Anticancer compounds, their pharmaceutical compositions and methods of treating cancer using same

Abstract

The present invention provides compounds having the general structure: (I) wherein R1, R2, R3, R4 are defined throughout the application.

Description

Docket: 92608-A-PCT / GJG / YX ANTICANCER COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATING CANCER USING SAME

[0001] Throughout this application, various publications are referenced, including referenced inparenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 672,864 filed July18, 2024, the contents of which is hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under CA237154 awarded by NationalInstitutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION

[0004] Taxoids, a class of microtubule-stabilizing agents, have been widely employed in cancertherapy due to their potent cytotoxic effects. However, first and second-generation taxoids, including paclitaxel and docetaxel, face challenges of multidrug resistance (MDR) and limited selectivity for tumor cells. To address these issues, third-generation taxoids with fluorinated moieties and structural modifications have been developed. The papers from Bioorganic Chemistry (2020, 2022) describe the synthesis, biological evaluation, and efficacy of these next-generation taxoids against drug-sensitive and MDR cancer cell lines (Wang 2020 and Ojima 2008).

[0005] The taxoids SB-T-1214, SB-T-12854-06, SB-T-12857-06, SB-T-121605, SB-T-121606evaluated in these studies include DFV-taxoids (difluorovinyl derivatives) and fluorotaxoids, synthesized using the Ojima-Holton coupling and the β-lactam synthon methods (Figure 1).

[0006] These compounds incorporate fluorinated benzoyl groups at the C2 position and a DFV groupat the C3′ position, enhancing their stability and cytotoxic potency. Molecular docking studies revealed that fluorine atoms formed unique van der Waals interactions with β-tubulin, contributing to superior microtubule binding affinity compared to paclitaxel and docetaxel (Wang 2020, Ojima 2008, Wang 2022, and Kuznetsova 2012).BRIEF SUMMARY OF THE INVENTION

[0007] The present invention provides a compound having the structure:R1R3O O O O O , whereinR1is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl; R2is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3is -H or alkyl; and R4 is alkyl, alkenyl, CHF2 or -CF3; andwherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0008] The present invention provides a method of inhibiting the growth of cancer cells in a subject,wherein the method comprises administering an effective amount of a compound having the structure: R1R3O ,wherein 2R1is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl; R2is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3is -H or alkyl; and R4 is alkyl, alkenyl, CHF2 or -CF3; andwherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0009] The present invention provides a process for producing a compound having the structure:R1O O R O3O , wherein the process compr ses: (a) reacting a compound of Formula I(Formula I) 3with to produce a compound of Formula II: (Formula II); and (b) conducting a deprotection reaction to produce a compound of Formula III:(Formula III), whereinR5, R6, R7, R8, and R9 are each independently -H, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl; preferably, R5, R6, R7, R8, and R9are each independently -H, -F, -Cl, -Br, -CN, C1-C6alkyl, C1-C6alkoxy, C1-C6acyl, or C1-C6alkylthio; 4R10, R11, R12, R13, and R14are each independently -H, -CHF2, -CH2F, -CF3, -O-CHF2, -O-CH2F, - O-CF3, -S-CHF2, -S-CH2F, -S-CF3,halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cyano, or azido; preferably, R10, R11, R12, R13, and R14are each independently -H, -F, -Cl, -Br, -CHF2, - CH2F, -CF3, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S- CHF2, -S-CH2F, or -S-CF3; more preferably, R10, R11, R12, R13, and R14are each independently -H, -O-CHF2, - O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F; more preferably, R10, R11, R12, R13, and R14 are each independently -H, -O- CHF2, or -O-CF3; and R15, R16, and R17 are each independently H, halogen, or alkyl; preferably, R15, R16 and R17 are -H, -F or methyl. 5BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1. Structures of previously designed 2nd and 3rd generation taxoids and DFV taxoids.

[0011] Figure 2. A: Structure of DTX-AI and in vivo safety evaluation of DTX-AI. Survival ratiochanges after i.v. injection of PBS, DTX injection, DTX / fat emulsion and DTX-AI / fat emulsion in HeLa tumor-bearing nude mice. B: Cytotoxicity assay of DTX-AI with drug sensitive cancer cell lined. Cell viability of MCF-7 cells and HeLa cells determined by MTT assay, which were incubated with DTX or DTX-AI at various concentrations for 72 h. C: Cell viability of normal / non-cancerous MRC-5 cells and L929 cells incubated with DTX and DTX-AI after 72 h at the various concentrations determined by MTT assay. Adapted from reference.

[0012] Figure 3A, 3B, 3C and 3D. Structures of newly designed 2nd and 3rd generation taxoids / DFVtaxoids.

[0013] Figure 4. Synthesis of DTX-AI.

[0014] Figure 5. Synthesis of a series of 2nd generation taxoids.

[0015] Figure 6 Synthesis of a series of 2nd generation DFV taxoids.

[0016] Figure 7. Synthesis of 05 series of 3rd generation taxoids.

[0017] Figure 8. Synthesis of 06 series of 3rd generation taxoids.

[0018] Figure 9. Synthesis of 05 series of 3rd generation DFV taxoids.

[0019] Figure 10. Synthesis of 06 series of 3rd generation DFV taxoids.6DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention provides a compound having the structure:R1O R3O O O O , whereinR1is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl; R2is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3is -H or alkyl; and R4 is alkyl, alkenyl, -CHF2, or -CF3; and wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0021] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is (a) unsubstituted, or (b) substituted.

[0022] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is substituted with one or more of halogen, -OCF3, -CHF2, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl.

[0023] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is substituted with one or more of halogen, -OH, -CN, -CHF2, -CH2F, -CF3, alkyl, alkenyl, alkynyl, carbonyl, alkoxy, thioether, aryloxy, heteroaryloxy, sulfonyl, nitro, nitrosyl; nitrile, mercapto; sulfanyl, cyano; amino, carboxyl. aryl, heteroaryl, cycloalkyl or heterocycloalkyl. 7

[0024] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is substituted with one or more of -F, -Cl, -Br, -I, -CN, -NH2, -NO2, -CHF2, -CH2F, -CF3, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl; -O-C1-C6alkyl, -O-C1-C6alkenyl, -O-C1-C6alkynyl, -S-C1-C6alkyl, -S-C1-C6alkenyl, -S-C1-C6alkynyl, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S-CF3, -CO- C1-C6alkyl, -CO-C1-C6alkenyl, or -CO-C1-C6alkynyl.

[0025] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is substituted with one or more of -H, -F, -Cl, -Br, -CN, -OCF3, -CHF2, C1-C6alkyl, C1- C6alkoxy, C1-C6acyl, or C1-C6alkylthio.

[0026] In some embodiments, any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl is substituted with one or more of -F, C1-C6 alkyl, -OCF3, -CHF2, C1-C6 alkoxy, C1-C6 alkylthio, or -C1-C6 alkanoyl.

[0027] In some embodiments, R1 is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl,-NH-alkyl-aryl, -NH-alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH- alkynyl-heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl.

[0028] In some embodiments, R1 is -NH-aryl, -NH-heteroaryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, or -NH-alkynyl-heteroaryl.

[0029] In some embodiments, R1 is -NH-aryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, or -NH-alkynyl-aryl.

[0030] In some embodiments, R1 is -NH-aryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, or -NH-alkynyl-aryl,and wherein aryl is a substituted aryl.

[0031] In some embodiments, R1 is -NH-aryl and wherein aryl is a substituted aryl.

[0032] In some embodiments, aryl is substituted with one or more of -F, -Cl, -Br, -CN, N3, -CHF2, -CH2F, -CF3, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl; C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C1-C6 alkylthio, C1-C6 alkenylthio, C1-C6 alkynylthio, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S- CF3, C1-C6 alkanoyl, C1-C6 alkenoyl, or C1-C6 alkynoyl.

[0033] In some embodiments, aryl is substituted with one or more of -F, -Cl, -Br, C1-C6 alkyl, C1-C6alkoxy, C1-C6 alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S-CF3, or C1-C6 alkanoyl.

[0034] In some embodiments, aryl is substituted with one or more of C1-C6 alkoxy, C1-C6 alkylthio,or C1-C6alkanoyl.

[0035] In some embodiments, R1 has the structure:8, wherein R5, R6, R7, R8, and R9are each independently -H, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl.

[0036] In some embodiments, R5, R6, R7, R8, and R9 are each independently -H, halogen, alkyl,alkanoyl, alkoxy, alkylthio, aryloxy, heteroaryloxy, cyano, or azido.

[0037] In some embodiments, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, C1-C6alkyl, alkoxy, carbonyl, thioether, or nitro.

[0038] In some embodiments, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, or C1-C6 alkylthio.

[0039] In some embodiments, R5, R6, R7, R8, and R9 are each independently H, C1-C6 alkoxy, C1-C6alkylthio, or C1-C6 alkanoyl.

[0040] In some embodiments, at least one of R5, R6, R7, R8, and R9 is not -H.

[0041] In some embodiments, one of R5, R6, R7, R8, and R9 is not -H.

[0042] In some embodiments, at least four of R5, R6, R7, R8, and R9 are same.

[0043] In some embodiments, four of R5, R6, R7, R8, and R9 are each -H.

[0044] In some embodiments, one of R5, R6, R7, R8, and R9 is C1-C6 alkoxy, C1-C6 alkylthio, or C1-C6alkanoyl.

[0045] In some embodiments, one of R5, R6, R7, R8, and R9 is C1-C6 alkoxy, C1-C6 alkylthio, or C1-C6alkanoyl and the remaining of R5, R6, R7, R8, and R9 are each -H.

[0046] In some embodiments, R1 has the structure:, ,or . 9

[0047] In some embodiments, R2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

[0048] In some embodiments, R2 is aryl, or heteroaryl.

[0049] In some embodiments, R2 is aryl.

[0050] In some embodiments, R2 is an unsubstituted or substituted phenyl.

[0051] In some embodiments, aryl is (a) unsubstituted, or (b) substituted.

[0052] In some embodiments, aryl is substituted with one or more of halogen, -OH, -CN, -N3, -CHF2,-CH2F, -CF3, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio-O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S- CH2F, or -S-CF3.

[0053] In some embodiments, aryl is substituted with one or more of -F, -Cl, -Br, -CN, -CHF2, -CH2F,-CF3, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl; C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C1-C6 alkylthio, C1-C6 alkenylthio, C1-C6 alkynyloxy, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S-CF3, C1-C6 alkanoyl, C1-C6 alkenoyl, or C1-C6 alkynoyl.

