R,,, -SC(O)NR10Rn, -NR7C(O)NR10Ri,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oR,i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)-OR7, -SS(O)POR7> -NR7S(O)pOR7, -NR7S(OpR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10R,., - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR87-OP(O)(OR7)Z, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted ary!, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R,ι, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R( 1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (II):
(H) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI ,, -SC(O)N R10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 I, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri ι, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7CCNR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR,0Ru, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(0)POR7, -NR7S(O)PR7, -
OS(OyMR10R11, -SS(O)PNR10R11, -NR7S(O)pNRl0Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rii, -SS(O)pNRl0R,,, - NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR^-OP(O)(ORv)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10R11, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, -
C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NRgS(O)pR7, or -S(O)pNR10R,,, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -
S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR,0R,i; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R2O, for each occurrence, is independently an optionally substituted alky!, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
157. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, OC(O)NR10R11, -SC(O)NR10R1,, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R,,, -SS(O)pNR10Rn, -NR7S(O)pNR10R,., -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NRg)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, -
NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)I;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri U -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR|0RM, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, -
NR7S(0)pNR,oRn, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Rn, -SC(NR8)NR10R11, -
NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR]0Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7^r -S(O)PNR10RM; R26 is a lower aikyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
158. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ru, -SC(O)NR
10R
H, -NR
7C(O)NR
10RU, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRi0Rπ, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 11 -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Rn, -SC(NR8)NRIORI I, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10Ri i, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,ORI I, -SCH2C(O)NR)0Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR,0R,,, -SS(O)PNR10RI 1, -NR7S(O)PNR10R1 I, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR10R11, - NR7S(O)PNR10R1 I, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NRi0R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NRg)OR7, -OC(NR8)NRI0RI i, -SC(NR8)NRi0Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; Rs is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R1 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
S9. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substitueπts in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10RiU -SC(O)NR
10Rn, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR1OR1 I7 -SS(O)PNR10R1 W -NR7S(O)PNR10R11, - OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ru, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(0)(OR7)2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R1,, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(0)pNR,oR,,, -NR7S(O)-NR10Ru, -OS(O)-OR7, -SS(O)pOR7l -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)pNRl0Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroary 1, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyciyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R]1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
160. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VIIO:
or a tautomβr, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0Rn, -SC(O)NRi0Rn, -NR7C(O)NR10RU, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7) -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10RM, -SS(O)pNR10Rn, -NR7S(O)11NR10R1 ,, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Ri1, -SC(NRg)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)15NR10R1 ,, -SS(O)pNR10Rπ, -NR7S(O)-NR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 ,, -SS(O)pNR10Rn, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiOR1U -SC(NRg)NR10Ri,, - NR7C(NR8)NR1ORiI, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR*, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)Z;
R7 and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)POR7, -NRsS(O)pR7, or -S(O)pNR10Ru; R2β is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
161. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (DC):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substiruents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10Rn, -NR7S(O)pNRi0RM, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NR10R1 1, -
NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RM, - NR7CCNR8)NRi0Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NRi0R11, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)pNRi0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR,0R||, -SS(O)pNRi0Rn, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR, 0R,,, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORu, -SC(NR-8)NR1ORn, - NR7C(NR8)NR1ORiI5 -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 5 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optional Iy substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, 0 an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R1O and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted S cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 0 R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
162. A pharmaceutical composition for treating a B-raf associated cancer in a subject, 5 comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or- a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR
7H, -OR
24, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CHz)
1nOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(0)NR,oRiι, -SC(O)NR
10R
11, -NR
7C(O)NR
10Rn, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
71 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri ,, -SCH2C(O)NR10R1I, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORn5 -SS(O)PNR1OR11, -NR7S(O)-NR10Rn, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1 1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NRg)NR10Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)j, Or -SP(O)(OR7^; R2' is an optionally substituted phenyl group; Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10R11, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR10Rπ, -NR7S(O)pNR10Ri,, -OS(O)POR7> -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)pNRI0Rn, - NR7S(O)pNRl0Rn, -OS(O)pOR7l -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NRg)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10RI I, - NR7C(NR8)NRi0Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rιo and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, I or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
163. A pharmaceutical composition for treating a B-raf associated cancer in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0Rιι, -SS(O)pNR,βRiι, -NR7S(O)pNR10Ru, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORH, - NR7C(NR8)NR10R, ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRi,, -SC(O)NR10Ri,, -NR7C(O)NR10R, ,, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Ru, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1,, -SS(O)PNR10R, ,, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNRI0Rn, -SS(O)pNRI0Rπ, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRβ,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R,o and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rι8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NRgS(O)pR7, or -S(O)pNR,0Rii;
R26 is a lower alky I; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
164. The pharmaceutical composition of any one of Claims 155-163, further comprising one or more additional therapeutic agents.
165. The pharmaceutical composition of Claim 164, wherein the additional therapeutic agent is an anticancer agent.
166. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 15 nM in CML cell line KU812.
167. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing CML cell line KU812 than geldanamycin analogs.
