Claims for Patent: 8,906,885

Summary for Patent: 8,906,885

Title:	Treating cancer with HSP90 inhibitory compounds
Abstract:	Methods of treating cancer with a compound of formulae (I) or (1a) are disclosed. Also provided are methods of treating a cancer with a mutation in ALK or a c-MET mutation with a compound of formulae (I) or (1a). Further provided are methods of treating non-small cell lung cancer with a mutation in ALK with a compound of formulae (I) or (1a); a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables structural formulae are defined herein.
Inventor(s):	El-Hariry; Iman (Boston, MA), Proia; David (Newton, MA), Vukovic; Vojo (Winchester, MA)
Assignee:	Synta Pharmaceuticals Corp. (Lexington, MA)
Application Number:	14/131,183
Patent Claims:	1. A method of treating cancer in a subject, comprising administering to a subject an effective amount of an Hsp90 inhibitor according to the following formulae: ##STR00120## or ##STR00121## or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Z is OH, SH, or NH.sub.2; X is CR.sub.4 or N; R.sub.1 is --H, --OH, --SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, 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, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7, --C(S)R.sub.7, --C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7, --C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7, --C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11, --C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7, --OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7, --SC(O)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7, --SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11, --OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7, --NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7, --NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7, --NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11, --NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7, --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7, --O(O).sub.pNR.sub.10R.sub.11, S(O).sub.pOR.sub.7, --NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7, --SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; R.sub.2 is --H, --OH, --SH, --NR.sub.7H, --OR.sub.15, --NHR.sub.15, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH, --O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.m0H, --S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H, --OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11, --NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7, --NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7, --NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7, --SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7, --OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7, --NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11, --SCH.sub.2C(O)NR.sub.10R.sub.11, --NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7, --SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11, or --NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11; R.sub.3 is --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, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, --C(O)R.sub.7, --(CH.sub.2).sub.mC(O)OR.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11, --S(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7, or --S(O).sub.pNR.sub.1OR.sub.11; R.sub.4 is --H, --OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, 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, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7, --NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11, or R.sub.3 and R.sub.4 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R.sub.7 and R.sub.5, 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.sub.10 and R.sub.11, 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.sub.10 and R.sub.11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R.sub.15, for each occurrence, is independently, a lower alkyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4, wherein the subject has cancer with a mutation in ALK. 2. The method of claim 1, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer, gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer, melanoma, hepatocellular cancer, solid tumor, liver cancer, head and neck cancer, small cell lung cancer, and non-small cell lung cancer (NSCLC). 3. The method of claim 2, wherein the cancer has been previously treated with an ALK inhibitor and is no longer responsive to the previous treatment. 4. The method of claim 3, wherein the ALK inhibitor is crizotinib. 5. The method of claim 1, wherein the Hsp90 inhibitor is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1- ,2,4]triazole or a tautomer or a pharmaceutically acceptable salt thereof. 6. The method of claim 1, wherein the Hsp90 inhibitor is 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-- 2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the cancer is non-small cell lung cancer. 8. The method of claim 7, wherein the non-small cell lung cancer has an ALK-EML4 fusion. 9. The method of claim 7, wherein the non-small cell lung cancer has an NPM-ALK fusion. 10. The method of claim 7, wherein the non-small cell lung cancer has a KIF5B-ALK fusion. 11. The method of claim 7, wherein the non-small cell lung cancer has a TFG-ALK fusion. 12. The method of claim 1, wherein the Hsp90 inhibitor is administered in combination with one or more additional therapeutic agents. 13. The method of claim 12, wherein the one or more therapeutic agents is selected from the group consisting of erlotinib, bevacizumab, paclitaxel, docetaxel, cisplatin, carboplatin, Abraxane.RTM., pemetrexed, bortezomib, topotecan, cetuximab, gemcitabine, crizotinib and tetracycline. 14. The method of claim 13, wherein the one or more therapeutic agents is erlotinib or bevacizumab. 15. The method of claim 13, wherein the one or more therapeutic agents is docetaxel, paclitaxel or Abraxane.RTM.. 16. The method of claim 13, wherein the one or more therapeutic agents is crizotinib. 17. A method of treating cancer in a subject, comprising administering to the subject an effective amount of 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1- ,2,4]triazole or a tautomer or a pharmaceutically acceptable salt thereof, in combination with crizotinib, wherein the subject has a cancer with a mutation in c-MET. 18. The method of claim 17, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, ocular melanoma, prostate cancer, gastrointestinal stromal tumors (GIST), advanced esophagogastric cancer, melanoma, hepatocellular cancer, solid tumor, liver cancer, head and neck cancer, small cell lung cancer, and non-small cell lung cancer (NSCLC). 19. The method of claim 18, wherein the cancer is non-small cell lung cancer. 20. The method of claim 18, wherein the cancer is breast cancer. 21. A method of treating cancer in a subject, comprising administering to the subject ganetespib or a tautomer or a pharmaceutically acceptable salt thereof, in the amount from about 100 mg/m.sup.2 to about 500 mg/m.sup.2, wherein the subject has a cancer with a mutation in ALK. 22. The method of claim 21, wherein the cancer is non-small cell lung cancer. 23. The method of claim 21, wherein further comprising administering crizotinib to the subject.

Details for Patent 8,906,885

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2031-07-07
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2031-07-07
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2031-07-07