[0054] In some embodiments, aryl is substituted with one or more of -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F.

[0055] In some embodiments, aryl is substituted with one or more of -O-CHF2 or -O-CF3.

[0056] In some embodiments, R2 has the structure:R1110,wherein R10, R11, R12, R13, and R14are each, gen, -CHF2, -CH2F, -CF3, -O-CHF2, -O- CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S-CF3, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cyano, or azido.

[0057] In some embodiments, R10, R11, R12, R13, and R14 are each independently -H, -F, -Cl, -Br, -CHF2, -CH2F, -CF3, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S- CH2F, or -S-CF3.

[0058] In some embodiments, R10, R11, R12, R13, and R14 are each independently -H, -F, -Cl, -Br, -CHF2, -CH2F, -CF3, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl; C1-C6alkoxy, C1-C6alkenyloxy, C1-C6alkynyloxy, C1-C6alkylthio, C1-C6alkenylthio, C1-C6alkynyloxy, 10

[0059] In some embodiments, R10, R11, R12, R13, and R14 are each independently -H, -F, -Cl, -Br, -CHF2, -CH2F, -CF3, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S- CH2F, or -S-CF3.

[0060] In some embodiments, R10, R11, R12, R13, and R14 are each independently -H, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F.

[0061] In some embodiments, R10, R11, R12, R13, and R14 are each independently -H, -O-CHF2, or -O-CF3.

[0062] In some embodiments, at least one of R10, R11, R12, R13, and R14 is not -H.

[0063] In some embodiments, one of R10, R11, R12, R13, and R14 is not -H.

[0064] In some embodiments, at least four of R10, R11, R12, R13, and R14 are same.

[0065] In some embodiments, all of R10, R11, R12, R13, and R14 are same.

[0066] In some embodiments, all of R10, R11, R12, R13, and R14 are each -H.

[0067] In some embodiments, one of R10, R11, R12, R13, and R14 is -O-CF3 or –O-CHF2.

[0068] In some embodiments, one of R10, R11, R12, R13, and R14 is -O-CF3 or –O-CHF2 and theremaining of R10, R11, R12, R13, and R14 are each -H.

[0069] In some embodiments, R2 has the structure:.

[0070] In some embodimen, 3 .

[0071] In some embodiments, R3 is -H or methyl.

[0072] In some embodiments, R3 is -H.

[0073] In some embodiments, R4 is alkyl, alkenyl, -CHF2, or -CF3.

[0074] In some embodiments, R4 is alkenyl, -CHF2, -CF3.

[0075] In some embodiments, R4 is an alkenyl.

[0076] In some embodiments, R4 is a substituted alkenyl.11

[0077] In some embodiments, R4 is a substituted alkenyl substituted with F, Cl, Br, or C1-C6 alkyl.

[0078] In some embodiments, R4 has the structure:, wherein R15, R16, and R17 are each independen r alkyl.

[0079] In some embodiments, R15, R16, and R17 are each independently -H, -F, -Cl, -Br, or alkyl.

[0080] In some embodiments, R15, R16, and R17 are each independently -H, -F, -Cl, -Br, or C1-C6 alkyl.

[0081] In some embodiments, R15, R16, and R17 are each independently -H, -F, or -CH3.

[0082] In some embodiments, at least one of R15, R16, and R17 is not H.

[0083] In some embodiments, at least two of R15, R16, and R17 are not H.

[0084] In some embodiments, at least two of R15, R16, and R17 are same.

[0085] In some embodiments, R16 and R17 are same.

[0086] In some embodiments, one of R15, R16, and R17 is -H and the other two of R15, R16, and R17 areeach -F or -CH3.

[0087] In some embodiments, R4 has the structure:.

[0088] The present inventioe structure:R1R3O , wherein12R1is -NH-aryl, -NH-heteroaryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl- heteroaryl, -NH-alkenyl-heteroaryl, or -NH-alkynyl-heteroaryl; R2is aryl or heteroaryl; R3is -H or methyl; and R4is alkyl, alkenyl, CHF2or -CF3; and wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0089] The present invention provides a compound having the structure:R1O O R O3O , whereinR1 is -NH-aryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, or -NH-alkynyl-aryl; R2 is aryl or heteroaryl; R3 is -H or methyl; and R4 is alkyl, alkenyl, CHF2 or -CF3; and wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0090] The present invention provides a compound having the structure:, 13wherein R1is -NH-aryl or -NH-alkyl-aryl; R2is aryl; R3is -H or methyl; and R4is alkyl, or alkenyl; and wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0091] The present invention provides a compound having the structure:, .14

[0092] The present invention provides a compound having the structure:.

[0093] .

[0094] e pese ve o pov es a co pound having the structure:. 15

[0095] The present invention provides a compound having the structure:, , ,,, ,16, , ,,, , 17, , ,,, or . 18

[0096] The present invention provides a compound having the structure:, ,, , ,, or19.

[0097] The present invention provides a compound having the structure:, ,, ,20, ,, or .

[0098] The present invention provides a s composition comprising the compound disclosed inparagraphs

[0020] -

[0097] and a pharmaceutically acceptable carrier or pharmaceutically active agent.

[0099] In some embodiments, the composition is a pharmaceutical composition.

[0100] The present invention provides a method of inhibiting the growth of cancer cells in a subject,wherein the method comprises administering an effective amount of a compound having the structure: , 21wherein R1is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl, R2is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3is -H or alkyl; and R4 is alkyl, alkenyl, -CHF2 or -CF3; andwherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

[0101] The present invention provides a method of treating cancer in a subject, wherein the methodcomprises administering an effective amount of a compound having the structure: , whereinR1 is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or NH-alkynyl-heterocycloalkyl, R2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3 is H or alkyl; and R4 is alkyl, alkenyl, -CHF2 or -CF3; andwherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted. 22

[0102] In the method, the compound structures are each of the compound embodiment above inparagraphs

[0020] -

[0097] .

[0103] In some embodiments, the effective amount of the compound disclosed herein or thecomposition disclosed herein inhibits the growth of more cancer cells than normal cells in the subject.

[0104] In some embodiments, the effective amount of the compound disclosed herein or thecomposition disclosed herein inhibits 10-10000 times more cancer cells than normal cells.

[0105] In some embodiments, the method further comprises administering an anticancer therapy.

[0106] In some embodiments, the subject is receiving the anticancer therapy prior to administering thecompound or the composition disclosed herein.

[0107] In some embodiments, the anticancer therapy and the compound or the composition disclosedherein are administered sequentially.

[0108] In some embodiments, the anticancer therapy and the compound or the composition disclosedherein are administered simultaneously.

[0109] In some embodiments, the compound or the composition disclosed herein is administeredorally, intravenously, subcutaneously , or intraperitoneally.

[0110] In some embodiments, the anticancer therapy is taxane.

[0111] In some embodiments, the cancer is prostate cancer, skin cancer, breast cancer, hepatocellularcarcinoma, cervical cancer, ovarian cancer, lung cancer, or colon cancer.

[0112] In some embodiments, the subject is a mammal.

[0113] In some embodiments, the mammal is human.

[0114] The present invention provides a method of inhibiting the growth of more breast cancer cellsthan normal cells in the subject, wherein the method comprises administering an effective amount of acompound of SB-T-1216C106, SB-T-1216C205, SB-T-12854C105, SB-T-1216C306, SB-T-12854C205,SB-T-12854C305, or SB-T-12854C306.

[0115] The present invention provides a method of inhibiting the growth of breast cancer cells in asubject, wherein the method comprises administering an effective amount of a compound having the structure: 23O HN .breastcancer cells than normal cells in the subject, wherein the method comprises administering an effectiveamount of a compound of SB-T-12854C105, SB-T-1216C206, SB-T-1216C106, SB-T-12854C306, SB-T-12854C205, or SB-T-1216C205.

[0117] The present invention provides a method of inhibiting the growth of triple-negative breastcancer cells in a subject, wherein the method comprises administering an effective amount of a compound having the structure: O ,or

[0118] The present invention provides a method of inhibiting the growth of cervical cancer cells thannormal cells in the subject, wherein the method comprises administering an effective amount of a compound 24of SB-T-12854C2, SB-T-1216C205, SB-T-1216C206, SB-T-12854C305, SB-T-12854C105, SB-T- 1216C306, SB-T-1216C106, SB-T-12854C205, SB-T-12854C106, or SB-T-12854C306.

[0119] The present invention provides a method of inhibiting the growth of cervical cancer cells in asubject, wherein the method comprises administering an effective amount of a compound having the structure: .wth of prostate cancer cells thannormal cells in the subject, wherein the method comprises administering an effective amount of a compound of SB-T-1216C2, SB-T-12854C1, SB-T-1216C205, SB-T-1216C206, SB-T-1216C106, SB-T-1216C306, SB-T-12854C105, SB-T-12854C205, SB-T-12854C206, or SB-T-12854C306.

[0121] The present invention provides a method of inhibiting the growth of prostate cancer cells in asubject, wherein the method comprises administering an effective amount of a compound having the structure: .

[0122] The present invention provides a method of inhibiting the growth of colon cancer cells thannormal cells in the subject, wherein the method comprises administering an effective amount of a compound 25of SB-T-1216C205, SB-T-1216C305, SB-T-1216C106, SB-T-1216C206, SB-T-1216C306, SB-T- 12854C105, or SB-T-12854C205.

[0123] The present invention provides a method of inhibiting the growth of colon cancer cells in asubject, wherein the method comprises administering an effective amount of a compound SB-T-1216C205.

[0124] In some embodiments, the mammal is human.