168. The method of Claim 167, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
169. The method of Claim 167, wherein the agent is an antibiotic or derivative thereof.
170. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (T):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)^NR7H, - OC(0)NR,oRιι, -SC(O)NR10R11, -NR7C(O)NR10Ru, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR1ORI 11 -SCH2C(O)NR1ORI I, - NR7CH2C(O)NRl0Rι ι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 I9 -SS(O)PNR1OR1 1, -NR7S(O)pNRI0R, , , - OS(O)pOR7j -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 I, -SC(S)NR10Ri i, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10Rn, - NR7C(NR8)NR1ORH, -OP(O)(OR7)2, or -SP(0)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRI0RI i, -SC(O)NR10Ri i, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRI0R1 i, -SCH2C(O)NR10R1 1, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 I, -SS(O)pNR10R,ι, -NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10Rn5 -SS(O)PNR10R1 I, - NR7S(O)-NR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1I1 -SC(NR8)NR1ORH, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, I or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
171. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (II):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRl0Riι, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10RH, -
NR7CH2C(O)NR10R.i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R117 -SS(O)PNR10Rn, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri ι, -SC(S)NR10R1,, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R, ,, -SC(NR8)NR10Ru, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)raSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0Rn, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10Ru, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R.i, -SS(O)pNRI0Rn, -NR7S(0)pNR,oRιi, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR,0R,ι, - NR7S(O)PNR10R11 , -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRe1-OP(O)(ORT)2, or -SP(0)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NRi0Ri i, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -
NRgS(O)pR7, or -S(O)pNRi0Rπ, or two to five substituents selected from the group consisting of an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Rn, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NRi0Ri i, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R7, or -S(O)pNR10R,,; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
(IH) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10RI 1, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NRi0Rιi, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNR10RM, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7> -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR1., -SC(NR8)NR10R1,, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR1ORu, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(0)pNRioRiu -NR7S(O)PNR10R11, -OS(O)POR7) -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)11R7, -OS(O)pNR10RM, -SS(O)PNR10RM, - NR7S(O)11NR1OR11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR«,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRI0RH, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7 , -S(O)POR7, -NR8S(O^R7, or -S(O)PN R10Rn; R26 is a lower alkyl; p, for each occurrence, is, independently, O, I or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.
A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI i, -SC(O)NRi0Ri i, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR1OR11, -SCH2C(O)NR10RM, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 N -SS(O)PNR1OR1 ,, -NR7S(O)PNR10R1 ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NRi0Ri i, -SC(NR8)NR10R11, - NR7C(NR8)NR|0Rπ, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri1, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)PNR10Ri1, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNRI0R,,, -SS(O)11NR1ORiI, - NR7S(0)pNR,oR,i, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R1,, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR87-OP(O)(OR7)Z, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered ary 1 ;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
174. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substiruents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI ,, -SC(O)NR10R1 1, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)PNR10R1 1, -NR7S(O)11NR10R1 ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ru, -SC(S)NR10Ru, -
NR7C(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 I, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 1, -SS(O)PNR10R11, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OSO^NR.oR, ,, -SS(O)pNR10Rn, - NR7S(O)PNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORH, - NR7C(NR8)NR10RI ,, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
S R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an 10 optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, I S an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; 0 p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
175. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound 5 represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are 0 optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
roOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10RI ,, -SC(0)NR,ORII, -NR
7C(O)NR
10RH, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10Rιi, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)11NR1OR1,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RU. -SC(S)NR10R1 1, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NRj)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R,,, -SC(NR8)NR10R1I, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRiι, -SCH2C(O)NR10RM, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R|,, -SS(O)pNR10Rn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1ORM1 -SS(O)PNRI0R1 ,, - NR7S(O)pNR,0RM, -OS(O)POR7, -SS(O)pOR7l -NR7S(O)pOR7l -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri i, -
NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7. -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RI I1 - NR7C(NR8)NRi0R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(O)pOR7, -NRjS(O)pR7, or -S(O)pNR10Rii; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
176. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (DC):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CH
2)JMR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, ■
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 I, - NR7CH2C(O)NR10R1 W -OS(O)PR7, -SS(O)pR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)PNR1ORI I, -NR7S(O)PNR|0R| |, -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, - NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10RiI, -SC(NR8)NR|0Rιi, - NR7C(NR8)NR10Ri1, -OP(O)(ORT)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)roSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R1,, -OS(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0Rn, -SS(O)pNR10RM, -NR7S(O)pNR,0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNRI0RI L -SS(O)PNR10R1 1, - NR7S(O)pNR10R,ι, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRiORi i, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRβ,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R1 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
177. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, .S(CHj)
111OH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R.., -SC(O)NR10R.., -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(0)NR,oR| 1, - NR7CH2C(O)NR10RH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNR10R,,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0Ri , , - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR.., -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH> -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R,,, -SC(O)NR10R,., -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR,,, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)p0R7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR10R1 I, -
NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R1 ,, -OC(NRs)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R,,, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R.26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
78. A method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
raSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(0)NR,oRι i, -SC(O)NR10Ri,, -NR7C(O)NR10R1 I, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNRI0R1 U -SS(O)PNR10R1 1, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7> -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NR10RM, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RM, -SC(NR8)NR10RM, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0(CH2J1nSH, -O(CH2)mNR7H, -S(CH2)roOH, -S(CH2)raSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7> - OS(O)pNR10Rπ, -SS(O)PNR10RM, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNRi0RM, -
NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR, 0Rn, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NRIORI I, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)J, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substitυents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10Rπ; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
179. The method of any one of Claims 166-178, wherein the compound is administered with an additional therapeutic agent.
180. The method of Claim 179, wherein the additional therapeutic agent is an anticancer agent.
181. A method of inducing degradation of a Bcr-Abl protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 15 nM in CML cell line KU812.
182. A method of inducing degradation of a Bcr-Abl protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing CML cell line KU812 than geldanamycin analogs.