[0125] The present invention provides a process for producing the compound disclosed herein, theprocess comprises: (a) reacting a compound of Formula I(Formula I) with to produce a compound of Formula II (Formula II); and 26(b) conducting a deprotection reaction to produce a compound of Formula III:(Formula III), whereinR5, R6, R7, R8, and R9are each independently -H, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl; preferably, R5, R6, R7, R8, and R9are each independently -H, -F, -Cl, -Br, -CN, C1-C6alkyl, C1-C6alkoxy, C1-C6acyl, or C1-C6alkylthio; R10, R11, R12, R13, and R14are each independently -H, -CHF2, -CH2F, -CF3, -O-CHF2, -O-CH2F, - O-CF3, -S-CHF2, -S-CH2F, -S-CF3,halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cyano, or azido; preferably, R10, R11, R12, R13, and R14are each independently -H, -F, -Cl, -Br, -CHF2, - CH2F, -CF3, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S- CHF2, -S-CH2F, or -S-CF3; more preferably, R10, R11, R12, R13, and R14are each independently -H, -O-CHF2, - O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F; more preferably, R10, R11, R12, R13, and R14are each independently -H, -O- CHF2, or -O-CF3; and R15, R16, and R17 are each independently H, halogen, or alkyl; preferably, R15, R16 and R17 are -H, -F or methyl. 27

[0126] In some embodiments, the compound has the structure:.

[0127] In the process, tcompound embodiment above inparagraphs

[0020] -

[0097] .

[0128] The process disclosed herein can be used to make any of the compound embodiment above inparagraphs

[0020] -

[0097] .

[0129] In some embodiments, step (a) is conducted in the presence of a base; preferably, the base isan organic base, more preferably, the base is a strong, non-nucleophilic base; more preferably, the base is an amide base; more preferably, the base is lithium bis(trimethylsilyl)amide (LiHMDS).

[0130] In some embodiments, step (a) is conducted in the presence of a solvent; preferably, the solventis an organic solvent; more preferably, the solvent is a heterocyclic compound; more preferably, the solvent is tetrahydrofuran (THF).

[0131] In some embodiments, step (a) is conducted at a temperature from -900C to -100C; preferably,from -800C to -200C; more preferably, from -700C to -300C; more preferably, from -600C to -300C; more preferably, from -500C to -300C; more preferably, from -450C to -350C; more preferably, at -400C.

[0132] In some embodiments, step (a) is conducted at a period from 40 to180 minutes; preferably,from 40 to 160 minutes; more preferably, from 40 to 140 minutes; more preferably, from 40 to 120 minutes; more preferably, from 60 to 120 minutes.

[0133] In some embodiments, step (b) is conducted in the presence of an acid; preferably, the acid isan inorganic base, more preferably, the acid is a strong, corrosive base; more preferably, the acid ishydrogen fluoride (HF). 28

[0134] In some embodiments, step (b) is conducted in the presence of one or more solvents; preferably,the one or more solvents is an organic solvent; more preferably, the one or more solvents is pyridine and acetonitrile (MeCN).

[0135] In some embodiments, step (b) is conducted at a temperature from -300C to 300C; preferably,from -200C to 300C; more preferably, from -100C to 300C; more preferably, from -50C to 300C; more preferably, from 00C to 250C.

[0136] In some embodiments, step (b) is conducted at a period of 10-40 hours; preferably, at 10-30hours; more preferably, at 15-25 hours; more preferably, at 18-24 hours; more preferably, at 21 hours,

[0137] In some embodiments, Formula III has the structure:.

[0138] In some embodimen s, e compoun o ormu a s pro uced from(a) reacting a compound of Formula (IV)(Formula IV)with a protecting agent to produce a compound of Formula V: 29(Formula V); and (b) reacting Formul to produce the compound of Formula I.

[0139] In some embodit contains a trimethylsilyl group; preferably, theprotecting agent is trimethylsilyl fluoride or trimethylsilyl chloride; more preferably, the protecting agent is trimethylsilyl chloride.

[0140] In some embodiments, step (a) is conducted in the presence of an organic compound;preferably, the organic compound is a heterocyclic organic compound, more preferably, the heterocyclic organic compound has a five-membered aromatic ring; more preferably, the organic compound is imidazole.

[0141] In some embodiments, step (a) is conducted in the presence of a solvent; preferably, the solventis an organic solvent; more preferably, the solvent is dimethylformamide (DMF).

[0142] In some embodiments, step (a) is conducted at a temperature from -300C to 300C; preferably,from -200C to 300C; more preferably, from -100C to 300C; more preferably, from -50C to 300C; more preferably, from 00C to 250C.

[0143] In some embodiments, step (a) is conducted at a period from 10 to 60 minutes; preferably, from10 to 50 minutes; more preferably, from 20 to 50 minutes; more preferably, from 30 to 50 minutes; more preferably, of 40 minutes.

[0144] In some embodiments, step (b) is conducted in the presence of a base; preferably, the base isan organic base, more preferably, the base is a strong, non-nucleophilic base; more preferably, the base is an amide base; more preferably, the base is lithium bis(trimethylsilyl)amide (LiHMDS). 30

[0145] In some embodiments, step (b) is in the presence of a solvent; preferably, the solvent is anorganic solvent; more preferably, the solvent is heterocyclic; more preferably, the solvent is tetrahydrofuran (THF).

[0146] In some embodiments, step (b) is conducted at a temperature from -900C to -100C; preferably,from -800C to -200C; more preferably, from -700C to -300C; more preferably, from -600C to -300C; more preferably, from -500C to -300C; more preferably, from -450C to -350C; more preferably, at -400C.

[0147] In some embodiments, step (b) is conducted at a period from 10 to 60 minutes; preferably, from10 to 50 minutes; more preferably, from 10 to 40 minutes; more preferably, from 20 to 35 minutes; more preferably, of 30 minutes.

[0148] The present invention provides a compound according to formula I:wherein:X is selected from O and S; R1is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and C0-6alkyl- unsubstituted or substituted with one or more substituents selected from halogen, C0-6alkyl-, C0-6alkyl-O-, C0-6alkyl-CO-, C0-6alkyl-S-, C0-6alkyl-NH-, aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl; Y1and Y2are each independently selected from halogen, C0-6alkyl-, and C0-6alkyl-O-; Z is selected from CF3-C0-6alkyl-O-, CHF2-C0-6alkyl-O-, C0-6alkyl-O-, C0-6alkyl-CO-, and C0-6alkyl-S-; and R2is C0-6alkyl-.

[0149] In some embodiments, R1 is selected from aryl and heteroaryl unsubstituted or substituted withone or more substituents selected from C1-3alkyl-O-, C1-3alkyl-CO-, and C1-3alkyl-S-. 31

[0150] In some embodiments, X is selected from C1-3alkyl-O-, C1-3alkyl-CO-, and C1-3alkyl-S-.

[0151] In some embodiments, Y1 and Y2 are each independently selected from fluorine, chlorine,bromine, methyl, ethyl, and propyl.

[0152] In some embodiments, wherein Z is selected from trifluoromethoxy and difluoromethoxy.

[0153] In some embodiments, the stereochemistry at the C-10 position is R or S.

[0154] The present invention provides a pharmaceutical composition comprising a compoundaccording to claim 33 and a pharmaceutically acceptable carrier.

[0155] The present invention provides a method of treating cancer in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of a compound according to formula I: wherein:X is selected from halogen, C0-6alkyl-, C0-6alkyl-O-, C0-6alkyl-CO-, C0-6alkyl-S-, C0-6alkyl-NH-, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl; Y1and Y2are each independently selected from halogen, C0-6alkyl-, C0-6alkyl-O-; and Z is selected from CF3-C0-6alkyl-O-, CHF2-C0-6alkyl-O-, C0-6alkyl-O-, C0-6alkyl-CO-, C0-6alkyl-S-.

[0156] The present invention provides a method of treating cancer in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of a compound disclosed herein in combination with another anticancer agent.

[0157] In some embodiments, the cancer is selected from ovarian cancer, breast cancer, lung cancer,colon cancer, and cervical cancer. 32

[0158] The present invention provides a method of treating cancer in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of a compound disclosed herein in combination with another anticancer agent.

[0159] In some embodiments, the cancer is selected from ovarian cancer, breast cancer, lung cancer,colon cancer, and cervical cancer.

[0160] The compounds of the subject invention may have spontaneous tautomeric forms. In caseswherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

[0161] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atomshaving less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.

[0162] This invention also provides isotopic variants of the compounds disclosed herein, includingwherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.

[0163] It is understood that the structures described in the embodiments of the methods hereinabovecan be the same as the structures of the compounds described hereinabove.

[0164] It is understood that where a numerical range is recited herein, the present inventioncontemplates each integer between, and including, the upper and lower limits, unless otherwise stated.

[0165] Except where otherwise specified, if the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. 33

[0166] Except where otherwise specified, the subject invention is also intended to include all isotopesof atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0167] It will be noted that any notation of a carbon in structures throughout this application, whenused without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.

[0168] It will also be noted that any notation of a hydrogen in structures throughout this application,when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein.

[0169] Isotopically-labeled compounds can generally be prepared by conventional techniques knownto those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.

[0170] In the compounds used in the method of the present invention, the substituents may besubstituted or unsubstituted, unless specifically defined otherwise.

[0171] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl.

[0172] In choosing the compounds used in the method of the present invention, one of ordinary skillin the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.

[0173] The present invention provides a use of the compound or the composition disclosed herein ininhibiting the growth of cancer cells or treating cancer.

[0174] The present invention provides the compound or the composition disclosed herein for use ininhibiting the growth of cancer cells or treating cancer.

[0175] In some embodiments, the present invention includes a pharmaceutically acceptable salt of anyof the above compounds of the present invention. 34

[0176] In some embodiments, a salt of the compound of the present invention is used in any of theabove methods, uses, packages or compositions.

[0177] In some embodiments, a pharmaceutically acceptable salt of the compound of the presentinvention is used in any of the above methods, uses, packages or compositions.

[0178] In some embodiments, an ester of the compound of the present invention is used in any of theabove methods, uses, packages or compositions.

[0179] Any of the above compounds may be used in any of the disclosed methods, uses, packages orpharmaceutical compositions.

[0180] Any of the compounds used in the disclosed methods, uses, packages or pharmaceuticalcompositions may be replaced with any other compound disclosed in the present invention.

[0181] Any of the above generic compounds may be used in any of the disclosed methods, uses,packages or compositions.

[0182] A person skilled in the art may use the techniques disclosed therein to prepare compoundswhich are not enriched in deuterium and thereafter use the techniques disclosed herein to prepare deuterium analogs thereof.

[0183] Except where otherwise specified, the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, scalemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

[0184] Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weightof 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.0156%. Thus, in a composition comprising molecules of a naturally occurring compound, the level of deuterium at a particular hydrogen atom site in that compound is expected to be 0.0156%. Thus, a composition comprising 35a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% is novel over its naturally occurring counterpart.

[0185] In the compounds used in the method of the present invention, the substituents may besubstituted or unsubstituted, unless specifically defined otherwise.