183. The method of Claim 182, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
184. The method of Claim 182, wherein the agent is an antibiotic or derivative thereof.
185. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)JMR
7H, - OC(O)NR
10R
1I, -SC(O)NR
10R
I I, -NR
7C(O)NR
10R
n, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNR10Rn, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, - SC(NR8)OR7, -NR7C(NRj)OR7, -OC(NRg)NR10Rn, -SC(NRs)NR10R11, - NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR,0R,,, -SS(O)PNRi0R11, -NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR1OR11, - NR7S(O)pNRl0Rιi, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R1 1, -
NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; Rs is an optionally substituted heteroaryl or an optionally substituted 8 to
14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
186. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (II):
(II) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, OC(O)NR10Ri I, -SC(O)NR,0Riι, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -S.S(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R, ,, -SC(S)NR10RM, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI I. -SC(NR8)NR10RU, -
NR7C(NR8)NR10RM, -OP(O)(OR7)2S or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RH, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Ru, -SS(O)PNR10RM, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)PNR,0RM, -
NR7S(O)PNR10R1 ,, -OS(O)pOR7, -SS(O)POR7> -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NRi0Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -
NR8S(O)PR7, or -S(O)pNR10Rn, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a hetβroalkyl, -NRioRn, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NRgS(O)pR7, or -S(O)pNR10Rι . ; and R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
187. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRιi, -SC(O)NR10Ri i, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10Ri i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R1W -SS(O)PNR10R1 1, -NR7S(O)11NR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10RU, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)roSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R1 ,, -SS(0)pNR,oRn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR10R11, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRI0R1 ,, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -C(O)OH3 -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(OpR7, or -S(O)pNR10RM; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
188. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RH, -SC(O)NR10RI I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 11 -SS(O)PNR1OR1 I, -NR7S(O)PNR10R1 1, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R1 1, -
NR7C(S)NR10Ru, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10RM, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10RM, -SS(O)PNRi0R11, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR|0Rπ, -SS(O)pNR10R.., - NR7S(O)-NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NRJ)NR1ORI I, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORu, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(ORT)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R∑β is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
189. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ri i, -SC(O)NR
10RI I, -NR
7C(O)NR
10RH, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
75 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R1 1, -NR.StO^NR.oR, ,, - OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R-7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR-,, - SC(NR8)OR7, -NR7C(NR8)OR7 1, -OC(NR8)NR10R1 1, -SCCNR8)NRi0R1 1, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7^; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)roSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10RM, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ru, -SCH2C(O)NR10RH, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 ,, -SS(O)pNR10Rπ, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR.7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR
7C(S)NR
10R
11, -OC(NR
8)R
7, -SC(NR
8)R
7, -NR
7C(NR
8)R
7, -OC(NR
8)OR
7, - SC(NR
8)OR
7, -NR
7C(NR
8)OR
7, -OC(NR
8)NR
10R
11, -SC(NR
8)NR
10R
n, - NR
7C(NR
8)NR
10R
11, -C(O)OH, -C(O)NHR
8, -C(O)SH, -S(O)OH, -S(O)
2OH, - S(O)NHR
8,
or -SPtOXOR,),;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
190. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VIH):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRI0RI i, -SC(O)NR10Rn, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10RI I, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)pNR10Ru, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi,, -SC(NR8)NR10Ru, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(0)NR,oRii, -SC(O)NR10RH, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRl0Ri i, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Riι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNRI0RH, -SS(O)PNR10RΠ , -NR7S(O)PNR10RΠ, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 W -SS(O)11NR1ORn, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substitυted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)PNR10R1,;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
191. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (LX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Rn, -SC(O)NR
10R
n, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0Rn, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)pNRi0Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR,0Rιi, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10RH, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)PNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-OP(θχθR7)2, or -SP(0)(OR7)2;
Rj is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkyny], an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyny 1, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RM, -SC(O)NR10RiI, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRι ι, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)11R7, -
OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNRI0R, ,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R,,, - NR7C(S)NR10R1 ,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SCOfR8)NR10R,,, -
NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR25, -SR26, -NHR26, -0(CH2)mOH, - O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri 1, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(0)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R1 I, -
NR7S(0)pNR,oRi i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri i, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7^ -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Ri I, -SC(NR8)NR10Rn, -
NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
193. A method of inducing degradation of a Bcr-Abl protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H. -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
raOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR,
0Rιi, -SC(O)NR
10Rii, -NR
7C(O)NR
10RH, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R1 1, - NR7CH2C(0)NR,oR| i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 15 -SS(O)PNR10R1 I, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10R11, - NR7C(S)NR10RH, -OC(NRe)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRs)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10Ri ], -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R1., -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1 ,, -SCH2C(O)NRi0R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)-R7, -S(O)POR7, -NR7S(O)-R7, - OS(O)PNR10R1 1, -SS(O)PNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10RI L -SS(O)PNRI0R1 1, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -
NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RU, -SC(NR8)NRi0Rn, - NR7C(NTl8)NRiORn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRg,-0P(0χ0R7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R]8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nirro, guanadino, a haloalkyl, -NR10Ru, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7> -OS(O)PR7, - S(O)POR7, -NR8S(O)pR7, or -S(O)pNRI0Rπ;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
194. The method of any one of Claims 181-193, wherein the compound is administered with an additional therapeutic agent.
195. The method of Claim 194, wherein the additional therapeutic agent is an anticancer agent.
196. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 15 nM in CML cell line K.U812.
197. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent is at least about S times more affective at killing CML cell line KU812 than geldanamycin analogs.
198. The pharmaceutical composition of Claim 196 or 197, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
199. The pharmaceutical composition of Claim 198, wherein the agent is an antibiotic or derivative thereof.
200. The pharmaceutical composition of any one of Claims 196-199, further comprising one or more additional therapeutic agents.