[0186] This invention also provides isotopic variants of the compounds disclosed herein, includingwherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.

[0187] It is understood that the structures described in the embodiments of the methods hereinabovecan be the same as the structures of the compounds described hereinabove.

[0188] It is understood that where a numerical range is recited herein, the present inventioncontemplates each integer between, and including, the upper and lower limits, unless otherwise stated.

[0189] Except where otherwise specified, if the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

[0190] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

[0191] As used herein, "alkyl" is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cnas in “C1–Cnalkyl" is defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12alkyl, C2-C12alkyl, C3-C12alkyl, C4-C12alkyl and so on. ”Alkoxy" represents an alkyl group as described above attached through an oxygen bridge. 36

[0192] The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched,containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present. Thus, C2-Cnalkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.

[0193] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2- Cn alkynyl. An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on.

[0194] “Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkeneand alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.

[0195] As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.

[0196] As used herein, "heterocycle" or " heterocycloalkyl " as used herein is intended to mean a 5- to10-membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. "Heterocycloalkyl " therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. 37

[0197] As used herein, "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbonatoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

[0198] As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 10 atoms andmay be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl.

[0199] As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 10 atoms that isfused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene.

[0200] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbonring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0201] As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiplefused ring structures, which may be unsubstituted or substituted.

[0202] The term “arylalkyl” refers to alkyl groups as described above wherein one or more bonds tohydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.

[0203] The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclicring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- 38membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra- hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0204] The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or morebonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.

[0205] The term "heterocycle" or “heterocyclyl” refers to a mono- or poly-cyclic ring system whichcan be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, 39pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

[0206] The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocycloalkyl substituents may besubstituted or unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

[0207] As used herein, the term “halogen” refers to F, Cl, Br, and I.

[0208] The terms “substitution”, “substituted” and “substituent” refer to a functional group asdescribed above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0209] It is understood that substituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. 40

[0210] In choosing the compounds of the present invention, one of ordinary skill in the art willrecognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.

[0211] The various R groups attached to the aromatic rings of the compounds disclosed herein may beadded to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

[0212] The compounds used in the method of the present invention may be prepared by techniqueswell known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0213] The compounds used in the method of the present invention may be prepared by techniquesdescribed in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5thEdition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5thEdition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0214] Another aspect of the invention comprises a compound used in the method of the presentinvention as a pharmaceutical composition.

[0215] In some embodiments, a pharmaceutical composition comprising the compound of the presentinvention and a pharmaceutically acceptable carrier.

[0216] As used herein, the term “pharmaceutically active agent” means any substance or compoundsuitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30thedition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid 41group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.

[0217] The compounds used in the method of the present invention may be in a salt form. As usedherein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).

[0218] The compounds of the present invention may also form salts with basic amino acids such alysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.

[0219] As used herein, “administering” an agent may be performed using any of the various methodsor delivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.

[0220] The compounds used in the method of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the 42two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

[0221] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptablesolvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.

[0222] The dosage of the compounds administered in treatment will vary depending upon factors suchas the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

[0223] A dosage unit of the compounds used in the method of the present invention may comprise asingle compound or mixtures thereof with additional antitumor agents. The compounds can be administeredin oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0224] The compounds used in the method of the present invention can be administered in admixturewith suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from 43non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0225] Techniques and compositions for making dosage forms useful in the present invention aredescribed in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0226] Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0227] The compounds used in the method of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as lecithin, 44sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions.

[0228] The compounds used in the method of the present invention may also be coupled to solublepolymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0229] Gelatin capsules may contain the active ingredient compounds and powdered carriers, such aslactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0230] For oral administration in liquid dosage form, the oral drug components are combined with anyoral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0231] Liquid dosage forms for oral administration can contain coloring and flavoring to increasepatient acceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable 45pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0232] The compounds used in the method of the present invention may also be administered inintranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

[0233] Parenteral and intravenous forms may also include minerals and other materials such as solutoland / or ethanol to make them compatible with the type of injection or delivery system chosen.

[0234] The compounds and compositions of the present invention can be administered in oral dosageforms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0235] Specific examples of pharmaceutically acceptable carriers and excipients that may be used toformulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept.2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0236] The active ingredient can be administered orally in solid dosage forms, such as capsules,tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, 46including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.

[0237] Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release ofthe active ingredient compounds before they reach the small intestine. Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate- methacrylic acid copolymers.

[0238] The compounds and compositions of the invention can be coated onto stents for temporary orpermanent implantation into the cardiovascular system of a subject.

[0239] Variations on those general synthetic methods will be readily apparent to those of ordinary skillin the art and are deemed to be within the scope of the present invention.

[0240] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

[0241] It is understood that substituents and substitution patterns on the compounds used in the methodof the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0242] The compounds used in the method of the present invention may be prepared by techniqueswell known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0243] The compounds used in the method of the present invention may be prepared by techniquesdescribed in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5thEdition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5thEdition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds. 47

[0244] The various R groups attached to the aromatic rings of the compounds disclosed herein may beadded to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reactions and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

[0245] Another aspect of the invention comprises a compound used in the method of the presentinvention as a pharmaceutical composition.

[0246] The compounds used in the method of the present invention may be in a salt form. As usedherein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat a disease or medical disorder, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols; alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the sodium, potassium, or lithium salts, and the like. Carboxylate salts are the sodium, potassium, or lithium salts, and the like. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).

[0247] As used herein, "treating" means preventing, slowing, halting, or reversing the progression ofa disease. Treating may also mean improving one or more symptoms of a disease. Definitions

[0248] Unless otherwise defined, all technical and / or scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. 48

[0249] In the discussion unless otherwise stated, adjectives such as “substantially” and “about”modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins.

[0250] It should be understood that the terms “a” and “an” as used above and elsewhere herein referto “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.

[0251] For purposes of better understanding the present teachings and in no way limiting the scope ofthe teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0252] In the description and claims of the present application, each of the verbs, “comprise,”“include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art. General

[0253] For the foregoing embodiments, each embodiment disclosed herein is contemplated as beingapplicable to each of the other disclosed embodiments.

[0254] As used herein, all headings are simply for organization and are not intended to limit thedisclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention. 49

[0255] Additional objects, advantages, and novel features of the present invention will becomeapparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0256] It is appreciated that certain features of the invention, which are, for clarity, described in thecontext of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0257] Examples are provided below to facilitate a more complete understanding of the invention. Thefollowing examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only. EXAMPLES

[0258] Synthesis of novel C-10 phenylcarbamoyl taxoids

[0259] Resynthesis of DTX-AI

[0260] For comparison of the efficacy of novel 3rd generation taxoids disclosed herein with Yan’sresults, DTX-AI was resynthesized using its reported procedure (Ojima 1996). The synthesis of 10-(p-acetylphenylcarbamoyl)-docetaxel began with using commercially available docetaxel. The first step in the synthesis of the 2ndgeneration analog of docetaxel involves the di-TES protection of the hydroxy functional group at the C-2’ and the C-7 position affording the silyl protected intermediate 2-1 in 90% yield. This reaction used about 10 equivalent of TES-Cl added over time for 6 hours. Next step of C-10 coupling between intermediate 2-1 and p-acetylphenylisocyanate mediated by proton extraction using LiHMDS produced the C-10 carbamoyl intermediate 2-2 in 90% yield. Final step in the synthesis is the deprotection of the di-silyl groups at the C-7 and C-2’ using 70% HF in pyriding afforded the desired 10-(p- acetylphenylcarbamoyl)-docetaxel 2-3 with an amazing yield of 93% as described in Figure 4.

[0261] Synthesis of 2nd generation taxoids

[0262] For the synthesis of 2nd generation taxoids and corresponding DFV taxoids, initially the C750hydroxyl of 10-deacetylbaccatin III was silyl-protected by subjecting it to chlorotriethylsilane (3 equiv.) in the presence of imidazole (4 equiv.), resulting in the formation of 2-4 with a high yield of 95%. Subsequent carbamoylation using p-acetylphenylisocyanate (C1) or p-methoxyphenylisocyanate (C2) or p- methylthiophenylisocyanate (C3) of the C10 hydroxyl, in the presence of lithium bis(trimethylsilyl)amide (LHMDS), yielded modified baccatins 2-5C1, 2-5C2, 2-5C3 with moderate to high yield between 74-91% (Figure 5).

[0263] Careful monitoring of the reaction progress via TLC was employed to prevent di-substitutionat the C13 hydroxyl group. The introduction of the C13 isoserine side chain to the taxoid skeleton, featuring C3’-(2-methyl-1-propenyl) and C3’N-t-BOC groups, was accomplished through the Ojima-Holton coupling reaction. Coupling of β lactam 1-8 to 7-TES-10-carbamoyl-baccatins in the presence of LHMDS yielded di-silyl protected taxoid 2-6C1, 2-6C2, 2-6C3 in yield 60-90%. Subsequent deprotection of the silyl groups with HF pyridine resulted in taxoids SB-T-1216C1, SB-T-1216C2 and SB-T-1216C3 with an excellent yield of 84-91% (Figure 5).

[0264] Synthesis of 2nd generation DFV taxoids

[0265] The synthesis of the corresponding difluorovinyl (DFV) derivatives commenced with theselectively C-7 TES-protected and C-10 para-substituted phenyl carbamoyl-coupled intermediate . The synthesis began with the introduction of the C-13 DFV isoserine side chain onto the taxoid core, which was accomplished using the Ojima-Holton coupling methodology. In this key step, the coupling of DFV β- lactams 1-12 with intermediate 2-5C1, 2-5C2, 2-5C3 in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) resulted in the formation of the di-silyl protected taxoid intermediate 2-7C1, 2-7C2, 2-7C3, with yields ranging from 59% to 74% as shown in Figure 6.

[0266] Following the coupling step, the di-silyl protecting groups at C-7 and C-2' were removed usinghydrofluoric acid (HF) in pyridine. This deprotection step proceeded smoothly, affording the taxoids SB- T-12854C1, SB-T-12854C2 and SB-T-12854C3 with excellent yields of 74% to 88% (Figure 6). The use of HF-pyridine efficiently cleaved the silyl groups, generating the final DFV taxoid derivatives with high purity and yield. This streamlined synthetic strategy highlights the efficient and modular modification of the taxoid scaffold, enabling the generation of novel DFV derivatives with potential for enhanced anticancer activity and selectivity.

[0267] Synthesis of 05 series 3rd generation taxoids

[0268] The synthesis of taxoid derivatives commenced with the C-2 trifluoromethoxy benzoate andC-7 mono TES protected intermediate 1-20b. 51

[0269] At the C-10 position, the hydroxyl proton proved to be more reactive than the C-13 proton.After selective deprotonation with lithium bis(trimethylsilyl)amide (LiHMDS) at -40°C, nucleophilic attack on p-acetylphenylisocyanate (C1), p-methoxyphenylisocyanate (C2), or p-methylthiophenylisocyanate (C3) occurred, producing the C-10-modified 10-DAB derivatives 2-8C1, 2-8C2, 2-8C3 with yields ranging from 60-88% as outlined in Figure 7.

[0270] The next step involved coupling the modified 10-DAB with an enantiopure β-lactam via theOjima-Holton coupling methodology, facilitated by LiHMDS. The C-13 hydroxyl group was deprotonated with LiHMDS, which led to nucleophilic attack on the β-lactam carbonyl group, breaking the ring and forming a lithium-13-alkoxy salt. This reaction produced the desired intermediates 2-9C1, 2-9C2, 2-9C3 with yields between 50-74%. To preserve the stereochemistry, the coupling reaction was conducted at - 40°C. Finally, the silyl groups at C-7 and C-2' were deprotected using hydrofluoric acid in pyridine, resulting in the formation of SB-T-121605C1, SB-T-121605C2 and SB-T-121605C3 with a remarkable yield of 78-90%. This efficient synthetic strategy successfully produced the target 3rdgeneration taxoid derivative with high yields and purity (Figure 7).

[0271] Synthesis of 06 series 3rd generation taxoids

[0272] The synthesis of the third-generation taxoid derivatives commenced with the preparation of theC-2 Difluoromethoxy benzoate and C-7 mono-TES-protected intermediate 1-20c. The subsequent functionalization at the C-10 position leveraged the higher reactivity of the C-10 hydroxyl proton compared to that at C-13. Selective deprotonation of the C-10 hydroxyl group was achieved using lithium bis(trimethylsilyl)amide (LiHMDS) at −40°C, facilitating nucleophilic attack on p-acetylphenylisocyanate, p-methoxyphenylisocyanate, or p-methylthiophenylisocyanate. This step yielded the C-10-modified 10- DAB derivatives 2-10C1, 2-10C2, 2-10C3 with good yields ranging from 74-88%, as illustrated in Figure 8.

[0273] The next phase involved the coupling of the modified 10-DAB scaffold with an enantiopure β-lactam through the Ojima-Holton coupling methodology, catalyzed by LiHMDS. In this key transformation, the C-13 hydroxyl group was selectively deprotonated, promoting nucleophilic attack on the β-lactam carbonyl group. This reaction led to ring opening and the formation of a lithium-13-alkoxy salt intermediate, ultimately generating the desired intermediate 2-11C1, 2-11C2, 2-11C3 with yields of 69-74% (Figure 8).

[0274] Finally, the silyl protecting groups at the C-7 and C-2' positions were cleaved usinghydrofluoric acid in pyridine, affording the fully deprotected 3rdgeneration taxoid derivative SB-T- 121606C1, SB-T-121606C2 and SB-T-121606C3 with remarkable yields of 80-88% (Figure 8). This 52streamlined and efficient synthetic route enabled the production of the target third-generation taxoid analog with high chemical purity and excellent yields, highlighting its scalability and potential for further biological evaluation.

[0275] Synthesis of 05 series 3rd generation DFV taxoids

[0276] The synthesis of the difluorovinyl (DFV) variant of the 05 series of third-generation taxoidscommenced with the intermediate 2-8C1, 2-8C2 and 2-8C3, which featured a C-10 phenyl carbamoyl group and a meta-trifluoromethoxy benzoate moiety at the C-2 position. This pre-functionalized intermediate served as the precursor for the subsequent C-10 coupling step.

[0277] In this step, C-10 functionalized intermediates were coupled with a modified enantiopure DFVβ-lactam 1-12 through the Ojima-Holton coupling methodology, employing lithium bis(trimethylsilyl)amide (LiHMDS) as the base. The reaction was initiated by the selective deprotonation of the C-13 hydroxyl group by LiHMDS, generating a highly reactive nucleophile. This nucleophilic species attacked the carbonyl group of the DFV β-lactam, triggering the opening of the β-lactam ring and forming a lithium-13-alkoxy salt as the key intermediate. The coupling reaction proceeded with yields ranging from 63-81% to produce intermediates 2-12C1, 2-12C2, 2-12C3 (Figure 9).

[0278] Following the successful coupling, the final step involved the removal of the silyl protectinggroups at the C-7 and C-2' positions. This was achieved through deprotection with hydrofluoric acid (HF) in pyridine, which efficiently cleaved the silyl groups while preventing undesired side reactions. The deprotection step yielded the final 3rdgeneration DFV taxoids SB-T-12854C105, SB-T-12854C105 and SB-T-12854C105 with excellent yields ranging from 84-91% as illustrated in Figure 9.

[0279] This synthetic strategy effectively incorporated the DFV moiety into the taxoid framework,generating a highly functionalized taxoid derivative with promising therapeutic potential which could effectively overcome the enzymatic hydroxylation in the first pass effect.

[0280] Synthesis of 06 series 3rd generation DFV taxoids

[0281] The synthesis of the difluorovinyl (DFV) variant of the 06 series of 3rd generation taxoidscommenced with the intermediate 2-10C1, 2-10C2 and 2-10C3, which featured a C-10 phenyl carbamoyl group and a meta-difluoromethoxy benzoate moiety at the C-2 position. This intermediate underwent C-10 coupling

[0282] Synthesis of 06 series of 3rd generation DFV taxoids

[0283] With the modified enantiopure DFV β-lactam 1-12 via the Ojima-Holton couplingmethodology, facilitated by LiHMDS, this reaction produced the desired C-13 coupled intermediates 2- 5313C1, 2-13C2 and 2-13C3 with 57-78% yields. Finally, the silyl groups at C-7 and C-2' were deprotected using hydrofluoric acid in pyridine, resulting in the formation of the 3rdgeneration DFV taxoids SB-T- 12854C106, SB-T-12854C206 and SB-T-12854C306 with a remarkable yield of 84-87% as illustrated in Figure 10.

[0284] Example 1

[0285] General Methods

[0286] 1H, 13C and 19F NMR spectra were measured on a Bruker 400, 500 and 700 MHz NMRspectrometer. Melting points were measured on a Thomas Hoover Capillary melting point apparatus and are uncorrected. Mass to charge values were measured by flow injection analysis on an Agilent Technologies LC / MSD VL. TLC was performed on Merck DC-alufolien with Kieselgel 60F-254 and column chromatography was carried out on silica gel 60 (Merck; 230-400 mesh ASTM). Compound purity was verified by reverse phase HPLC on a Shimadzu LC-2010A machine with a Phenomenex C18 column, Curosil-B 250 X 4.60mm (acetonitrile-water; flow rate: 0.3 ml / min; UV at 254 and 220 / 215 nm).

[0287] Materials

[0288] The chemicals were purchased from Aldrich Co. and Sigma. Tetrahydrofuran was freshlydistilled from sodium metal and benzophenone. Dichloromethane was also distilled immediately prior to use under nitrogen from calcium hydride.10-DAB III was donated by Fujian Yew Park Biological Co. Ltd.

[0289] Experimental Procedures

[0290] 7, 2’ Ditriethylsilyl docetaxel [2-1]

[0291] Under room temperature condition, in a round bottom flask, add 150 mg docetaxel (DTX), 1.2mL of pyridine was added, 10 equiv of triethylchlorosilane (TESCl) was added dropwise, and the temperature. Continue to keep stirring overnight after feeding. After the reaction was monitored by TLC, 60 mL of water was added. Stir for 0.5 hours. Subsequent extraction with ethyl acetate (10 mL×3), washing with water, washing with saturated brine, anhydrous sodium sulfate to afford crude product. The crude product was further purified using flash chromatography to afford after drying 2-1174 mg, 90% (white powdery solid).1H NMR (700 MHz, ) δ 8.14 (d, J = 7.7 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (q, J = 7.3 Hz, 3H), 7.28 (s, 8H), 6.35 (t, J = 9.2 Hz, 1H), 5.69 (d, J = 7.1 Hz, 1H), 5.51 (d, J = 9.7 Hz, 1H), 5.15 (d, J = 2.0 Hz, 1H), 4.98 (d, J = 9.2 Hz, 1H), 4.57 (s, 1H), 4.42 (dd, J = 10.7, 6.6 Hz, 1H), 4.35 (d, J = 8.6 Hz, 1H), 4.29 (d, J = 1.9 Hz, 1H), 4.23 (d, J = 8.6 Hz, 1H), 3.93 (d, J = 7.1 Hz, 1H), 2.56 (s, 3H), 2.50 (ddd, J = 15.5, 9.6, 6.6 Hz, 1H), 2.38 (dd, J = 15.3, 9.7 Hz, 1H), 2.18 (s, 1H), 1.95 (s, 4H), 1.77 (s, 3H), 1.63 (s, 1H), 1.58 (s, 6H), 1.33 (s, 9H), 1.29 (s, 3H), 1.14 (s, 3H), 540.98 (dt, J = 21.5, 8.1 Hz, 16H), 0.80 (t, J = 8.0 Hz, 9H), 0.65 – 0.51 (m, 10H), 0.41 (ddt, J = 45.6, 15.3, 7.7 Hz, 6H). All data are consistent with literature values (Ojima 2012).