201. The pharmaceutical composition of Claim 200, wherein the additional therapeutic agent is an anticancer agent.
202. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
OC(O)NR10R1 I, -SC(O)NR10Ru, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ru, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 U -SS(O)PNR1OR1 I, -NR7S(O)PNR10RI I, - OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7^; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CHz)1nOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RU, -SC(O)NR10R11, -NR7C(O)NRI0R1 1, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0Ru, -SS(O)PNR10R1 ,, -NR7S(O)pNRl0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Ru, -SS(O)pNRI0Rn, - NR7S(0)pNR|oRu, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri i, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORu, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(ORv)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
203. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (II):
(H) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RM, -SC(O)NR10RI ,, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR10R11, -NR7S(O)pNR10Rπ, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR4)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri ,, -SC(NR8)NR1ORH, - NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10R11, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 I, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRi0R,,, -SS(O)pNR10Rn, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR10R11, - NR7S(O)PNR10R1 1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR|ORU> - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R11, - NR7C(NR8)NRi0Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7),, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NR10Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, -
C(O)NR10Ri 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(OyI7, or -S(O)PNR10R11, or two to five substituents selected from the group consisting of an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRI0RU, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NRi0R11, -NR11C(O)R7, -SR7, -
S(O)PR7, -OS(O)pR7, -S(O)POR7, -NRgS(O)pR7, or -S(O)pNR10R,i; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rj0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R2O, for each occurrence, is independently an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
204. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (III):
(III)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rn, -SC(O)NR10R,,, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri,, -SCH2C(O)NR10R1 ,, -
NR7CH2C(O)NR10R11, -OS(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)PNR1OR1 ,, -NR7S(O)PNR10R, I, -
OS(O)POR7, -SS(O)POR7> -NR7S(O)p0R7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RH, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R,,, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)-R7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)pNR10R, , , -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRe)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, ■ S(O)NHR8, -S(O)2NHRβ,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally 5 substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R|0 and Rn, taken together with the
10 nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an I S optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, 0 -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10RM;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
5 205. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a 30 prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are
optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
raSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R,,, -SC(O)NR
10R,,, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R, ,, -SCH2C(O)NR10RI 1, - NR7CH2C(O)NR1OR1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)11NR10R1,, -NR7S(O)pNR,0R,,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri1, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R1 1, -OP(O)(OR7)2, or -SP(O)(OR,)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0R11, -SC(O)NR10R11, -NR7C(O)NR10R1,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oR,,, -SS(O)pNR10R,i, -NR7S(O)pNR10Ri,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R115 -SS(O)PNR1ORI 1, - NR7S(O)pNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR,oRπ, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHRg,-OP(0)(OR7)2, or -SP(0)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R1), taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
206. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1,, -SC(O)NR
10R
11, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR,0R||, -SC(S)NR10R11, - NR7C(S)NR10RM, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri 1, -SC(NR8)NRi0R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)Z; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CHj)111OH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10RM, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 ,, -SS(O)pNR10R,i, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 1 1 -SS(O)PNRIORM, - NR7S(O)pNR10RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10RM, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NRi0R11, -SC(NR8)NRi0R1 1, - NR7C(NR8)NR10RM, -C(O)OH, -C(O)NHR8, -C(O)SH,. -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR81-OP(O)(OR7),, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl;
p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, I, 2, 3, or 4.
A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the ary 1 or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CHz)
111SH, -S(CH
2)
mNR
7H, - OC(O)NR,
0Rιi, -SC(O)NR,
0Riι, -NR
7C(O)NR
10RI i, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R1 ,, - NR7CH2C(O)NR10R11, -OS(O)-R7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 15 -SS(O)PNR1OR11, -NR7S(O)PNR10RI I, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RH, -SC(S)NR10R11, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NRe)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR1OR1., - NR7C(NR8)NR10R1I, -OP(O)(OR7)2, or -SP(O)(OR7)Z; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI ,, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR|0Rπ, -SCH2C(O)NR, 0Rn, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rπ, -SS(O)PNR10R1,, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)pOR7j -NR7S(O)POR7, -NR7S(O)-R7, -OS(O)PNR1ORI I1 -SS(O)PNR1ORI I, - NR7S(0)pNR,oRu, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10Ri i, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR45)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)., or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Ru, -OR7, -C(O)R7, -C(O)OR7, -
OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)11R^ Or -S(O)PNR10R11; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (IX):
K3 (EK) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)H1SH, -S(CH2)mNR7H, -
OC(0)NR,oRι i, -SC(O)NR10Rn, -NR7C(O)NR10RM, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI 15 -SS(O)PNRIORI I, -NR7S(O)PNR,0RI I, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORi I, -SC(NR8)NRi0R1 1, -
NR7C(NR8)NRi0Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CHi)1nOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR|0Rn, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)11NR10R1 ,, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)-OR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR,0Rn, -
NR7S(O)pNR|0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR1ORiI, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Ri1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
209. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Ky, R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R,,, -SC(O)NR10R11, -NR7C(O)NR10Ri,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R,ι, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R111 -SS(O)PNR10R1 1, -NR7S(O)-NR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, • OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OCCNR8)NR10Rv1, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group;
Rj is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10R, , , -SS(O)PNR, 0R, , , -NR7S(O)pNR10R , , , -OS(O)POR7, -SS(O)11OR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R11^SS(O)PNR10R11, - NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORn, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, ■ S(O)NHR8, -S(O)2NHR«,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
210. A pharmaceutical composition for treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
(XI). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, ■ NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R115 -SS(O)PNR1ORn, -NR7S(O)PNR10R11, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RU, -SC(S)NR10R. i, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NRa)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Ru, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)PR7, - OS(O)-NR10R11, -SS(O)pNR10Rn, -NR7S(O)pNRI0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 N -SS(O)PNR1OR1 1, - NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORu, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted
cycloalkenyl, or a substituted alky!, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)15OR7, -NRgS(O)pR7, or -S(O)pNRI0Rn;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
21 1. The pharmaceutical composition of any one of Claims 202-210, wherein the compound is administered with an additional therapeutic agent.
212. The pharmaceutical composition of Claim 21 1 , wherein the additional therapeutic agent is an anticancer agent.
213. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 10 nM in ALCL cell line Karpas-299.
214. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing ALCL cell line Karpas-299 than geldanamycin analogs.
215. The method of Claim 214, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
216. The method of Claim 214, wherein the agent is an antibiotic or derivative thereof.
A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (I):
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substitυents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR,H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R,,, -SC(0)NRioRn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri,, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 11 -SS(O)PNR1ORM, -NR7S(O)pNR10Rn, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)raOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10Ri „ - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR10Rn> -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)pR7) -OS(O)pNR,0Rii, -SS(O)pNR10R,i, - NR7S(O)pNRI0Rii, -OS(O)POR7, -SS(O)POR7> -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R1I, -
5 NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)Z, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 10 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, I S an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R) 1, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
20 cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 5 R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
218. A method of treating a cancer that expresses an NPM-ALK fusion protein in a 0 subject, comprising administering to the subject an effective amount of a compound represented by formula (II):
(IO or a tautomβr, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to Rj; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0Ri i, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRι i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Ri 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R111 -SS(O)11NR10R11, -NR7S(O)11NR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10R,,, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR3)R7, -NR7C(NR5)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 ,, -OP(O)(OR7)2, or -SP(O)(ORT)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -0(CH2J111NR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri i, -
NR7CH2C(O)NRI0RH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Ri,, -SS(O)pNR,0R,,, -NR7S(O)11NR10R11, -OS(O)POR7> -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7> -OS(O)11NR10R1 L -SS(O)PNR10R11, - NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NRioR, I, -SC(S)NR10R11, -
NR7C(S)NRi0Ru, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NRs)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-OP(0)(OR7)2, or -SP(O)(OR7)2; R2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxy lalkyl, alkoxyalkyl, guanadino, -NR10Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NRgS(O)pR7, or -S(O)pNRi0Rn, or ii) two to five substituents selected from the group consisting of an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted . alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Ru, -NR8C(O)R7, -SR7, - S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R7, or -S(O)PNR10R11; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rt0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
219. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Rι ι, -SC(O)NR10RI I, -NR7C(O)NR10RH , -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(0)NR,oRiι, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R113 -SS(O)PNR10R1 1, -NR7S(O)pNR10Ru, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ru, -SC(S)NR10Ri 1, -
NR7C(S)NR10RM , -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NRe)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NRg)NR10Rn, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1I, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)pNR,0Ru, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNR10Rn, - NR7S(O)11NR10R11, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NRi0Rn, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7),, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rj0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7> -OS(O)PR7, -S(O)POR7, -NRgS(O)pR7, or -S(0)pNR,oRπ;
R26 is a lower alky I; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
220. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -0(CH
2)JMR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10RM, -SC(O)NR
10R
M, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri ,, -SCH2C(O)NR1ORn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)11NR10R1W -SS(O)PNR10R11, -NR7S(O)PNR10RM , -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRI0RI i, -SC(O)NR10Ri i, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(0)NR,oRi i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR,0Rπ, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR1OR1 I, - NR7S(O)PNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRs,-OP(O)(OR7)2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and RM, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, -
0(CHz)1nSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR|0Ri 1, -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)PR7, - OS(O)PNR10R1,, -SS(O)pNR10R,i, -NR7S(O)pNR10Rπ, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRiORn, -SC(NR8)NR10R,,, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R,,, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R11, -SS(O)pNR10Rπ, -NR7S(O)pNR10R,ι, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7> -NR7S(O)PR7, -OS(O)pNR10Ru, -SS(O)PNR10RM, - NR7S(O)pNR10R,,, -OS(O)pOR7j -SS(O)POR7, -NR7S(O)POR7> -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Rn, - NR7C(S)NRi0Ri ,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORM, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORM, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloaikyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloaikyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
222. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
roNR
7H, -
OC(O)NR10RI I, -SC(O)NR10RI i, -NR7C(O)NR10RiI, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Ri ι, - NR7CH2C(O)NRi0R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0Ri i, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rn, -SS(O)PNR10R11, -NR7S(O)pNR,0R,i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNRl0Rn, -SS(O)pNR,0Rn> -
NR7S(O)pNR,0Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -
NR
7C(NR
8)NR
10R
n, -C(O)OH, -C(O)NHR
8, -C(O)SH, -S(O)OH, -S(O)
2OH, - S(O)NHR
8,
or -SP(O)(OR
7)
2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri ι, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7> -NR8S(O)PR7, or -S(O)pNR10R,,; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
223. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (IX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
25, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ri i, -SC(O)NR,
0Ri i, -NR
7C(O)NR
10R. ,, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
75 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R, ,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 11 -SS(O)PNR10R1,, -NR7S(O)pNR,0R, ,, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R1 1, -SC(NR8)NR1ORH, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CHi)1nSH, -S(CH2)mNR7H, -
OC(O)NR10Rn, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10Rn, - NR7CH2C(O)NRi0R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10R,l 5 -SS(O)pNR,0R,,5 -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7> -NR7S(O)POR75 -NR7S(O)PR7, -OS(O)pNR,0R, l5 -SS(O)pNR,0R,,5 - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2) or -SP(O)(OR7J2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
224. A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1 1, -SC(O)NR
10R
11, -NR
7C(O)NR
10Rn, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1U -SS(O)PNR10R11, -NR7S(O)PNR10R11, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRIORI I, - NR7C(NR8)NR1ORH, -OP(O)(OR7)2> or -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(0)NR,oRM, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1L -SS(O)PNR10R11, - NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(ORT)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri0 and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR1OR, , , -SC(O)NR10Ri,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R, i, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)nOR7, -NR7S(O)PR7, - OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Rn, -SC(S)NRi0Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10Rn, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R,,, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)pNR10Rn, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7) -NR7S(O)PR7, -OS(O)PNR1ORI U -SS(O)PNR1OR1 1, - NR7S(O)pNR10Ri ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, - NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHRj1, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and RM > taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -
S(0)pOR
7,
-S(O)
pNR
l0Rπ; R
26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
226. The method of any one of Claims 213-225, wherein the compound is administered with an additional therapeutic agent.
227. The method of Claim 226, wherein the additional therapeutic agent is an anticancer agent.
228. A method of inducing degradation of an NPM-ALK fusion protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC50 for cell survival of less than about 10 nM in ALCL cell line Karpas-299.