[0292] 7, 2’ Ditriethylsilyl-10-(p-acetylphenylcarbamoyl)-docetaxel [2-2]

[0293] Under room temperature condition, in round bottom flask, add 174 mg 2-1, 30.0mgdimethylamine successively pyridine (DMAP), 90.0 mg of 4-acetophenyl isocyanate, and then 5.0 mL of anhydrous tetrahydrofuran was added under nitrogen. After the reaction is monitored by TLC, the reaction solution is cooled and cooled directly. The crude product was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography to obtain 181 mg, 90% yield of white solid 2-2. Column chromatography conditions: petroleum ether: Ethyl acetate = 4:1—2:1.1H NMR (700 MHz, ) δ 8.14 (d, J = 7.7 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 3H), 7.34 – 7.27 (m, 3H), 6.50 (s, 1H), 6.33 (t, J = 9.3 Hz, 1H), 5.73 (d, J = 7.1 Hz, 1H), 5.51 (d, J = 9.8 Hz, 1H), 5.34 – 5.30 (m, 1H), 4.99 (d, J = 9.5 Hz, 1H), 4.59 (s, 1H), 4.54 (dd, J = 10.7, 6.7 Hz, 1H), 4.34 (d, J = 8.6 Hz, 1H), 4.22 (d, J = 8.7 Hz, 1H), 3.88 (d, J = 7.0 Hz, 1H), 2.60 (s, 2H), 2.57 (s, 4H), 2.54 (d, J = 15.7 Hz, 1H), 2.41 (dd, J = 15.3, 9.6 Hz, 1H), 2.25 – 2.19 (m, 1H), 2.13 (s, 2H), 1.97 – 1.91 (m, 1H), 1.89 (s, 1H), 1.84 (s, 1H), 1.74 (s, 3H), 1.32 (s, 7H), 1.30 – 1.23 (m, 9H), 0.94 (t, J = 8.0 Hz, 8H), 0.79 (t, J = 8.0 Hz, 8H), 0.62 (qd, J = 7.9, 3.0 Hz, 5H), 0.40 (ddt, J = 43.7, 15.2, 7.6 Hz, 5H).13C NMR (176 MHz, CDCl3) δ 202.76, 196.98, 196.54, 171.61, 171.22, 170.14, 167.12, 155.26, 151.66, 151.13, 142.26, 141.64, 138.95, 133.63, 133.14, 132.40, 130.83, 130.24, 129.85, 129.22, 128.71, 128.55, 127.89, 127.71, 126.43, 117.96, 113.73, 84.28, 81.09, 79.88, 78.96, 77.24, 77.06, 76.88, 76.55, 76.20, 75.18, 74.97, 72.35, 71.31, 60.43, 58.37, 56.67, 46.73, 43.36, 37.22, 35.43, 28.16, 26.63, 26.44, 26.40, 26.10, 23.03, 21.68, 21.08, 14.21, 10.17, 6.94, 6.79, 6.62, 6.52, 5.82, 5.52, 5.35, 5.19, 4.44, 4.27, 4.11, 4.03. All data are consistent with literature values (Ojima 2012).

[0294] DTX-AI [2-3]

[0295] Compound 2-2 (100 mg, 0.1 mmol) was dissolved in a mixture of acetonitrile and pyridine(1:1) and cooled to 0 °C. Excess of HF / pyridine (0.8 ml) was added dropwise at 0 °C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction was monitored via TLC, upon completion, the reaction was quenched with 0.2 M citric acid (4 mL). The reaction mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with saturated copper sulfate (4 mL) and brine (4 mL), dried over anhydrous MgSO4and concentrated in vacuo to obtain crude product. Further purification was made by column chromatography on silica gel with hexanes / ethyl acetate (1:1) as eluent to give white solid product DTX-AI (74 mg, 0.08 mmol) in yield of 85%. The product was characterized by1H NMR.1H NMR (700 MHz, ) δ 8.13 (d, J = 7.6 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.2 Hz, 4H), 7.41 (dt, J = 13.6, 7.4 Hz, 5H), 7.35 (d, J = 6.4 Hz, 2H), 7.28 (s, 1H), 6.36 (s, 551H), 6.26 (d, J = 9.5 Hz, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.42 (d, J = 9.4 Hz, 1H), 5.31 – 5.27 (m, 1H), 4.99 (d, J = 9.4 Hz, 1H), 4.66 (s, 1H), 4.51 – 4.45 (m, 1H), 4.33 (d, J = 8.5 Hz, 1H), 4.20 (d, J = 8.6 Hz, 1H), 3.83 (d, J = 6.9 Hz, 1H), 3.44 (d, J = 5.6 Hz, 1H), 2.79 (s, 1H), 2.60 (s, 4H), 2.41 (s, 3H), 2.32 (dt, J = 24.8, 11.6 Hz, 2H), 1.93 (s, 5H), 1.84 (s, 1H), 1.71 (d, J = 16.0 Hz, 6H), 1.36 (s, 10H), 1.29 (s, 4H), 1.27 (d, J = 6.9 Hz, 1H), 1.20 (s, 3H).13C NMR (176 MHz, CDCl3) δ 204.82, 197.01, 172.96, 171.24, 170.26, 167.10, 155.43, 152.74, 143.31, 141.61, 138.25, 133.79, 132.74, 130.22, 129.85, 129.07, 128.91, 128.75, 128.15, 126.75, 118.13, 84.45, 81.10, 80.29, 79.10, 77.23, 77.05, 76.87, 76.48, 76.21, 74.98, 73.67, 72.36, 72.30, 60.45, 58.65, 56.23, 53.46, 45.66, 43.20, 35.66, 35.53, 29.72, 28.20, 26.91, 26.48, 22.64, 22.17, 21.09, 14.99, 14.22, 9.53. HRMS (ESI-TOF): m / z: Calcd. For C52H60N2O16H+, 969.4015. Found, 969.4035. All data are consistent with literature values (Ojima 2012).

[0296] 7-triethylsilyl-10-(p-acetylphenylcarbamoyl)-10-DAB III [2-5C1]

[0297] Compound 2-4 (200 mg, 0.23 mmol) was dissolved in THF (11.5 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.59 mL) was added dropwise, followed by the dropwise addition of p-acetylphenylcarbamoyl chloride (0.03 mL, 0.3 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel(hexanes:ethyl acetate = 67:33) to afford 2-5C1222 mg, 91% yield as a white solid: 1H NMR (700 MHz,CDCl3 ) δ 8.15 – 8.11 (m, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.42 (s, 1H), 6.48 (s, 1H), 5.67 (d, J = 7.0 Hz, 1H), 5.00 (d, J = 9.4 Hz, 1H), 4.90 (s, 1H), 4.55 (dd, J = 10.5, 6.8 Hz, 1H), 4.34 (d, J = 8.6 Hz, 1H), 4.18 (d, J = 8.5 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 2.60 (s, 3H), 2.59 – 2.54 (m, 1H), 2.32 (d, J = 7.2 Hz, 7H), 2.26 (s, 1H), 1.94 – 1.85 (m, 2H), 1.75 (s, 1H), 1.73 (s, 3H), 1.18 (d, J = 3.7 Hz, 3H), 1.05 (d, J = 3.1 Hz, 3H), 0.93 (t, J = 8.0 Hz, 8H), 0.67 – 0.56 (m, 5H).13C NMR (176 MHz, CDCl3) δ 203.45, 196.98, 171.23, 170.77, 167.08, 151.70, 145.09, 142.34, 133.69, 132.35, 132.34, 130.14, 129.87, 129.38, 128.65, 117.87, 84.24, 80.82, 78.70, 77.22, 77.04, 76.90, 76.86, 76.52, 74.61, 72.54, 68.03, 60.44, 58.68, 53.45, 47.35, 42.76, 38.36, 37.24, 26.88, 26.44, 22.72, 21.08, 20.22, 15.06, 14.21, 10.00, 6.78, 5.50, 5.33, 5.16. HRMS (ESI-TOF): m / z: Calcd. For C52H60N2O16H+, 969.4015. Found, 969.4035.

[0298] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C1 [2-6C1]

[0299] Compound 2-5C1 (222 mg and 1-8 (65 mg, 0.162 mmol) were dissolved in THF (5 mL; 1.2mL; 13 mL), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.52 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 5670:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-6C1 (196 mg, 90% yield) as a white solid:1H NMR (700 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.60 (s, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.7 Hz, 2H), 6.49 (s, 1H), 6.13 (d, J = 9.5 Hz, 1H), 5.72 (d, J = 7.2 Hz, 1H), 5.37 (d, J = 9.0 Hz, 1H), 4.98 (d, J = 9.6 Hz, 1H), 4.86 (s, 1H), 4.80 (s, 1H), 4.54 (dd, J = 10.7, 6.7 Hz, 1H), 4.47 (d, J = 2.7 Hz, 1H), 4.34 (d, J = 8.6 Hz, 1H), 4.23 (d, J = 8.7 Hz, 1H), 3.88 (d, J = 7.1 Hz, 1H), 2.60 (s, 3H), 2.44 (dd, J = 15.1, 9.2 Hz, 1H), 2.39 (s, 3H), 2.12 (s, 3H), 1.88 (s, 2H), 1.82 (s, 3H), 1.78 (d, J = 8.7 Hz, 4H), 1.74 (s, 3H), 1.67 (s, 2H), 1.63 (s, 5H), 1.37 (s, 9H), 1.36 (s, 7H), 1.29 (d, J = 7.3 Hz, 1H), 1.16 (d, J = 7.9 Hz, 9H), 1.14 (d, J = 5.9 Hz, 19H), 0.93 (t, J = 7.9 Hz, 9H), 0.67 – 0.61 (m, 5H), 0.61 (d, J = 7.5 Hz, 3H).13C NMR (176 MHz, CDCl3) δ 202.76, 196.92, 171.90, 171.20, 169.89, 166.89, 155.21, 151.55, 142.14, 136.23, 133.64, 132.95, 132.46, 130.18, 129.87, 129.38, 128.61, 122.16, 117.93, 84.31, 81.04, 79.46, 78.85, 77.21, 77.03, 76.85, 76.52, 76.37, 75.27, 74.98, 72.34, 71.89, 60.43, 58.39, 53.45, 52.01, 46.79, 43.25, 37.18, 35.55, 28.27, 26.45, 25.73, 22.60, 21.45, 21.09, 18.60, 18.06, 17.99, 14.47, 14.22, 14.15, 12.71, 12.55, 10.12, 6.77, 5.54, 5.37. HRMS (ESI-TOF): m / z: Calcd. For C65H96N2O16Si2H+, 1217.6371. Found, 1217.6344.