229. A method of inducing degradation of an NPM-ALK fusion protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times more affective at killing ALCL cell line Karpas-299 than geldanamycin analogs.
230. The method of Claim 229, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
231. The method of Claim 229, wherein the agent is an antibiotic or derivative thereof.
232. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I):
(D or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substitueπts in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R11, -SC(O)NR10RI I, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR]0Ri i, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10Ri 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1U -SS(O)PNR10Rn, -NR7S(O)PNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri 1, -SC(S)NR10R11, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Ri i, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)roOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 I, -SS(O)pNR10Rιι, -NR7S(O)pNR|0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)11OR71 -NR7S(O)PR7, -OS(O)pNR10Rι,; -SS(O)PNR10R11, - NR7S(O)pNR10Ru, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NRi0Rn, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRβ,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted hetβrocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
233. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (II):
(II) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR I0R11, -
NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR1ORn, -NR7S(O)pNR10Rn, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7) -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)H1NR7H, - OC(O)NR10Ri1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRi ι, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10RJ U -SS(O)PNR10R11, - NR7S(0)pNRioRπ, -OS(O)POR7> -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Rn, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRIORI I, -SC(NR8)NR10Rn, - NR7C(NR8)NRi0R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from nitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NRi0R1 ,, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, -
C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)-R7, or -S(O)pNRi0R,,, or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri u -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10Ri,, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNR,0Rιi; and
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R.6 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
234. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (III):
(HI) or a tautomβr, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10RU, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R^ -SS(O)PNR10R11, -NR7S(O)pNR10RM, - OS(O)pOR7> -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0RM, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1,, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NRi0R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10RM, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)pNRi0R, ,, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, - NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10Ri i, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(OR7)Z, or -SP(O)(OR7)2; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and RM, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRioRn, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)11NR10R1 ,; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
235. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)^OH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1,, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR1ORiI, -SCH2C(O)NR10Ri i, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, - OS(O)PNR1ORI U -SS(O)PNR1OR1 1, -NR7S(O)pNRl0R, ,, -
OS(O)POR7, -SS(0)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, ■ OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1 I, -
NR7C(S)NR10Ri ,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10Rn, - NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mQH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0Rn, -SCH2C(O)NRi0Rn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)pNR10Rn, -SS(O)PNR10R1 ,, -NR7S(O)11NR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNRI0R1 11 -SS(O)PNR10R1 I, - NR7S(O)pNR,0Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R1 1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR5)OR7, -
SC(NR8)OR7, -NR7C(NR4)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORH, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR87-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
236. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
roNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ri
1, -SC(O)NR
10Rii, -NR
7C(O)NRI
0R
1 1, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
71 -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORI 15 -SS(O)PNR1ORI I, -NR7S(O)pNR10R, , , - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10RM, -
NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NRe)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10RH, - NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R1,, -
NR
7CH
2C(O)NR
10R
n, -OS(O)
PR
7, -SS(O)
PR
7, -S(O)
POR
7, -NR
7S(O)
PR
7, - OS(O)
PNRi
0R
1 ,, -SS(O)
11NR
10R
1 ,, -NR
7S(O)
pNR
10R,,, -OS(O)
POR
7, -SS(O)
POR
7, -NR
7S(O)
POR
7, -NR
7S(O)
PR
7,
- NR
7S(O)
15NR
10R
1 ,, -OS(O)
pOR
7, -SS(O)
POR
7, -NR
7S(O)
POR
7, -OC(S)R
7, - SC(S)R
7, -NR
7C(S)R
7, -OC(S)OR
7, -SC(S)OR
7, -
NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Rn, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8)-OP(θχθR7)2, or -SP(0)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rιo and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, I or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
237. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (VlII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NRi0R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 U -SS(O)PNR10R11, -NR7S(O)PNR10RΠ, - OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri1, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7,
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR1ORiI, - NR7C(NR8)NR10Ri1, -OP(O)(OR7)z, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CHz)1nNR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rii, -SS(O)PNR10R11, -NR7S(O)pNR10Rιi, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10R,ι, -SS(O)PNR10RM, - NR7S(0)pNR,oRπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RM, -SC(S)NRI0R1 I, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI i, -SC(NR8)NR10Ru, - NR7C(NR8)NR1ORH, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8^OP(O)(OR7),, or -SP(O)(OR7),;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and RM, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0RiI, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7> - S(O)POR7> -NR8S(O)PR7, or -S(O)pNRl0Rii;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
238. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (EX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R,,, -SC(O)NR
10R
1 1, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R1 U -SS(O)11NR10R11, -NR7S(O)pNR10Rπ, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10R11, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 1, -SC(NR8)NR10R11, - NR7C(NR8)NR10RM, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10Ru, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)pNR10Rιi, -NR7S(O)11NR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(OyMR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10RiI, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR81-OP(O)(ORT)2, or -SP(O)(OR7)2;
R3 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10R11, -SC(O)NRi0Ri i, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, - NR7CH2C(0)NR,oRι ι, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI 11 -SS(O)PNR10R1 1, -NR7S(O)PNR,0RΠ, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR,0Rn, -SC(S)NR10Ri i, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RM, -SC(NRS)NRI0RI ,, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7J2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10RM, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7>
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)11NR10R1 L -SS(O)PNR10R11, -
NR7S(O)PNR10Rn, -OS(O)pOR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NRi0R11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(0)2NHR8,-0P(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
240. A method of inducing degradation of an NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (XT):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Ru, -SC(O)NR
10RiI, -NR
7C(O)NR
10Rn, -OC(O)R
7, -SC(O)R
7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R,,, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(0)pNR,oRπ, -SS(0)pNR,oRi,, -NR7S(O)pNR,0R,i, -
OS(0)POR7, -SS(O)POR7> -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, - NR7C(S)NR10R1 1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NRg)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R, ,, -SC(NR8)NRIOR1 ,, - NR7C(NR8)NR10R, 1, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)JMR7H, - OC(O)NR10RI ,, -SC(O)NR10R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R77 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR
7CH
2C(O)OR
7, -OCH
2C(O)NR
10Ri 1, -SCH
2C(O)NR
10R
11, - NR
7CH
2C(O)NRi
0Rn, -OS(O)
PR
7, -SS(O)
PR
7, -S(O)
POR
7, -NR
7S(O)
PR
7, - OS(0)
pNR,oR,,, -SS(O)
PNR
10R
11, -NR
7S(O)
pNR
10R,,, -OS(O)
POR
7) -SS(O)
POR
7, -NR
7S(O)
POR
7, -NR
7S(O)
PR
7,
- NR
7S(O)
pNR
10Rπ, -OS(O)
POR
7, -SS(O)
POR
7, -NR
7S(O)
POR
7, -OC(S)R
7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R,,, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8^OP(O)(OR7)Z, or -SP(O)(OR7)2;
R7 and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R]0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryi; Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryi, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10R,,;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
241. The method of any one of Claims 228-240, wherein the compound is administered with an additional therapeutic agent.
242. The method of Claim 241, wherein the additional therapeutic agent is an anticancer agent.
243. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent has an ICso for cell survival of less than about 10 nM in ALCL cell line Karpas-299.
244. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated agent that inhibits Hsp90, wherein the agent is at least about S
times more affective at killing ALCL cell line Karpas-299 than geldanamycin analogs.
245. The pharmaceutical composition of Claim 243 or 244, wherein the agent is a molecule having a molecular weight of about 1000 Daltons or less.
246. The pharmaceutical composition of Claim 24S, wherein the agent is an antibiotic or derivative thereof.
247. The pharmaceutical composition of any one of Claims 243-246, further comprising one or more additional therapeutic agents.
248. The pharmaceutical composition of Claim 247, wherein the additional therapeutic agent is an anticancer agent.
249. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (I):
(D or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, OC(0)NR,oRn, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10R11, -
NR7CH2C(O)NR10RI I, -OS(O)PR7, -SS(O)PR7) -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 U -SS(O)PNR1OR, ,, -NR7S(O)11NR1OR,,, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, - NR7C(S)NR10RI I, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORn, -OP(O)(OR7)2, or -SP(O)(OR7)Z;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NR10Ri i, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R, i, -SCH2C(O)NRi0R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRl0R,,, -SS(0)pNR,oRu, -NR7S(O)pNR,0Rj,, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR,0R,,, -SS(O)pNR,0Rπ, - NR7S(0)pNR,oR.i, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri ,, - NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri1, -SC(NR8)NR10RI ,, - NR7C(NR8)NR10Rn, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2;
R3 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl; or Rj0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
250. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (II):
(II) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R,,, -SC(O)NR10Ru, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1ORI 15 -SS(O)PNR1ORH, -NR7S(O)PNR10R1 I , -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1,, -SC(S)NR10R11, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R1 , , -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - 0(CHz)1nSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI I, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR11, -SS(O)11NR10R11, -NR7S(O)pNR10R,,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10RI I 1 -SS(O)PNR10RI 1, - NR7S(O)PNR10R1 1, -OS(O)POR7, -SS(O)pOR7a -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10RU, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R2 is a substituted phenyl, wherein the phenyl group is substituted with: one substituent selected from πitro, cyano, a haloalkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkeπyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl, guanadino, -NRi0Rn, -0-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, - C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, - NR8S(O)PR^ Or -S(O)PNR10Ri11 Or two to five substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyi, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Ri 1, -OR7, -C(O)R7, - C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, - S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)11R7, or -S(O)pNR10Rl i; and R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
251. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (III):
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R3; R, is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RI U -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R^ -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, -SCH2C(O)NR10R11, - NR7CH2C(O)NR1ORM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R115 -SS(O)PNR10R11, -NR7S(O)15NR10R1 ,, -
OS(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10Rn, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR4)R7, -NR7C(NR8)R7, -OC(NRg)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri1, -SC(NR8)NR10R11, - NR7C(NR8)NR10R1 , , -OP(O)(OR7)2, or -SP(O)(OR7)2 ;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NRi0Ri,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)pNRI0Rn > -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)pNR10Rn, -SS(O)pNR10RM, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Ri1, - NR7C(NR8)NRIOR1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl,
an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Ru, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rig is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR|0Ru, -OR7, -C(O)R7, -
C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7 , -S(O)POR7> -NR,,S(O)pR7, or -S(O)pNRI0Rii; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
252. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (Vl):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10Rn, -SC(O)NR
10R,,, -NR
7C(O)NR
10R
H, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, - SCH
2C(O)R
7, -NR
7CH
2C(O)R
7, -OCH
2C(O)OR
7, -SCH
2C(O)OR
7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NRI0RM, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)15OR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)PNR1ORM, -NR7S(O)PNR10RM, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10Ru, -
NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SPCOχOR,^;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S^H^OH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10Ri,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R,,, -SCH2C(O)NR|0R,,, - NR7CH2C(O)NRI0RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7) -NR7S(O)PR7, -
OS(O)pNR10R,,, -SS(O)PNR10R11, -NR7S(O)pNR,0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10RI L -SS(O)PNRI0R1 1, - NR7S(O)pNR|0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORM, -SC(NR8)NR1ORU, - NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7)Z, or -SP(O)(OR7)2; R5 is an optionally substituted heteroaryl or an optionally substituted 8 to
14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyhyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
253. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, - OC(O)NR
10R
1 I, -SC(O)NR
10R
n, -NR
7C(O)NR
10R
11, -OC(O)R
7, -SC(O)R
7, - NR
7C(O)R
7, -OC(O)OR
7, -SC(O)OR
7, -NR
7C(O)OR
7, -OCH
2C(O)R
7, -
SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(0)NR,oRπ, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 W -SS(O)PNR1ORU, -NR7S(O)PNR10RM, - OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7,
OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R,,, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OCCNR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR1ORH, - NR7C(NR8)NR10RI 1, -OP(O)(OR7)2, OΓ -SP(O)(OR7)2;
R2' is an optionally substituted phenyl group; R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -
O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R1 1, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rn, -
NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR10R11, -SS(O)pNR10Rπ, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 L -SS(O)PNR10R11, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -
NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, - NR7C(NR8)NR1ORM, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHRg,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclόalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alky I, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and
m, for each occurrence, is independently, 1 , 2, 3, or 4.