[0300] SB-T-1216C1

[0301] Compound 2-6C1 (100 mg, 0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4 and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 100:0–50:50) to afford SB-T-1216C1 (71 mg, 0.07 mmol, 91%) as a crystalline white solid:1H NMR (700 MHz, CDCl3) δ 8.14 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.52 (s, 4H), 6.37 (s, 1H), 6.22 (t, J = 8.7 Hz, 1H), 5.72 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 9.6 Hz, 1H), 4.78 (s, 2H), 4.50 (s, 1H), 4.24 (dd, J = 17.3, 7.8 Hz, 2H), 3.85 (d, J = 6.9 Hz, 1H), 3.50 (q, J = 7.0 Hz, 4H), 2.74 (s, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 2.07 (s, 5H), 1.99 (s, 3H), 1.80 (d, J = 4.6 Hz, 6H), 1.73 (s, 4H), 1.58 (s, 34H), 1.46 (s, 2H), 1.38 (s, 8H), 1.32 – 1.26 (m, 10H), 1.26 (s, 14H), 1.23 (dd, J = 14.4, 7.5 Hz, 9H), 0.90 57(t, J = 6.8 Hz, 2H), 0.86 (s, 7H).13C NMR (176 MHz, CDCl3) δ 205.67, 171.23, 165.87, 156.20, 151.53, 143.72, 135.77, 132.59, 131.13, 130.93, 130.25, 128.46, 128.26, 127.96, 127.20, 125.54, 124.82, 119.82, 115.72, 84.69, 81.01, 79.86, 79.42, 77.23, 77.05, 76.87, 76.26, 75.74, 75.03, 72.21, 71.68, 60.44, 58.31, 56.00, 53.46, 48.85, 45.71, 43.14, 38.73, 38.00, 36.66, 36.05, 35.38, 34.24, 33.15, 31.94, 30.33, 29.72, 29.44, 29.38, 29.34, 28.19, 27.23, 26.76, 25.74, 23.47, 23.38, 22.71, 22.38, 22.26, 21.20, 21.08, 20.60, 18.39, 14.83, 14.21, 14.15, 9.41.). HRMS (ESI-TOF): m / z: Calcd. For C50H62N2O16H+, 947.4172. Found, 947.4189.

[0302] 7-triethylsilyl-10-(p-methoxyphenylcarbamoyl)-10-DAB III [2-5C2]

[0303] Compound 2-4 (100 mg, 0.15 mmol) was dissolved in THF (3 mL) and cooled to -40 oC underinert conditions. To the mixture LiHMDS, 1.0 M in THF (0.59 mL) was added dropwise, followed by the dropwise addition of p-methoxyphenylisocyanate (37 mg, 0.2 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethylacetate = 70:30) to afford 2-5C290 mg, 74% yield as a white solid. 1H NMR (400 MHz, ) δ 8.17 – 8.10(m, 2H), 7.67 – 7.58 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 6.95 – 6.84 (m, 3H), 6.46 (s, 1H), 5.66 (d, J = 7.0 Hz, 1H), 5.00 (d, J = 8.3 Hz, 1H), 4.88 (t, J = 8.2 Hz, 1H), 4.54 (dd, J = 10.5, 6.7 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 3.81 (s, 3H), 2.56 (ddd, J = 14.3, 9.6, 6.7 Hz, 1H), 2.31 (q, J = 2.7 Hz, 7H), 1.91 (ddd, J = 14.3, 10.6, 2.1 Hz, 1H), 1.73 (s, 3H), 1.21 (s, 2H), 1.07 (s, 2H), 0.95 (t, J = 7.9 Hz, 10H), 0.62 (qd, J = 7.9, 2.4 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 171.18, 170.76, 167.11, 133.63, 132.72, 130.13, 129.44, 128.61, 114.27, 84.29, 80.90, 78.77, 77.35, 77.23, 77.03, 76.71, 74.72, 72.47, 68.07, 60.42, 58.65, 55.51, 53.44, 47.39, 42.78, 38.25, 37.28, 22.71, 21.07, 14.99, 14.21, 10.00, 6.78, 5.32. HRMS (ESI-TOF): m / z: Calcd. For C43H57NO12SiH+808.3723. Found, 808.3708.

[0304] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C2 [2-6C2]

[0305] Compound 2-5C2 (90 mg, 0.1 mmol and (+)-4 (65 mg, 0.162 mmol) were dissolved in THF(2.5 mL;), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.3 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 90:10), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-6C2 (71 mg, 60% yield) as a white solid:1H NMR (500 MHz, , CDCl3) δ 8.08 58(d, J = 7.8 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.2, 2.4 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.92 – 6.84 (m, 3H), 6.48 (s, 1H), 6.13 – 5.97 (m, 1H), 5.70 (d, J = 7.1 Hz, 1H), 5.35 (d, J = 9.6 Hz, 1H), 4.98 (dd, J = 9.6, 2.2 Hz, 1H), 4.88 – 4.71 (m, 2H), 4.52 (dd, J = 10.5, 6.7 Hz, 1H), 4.44 (d, J = 2.7 Hz, 1H), 4.31 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.89 (d, J = 6.9 Hz, 1H), 3.81 (s, 4H), 2.55 (ddd, J = 14.1, 9.5, 6.5 Hz, 1H), 2.39 (s, 1H), 2.37 (s, 3H), 2.11 (s, 3H), 1.92 (ddd, J = 13.7, 10.5, 4.3 Hz, 1H), 1.83 – 1.74 (m, 7H), 1.72 (s, 4H), 1.35 (s, 8H), 1.24 (t, J = 7.1 Hz, 4H), 1.13 (d, J = 4.4 Hz, 24H), 0.94 (t, J = 7.9 Hz, 11H), 0.61 (tt, J = 7.7, 4.0 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 171.87, 171.18, 169.77, 165.39, 155.21, 149.22, 133.10, 131.48, 130.25, 128.72, 126.03, 122.22, 122.03, 121.32, 119.41, 114.26, 84.34, 81.03, 78.85, 77.29, 77.04, 76.78, 76.41, 75.54, 75.27, 72.31, 71.91, 60.41, 58.32, 55.50, 53.44, 46.80, 43.22, 37.17, 35.36, 31.60, 28.25, 27.71, 26.35, 25.65, 22.67, 22.38, 21.06, 18.40, 18.05, 17.97, 17.85, 14.45, 14.21, 14.13, 12.56, 10.04, 6.78, 5.34, 5.29. HRMS (ESI-TOF): m / z: Calcd. For C64H96N2O16Si2H+1205.6371. Found, 1205.6363.

[0306] SB-T-1216C2

[0307] Compound 2-6C2 (71 mg, 0.06 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4 and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 100:0–50:50) to afford SB-T-1216C2 (48 mg, 0.054 mmol, 88%) as a crystalline white solid:1H NMR (400 MHz, CDCl3 ) δ 8.20 – 8.07 (m, 2H), 7.68 – 7.59 (m, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.91 – 6.85 (m, 2H), 6.83 (s, 1H), 6.34 (s, 1H), 6.21 (s, 1H), 5.70 (d, J = 7.1 Hz, 1H), 5.37 – 5.30 (m, 1H), 4.99 (t, J = 10.6 Hz, 1H), 4.79 (s, 1H), 4.49 (dd, J = 11.0, 6.4 Hz, 1H), 4.39 – 4.27 (m, 1H), 4.27 – 4.17 (m, 2H), 3.81 (s, 4H), 2.64 – 2.48 (m, 1H), 2.39 (s, 3H), 2.34 (s, 1H), 1.97 (d, J = 1.4 Hz, 3H), 1.94 – 1.85 (m, 1H), 1.79 (t, J = 1.7 Hz, 4H), 1.72 (s, 3H), 1.53 (s, 1H), 1.38 (s, 7H), 1.29 (d, J = 5.9 Hz, 5H), 1.21 (s, 2H).13C NMR (176 MHz, CDCl3) δ 205.20, 171.22, 170.14, 167.01, 166.94, 156.42, 155.51, 153.51, 133.72, 130.18, 130.10, 129.79, 129.22, 128.79, 128.67, 121.19, 120.63, 115.20, 114.28, 84.56, 81.10, 79.25, 77.22, 77.04, 76.86, 76.48, 75.13, 73.81, 72.34, 60.44, 58.63, 55.52, 51.63, 49.61, 45.60, 43.19, 35.62, 35.50, 34.47, 29.72, 28.38, 28.36, 28.31, 28.25, 27.95, 26.88, 25.76, 24.15, 22.43, 21.09, 19.79, 18.60, 15.09, 14.22, 9.48.HRMS (ESI-TOF): m / z: Calcd. For C49H62N2O16, 935.4172. Found, 935.4184. 59

[0308] 7-triethylsilyl-10-(p-methylthiophenylcarbamoyl)-10-DAB III [2-5C3]

[0309] Compound 2-4 (100 mg, 0.15 mmol) was dissolved in THF (3 mL) and cooled to -40 oC underinert conditions. To the mixture LiHMDS, 1.0 M in THF (0.59 mL) was added dropwise, followed by the dropwise addition of p-methylthiophenylisocyanate (38 mg, 0.2 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethylacetate = 70:30) to afford 2-5C3 (76 mg, 0.09 mmol, 61% yield) as a white solid: 1H NMR (400 MHz, ) δ8.15 – 8.10 (m, 2H), 7.66 – 7.59 (m, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (dd, J = 8.7, 2.2 Hz, 1H), 7.28 – 7.20 (m, 2H), 6.47 (d, J = 6.3 Hz, 1H), 5.66 (d, J = 7.0 Hz, 1H), 5.00 (d, J = 9.3 Hz, 1H), 4.88 (t, J = 8.2 Hz, 1H), 4.54 (dd, J = 10.4, 6.7 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 2.56 (ddd, J = 16.1, 10.1, 7.0 Hz, 1H), 2.48 (s, 2H), 2.37 – 2.23 (m, 7H), 2.16 – 2.06 (m, 2H), 2.03 (s, 1H), 1.72 (s, 3H), 1.20 (t, J = 3.7 Hz, 3H), 1.08 – 0.85 (m, 13H), 0.61 (qd, J = 7.9, 2.1 Hz, 6H). HRMS (ESI-TOF): m / z: Calcd. For C43H57NO11SSiH+824.3494, Found, 824.3498.