A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (VIII):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3;
R1 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10R,,, -SC(O)NR10RI I, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NRiOR, i, -SCH2C(O)NR10R1,, - NR7CH2C(O)NR1ORH, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)PNR1OR1 L -SS(O)PNR1OR1 1, -NR7S(O)PNR10R11, -
OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri,, -SC(S)NR10R11, -
NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Ri,, -SC(NR8)NR10R1 1, - NR7C(NR8)NR10R11, -OP(O)(OR7)2, Or -SP(O)(OR7V,
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -
OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R, ,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(0)pNRioR,i, -SS(O)pNR10R, ,, -NR7S(O)pNR,0Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -NR7S(COpR7, -OS(O)pNRl0R,,, -SS(0)pNR,oR, „ - NR7S(O)PNRI0RM, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10RI I, -SC(S)NR10RiI, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, - NR7C(NR8)NR10RI ,, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Ri8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)-R7, -
S(O)POR7, -NR8S(O)PR7, or -S(O)pNR,βRi ■;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (IX):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH
1 -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)^SH, -S(CH
2)
mNR
7H, -
OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10Ri 1, - NR7CH2C(O)NR10RN, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 L -SS(O)PNR10R11, -NR7S(O)PNR10R1 1, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 1, -SC(S)NR10Ri 1, - NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1OR11, -SC(NR8)NR10R11, -
NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)^SH, -S(CH2)mNR7H, - OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R1,, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -
SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNR10Rπ, -SS(O)pNR,0Rπ, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -NR7S(O)PR7, -OS(O)PNRI0R1 I. -SS(O)PNR10R, ,, -
NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI i, -SC(NR8)NR10RI I, - NR7IC(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)Z;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
256. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (X):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R, is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CH
2)
mOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10Ri i, -SC(O)NR10Ri,, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R79 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, - NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR1ORI U -SS(O)PNR10R11, -NR7S(O)PNR10R1 ,, -
OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R11, - NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Rn, -SC(NR8)NR10R11, -
NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or -SP(O)(OR7)2; R2' is an optionally substituted phenyl group;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10RM, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -
NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R1 1, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, - OS(O)pNRi0Rn, -SS(O)pNR,0Rn, -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNR10Rn, - NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, - SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR,0Ri i, -SC(S)NR10R1 1, - NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -
SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R1 I, -SC(NR8)NR10R1 1, - NR7C(NR8)NRi0R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, - S(O)NHR8, -S(O)2NHR85-OP(O)(OR7),, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkeny], an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
257. A pharmaceutical composition for treating a cancer that expresses an NPM-ALK fusion protein in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of a compound represented by formula (XI):
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R
3; R
1 is -OH, -SH, -NR
7H, -OR
26, -SR
26, -NHR
26, -O(CH
2)
mOH, - O(CH
2)
mSH, -O(CH
2)
mNR
7H, -S(CHz)
1nOH, -S(CH
2)
mSH, -S(CH
2)
mNR
7H, -
OC(O)NR10RH, -SC(O)NR10Ri1, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, ■ NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, - NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1 I, - NR7CH2C(O)NR10RM, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -
OS(O)PNR10R1 U -SS(O)PNR10R11, -NR7S(O)PNR10R11 , -
OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, - OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10RM, - NR7C(S)NR10Rii, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R1 I, - NR7C(NR8)NR10Ri i, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, - O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, - OC(O)NR10Ri i, -SC(O)NRi0R11, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, - NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, - SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -
NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NRiORi,, - NR7CH2C(O)NR10R1 1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR,S(O)PR7, - OS(O)PNR10RM, -SS(O)pNR10Rn, -NR7S(O)pNR10Rπ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR10R1 I1 -SS(O)11NR1ORI 1, - NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -
SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, - NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Rn, -
NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, - SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR1ORiI, - NR7C(NR8)NR10Ri 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -
S(O)NHR8, -S(O)2NHR8,-OP(O)(OR7)2, or -SP(O)(OR7)2;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R18 is an optionally substituted cycloalkyl, and optionally substituted
cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, - OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, - S(O)POR7, -NR8S(O)PR7, or -S(0)pNR,oRιi;
R26 is a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
258. The method of any one of Claims 249-257, wherein the compound is administered with an additional therapeutic agent.
259. The method of Claim 258, wherein the additional therapeutic agent is an anticancer agent.