[0310] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C3 [2-6C3]

[0311] Compound 2-5C3 (76 mg, 0.09 mmol) and 1-8 (55 mg, 0.135 mmol) were dissolved in THF(2.5 mL; 1.2 mL; 13 mL), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.2 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-6C3 (69 mg, 0.06 mmol, 67% yield) as a white solid:1H NMR (500 MHz, CDCl3 ) δ 8.13 (d, J = 7.7 Hz, 2H), 7.65 – 7.61 (m, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 6.47 (s, 1H), 6.13 (t, J = 9.2 Hz, 1H), 5.71 (d, J = 7.1 Hz, 1H), 5.37 (d, J = 8.8 Hz, 1H), 4.97 (dd, J = 9.7, 2.1 Hz, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.53 (dd, J = 10.6, 6.6 Hz, 1H), 4.46 (d, J = 2.9 Hz, 1H), 4.33 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 8.5 Hz, 1H), 3.88 (d, J = 7.0 Hz, 1H), 2.55 (ddd, J = 14.1, 9.8, 6.5 Hz, 1H), 2.49 (s, 3H), 2.46 – 2.40 (m, 1H), 2.39 (s, 3H), 2.11 (s, 5H), 1.92 (ddd, J = 13.3, 10.7, 2.4 Hz, 1H), 1.82 (s, 3H), 1.75 (d, J = 23.6 Hz, 7H), 1.43 (d, J = 16.1 Hz, 2H), 1.36 (s, 8H), 1.24 (d, J = 11.7 Hz, 5H), 1.13 (d, J = 4.6 Hz, 25H), 0.93 (t, J = 7.9 Hz, 9H), 0.61 (qd, J = 7.7, 4.1 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 203.06, 171.83, 171.21, 169.85, 166.88, 155.21, 141.71, 136.19, 135.44, 133.59, 133.18, 130.18, 129.43, 128.59, 128.35, 122.19, 119.74, 119.73, 114.77, 84.34, 81.06, 79.51, 78.86, 77.30, 77.25, 6077.04, 76.79, 76.53, 76.12, 76.12, 75.26, 75.04, 72.33, 71.89, 60.43, 58.41, 58.36, 52.06, 46.83, 43.25, 37.19, 35.57, 29.72, 28.35, 28.28, 26.41, 25.73, 22.60, 21.40, 21.07, 18.59, 18.06, 17.99, 17.86, 17.81, 17.70, 17.66, 16.91, 14.43, 14.22, 12.55, 12.31, 12.23, 11.87, 10.13, 6.77, 5.35, 5.12. HRMS (ESI-TOF): m / z: Calcd. For C64H96N2O15SSi2H+1221.6143, Found, 1221.6139.

[0312] SB-T-1216C3

[0313] Compound 2-6C3 (69 mg, 0.06 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate =50:50) to afford SB-T-1216C3 (40 mg, 0.05 mmol, 84%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 8.1, 1.4 Hz, 2H), 7.64 – 7.61 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.28 – 7.17 (m, 2H), 6.99 (s, 1H), 6.34 (s, 1H), 6.20 (t, J = 8.9 Hz, 1H), 5.70 (d, J = 7.1 Hz, 1H), 5.37 – 5.30 (m, 1H), 5.00 (dd, J = 9.7, 2.3 Hz, 1H), 4.77 (s, 1H), 4.48 (dd, J = 11.0, 6.7 Hz, 1H), 4.33 (d, J = 8.5 Hz, 1H), 4.27 – 4.18 (m, 2H), 3.84 (d, J = 7.0 Hz, 1H), 2.59 (ddd, J = 14.7, 9.7, 6.6 Hz, 1H), 2.49 (s, 3H), 2.39 (s, 5H), 2.34 – 2.13 (m, 4H), 2.00 – 1.87 (m, 4H), 1.79 (t, J = 1.8 Hz, 6H), 1.38 (s, 9H), 1.28 (d, J = 3.2 Hz, 3H), 1.19 (s, 3H), 0.85 (d, J = 12.8 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 205.06, 173.06, 171.22, 170.16, 166.99, 155.52, 143.43, 137.97, 134.77, 133.72, 132.82, 130.18, 129.23, 128.67, 128.18, 124.89, 120.65, 119.73, 84.53, 81.09, 80.04, 79.22, 79.16, 77.29, 77.24, 77.04, 76.79, 76.47, 76.02, 75.12, 73.82, 72.31, 60.44, 58.63, 51.65, 45.64, 43.18, 35.65, 35.55, 29.72, 28.25, 26.82, 25.75, 22.42, 22.13, 21.51, 21.08, 18.59, 16.75, 15.08, 14.21, 9.50. HRMS (ESI-TOF): m / z: Calcd. For C49H62N2O15SH+1221.6143, Found, 1221.6139.

[0314] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C1 [2-7C1]

[0315] Compound 2-5C1 (89 mg, 0.1 mmol) and 1-12 (65 mg, 0.162 mmol) were dissolved in THF(3 mL) and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to 61afford 2-7C1 (71 mg, 60% yield) as a white solid:1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.66 – 7.46 (m, 5H), 7.37 (s, 1H), 6.49 (s, 1H), 6.21 (t, J = 9.1 Hz, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.02 – 4.94 (m, 2H), 4.55 (d, J = 2.5 Hz, 2H), 4.53 – 4.45 (m, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.17 (dd, J = 28.6, 7.8 Hz, 2H), 3.86 (d, J = 6.9 Hz, 1H), 2.59 (s, 3H), 2.58 – 2.49 (m, 1H), 2.38 (d, J = 17.9 Hz, 4H), 2.28 (t, J = 12.8 Hz, 1H), 2.12 (s, 3H), 2.01 – 1.89 (m, 2H), 1.87 (s, 1H), 1.73 (s, 3H), 1.32 (s, 10H), 1.22 (d, J = 3.3 Hz, 7H), 1.14 (t, J = 2.8 Hz, 23H), 0.93 (t, J = 7.9 Hz, 10H), 0.61 (qd, J = 7.8, 2.1 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 202.80, 196.94, 170.90, 170.04, 167.05, 154.90, 151.68, 142.23, 141.47, 133.63, 133.25, 132.45, 130.23, 129.85, 129.23, 128.70, 118.03, 84.26, 81.05, 80.16, 78.80, 77.37, 77.25, 77.05, 76.73, 76.52, 76.27, 74.90, 72.39, 71.79, 60.42, 58.42, 49.01, 46.78, 43.30, 37.20, 35.42, 28.16, 26.51, 26.41, 22.43, 21.43, 21.06, 18.05, 17.97, 14.39, 14.21, 12.56, 10.11, 6.76, 5.37.19F NMR (376 MHz, CDCl3) δ -84.61 (dd, J = 38.2, 25.0 Hz), -86.17 (d, J = 37.6 Hz). HRMS (ESI-TOF): m / z: Calcd. For C63H90F2N2O16Si2H+1225.5870, Found, 1225.5913.

[0316] SB-T-12854C1

[0317] Compound 2-7C1 (71 mg, 0.06 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.8 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate =50:50) to afford SB-T-12854C1 (48 mg, 0.054 mmol, 88%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 7.7 Hz, 2H), 7.95 – 7.90 (m, 2H), 7.63 (dd, J = 13.8, 6.5 Hz, 2H), 7.51 (dt, J = 7.5, 3.4 Hz, 4H), 6.37 (s, 1H), 6.26 (t, J = 9.1 Hz, 1H), 5.69 (d, J = 7.0 Hz, 1H), 5.08 (d, J = 9.4 Hz, 1H), 5.00 (dd, J = 9.5, 2.3 Hz, 1H), 4.88 (d, J = 9.9 Hz, 1H), 4.61 (ddd, J = 24.9, 9.7, 1.7 Hz, 1H), 4.52 – 4.44 (m, 1H), 4.33 (q, J = 4.3 Hz, 2H), 4.20 (d, J = 8.5 Hz, 1H), 3.83 (d, J = 7.0 Hz, 1H), 3.75 (s, 1H), 2.89 (s, 1H), 2.58 (s, 4H), 2.35 (dt, J = 24.3, 12.1 Hz, 3H), 2.01 – 1.91 (m, 6H), 1.89 (d, J = 2.3 Hz, 1H), 1.71 (s, 3H), 1.32 (s, 9H), 1.25 (d, J = 4.0 Hz, 3H), 1.17 (s, 3H).13C NMR (126 MHz, CDCl3) δ 204.97, 197.24, 172.43, 170.37, 167.10, 155.01, 143.02, 141.84, 133.76, 132.91, 132.58, 130.22, 129.83, 129.08, 128.75, 118.18, 84.45, 81.03, 80.44, 79.03, 76.46, 76.19, 75.05, 73.20, 72.50, 72.24, 60.46, 58.59, 47.99, 45.75, 43.20, 35.72, 35.54, 28.14, 26.81, 26.45, 22.33, 22.31, 22.16, 22.15, 21.08, 14.97, 14.20, 9.58.19F NMR (376 MHz, CDCl3) δ -83.92 (dd, J = 36.4, 24.7 Hz), -85.80 (d, J = 36.5 Hz). HRMS (ESI-TOF): m / z: Calcd. For C48H56F2N2O16H+955.3671, Found, 955.3682. 62

[0318] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C2 [2-7C2]

[0319] Compound 2-5C2 (59 mg, 0.07 mmol) and 1-12 (45 mg, 0.1 mmol) were dissolved in THF (2mL;), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.2 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-7C2 (49 mg, 59% yield) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.13 – 8.07 (m, 2H), 7.64 – 7.57 (m, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.26 – 7.19 (m, 2H), 6.96 – 6.90 (m, 2H), 6.39 (s, 1H), 6.13 (t, J = 9.1 Hz, 1H), 5.57 (d, J = 7.0 Hz, 1H), 4.99 – 4.91 (m, 2H), 4.52 (d, J = 2.4 Hz, 1H), 4.46 (dt, J = 10.7, 5.5 Hz, 2H), 4.30 (d, J = 8.5 Hz, 1H), 4.15 (dd, J = 7.7, 3.4 Hz, 1H), 3.83 (s, 3H), 3.77 (d, J = 7.0 Hz, 1H), 2.54 (ddd, J = 14.2, 9.7, 6.6 Hz, 1H), 2.37 (s, 2H), 2.31 (dd, J = 15.4, 9.2 Hz, 1H), 2.02 (d, J = 1.4 Hz, 3H), 1.89 (ddd, J = 13.3, 10.6, 2.3 Hz, 1H), 1.61 (s, 1H), 1.60 – 1.39 (m, 12H), 1.32 (s, 8H), 1.31 – 1.24 (m, 2H), 1.23 – 1.04 (m, 24H), 0.98 (t, J = 8.0 Hz, 9H), 0.93 (s, 3H), 0.65 (q, J = 7.9 Hz, 6H), 0.57 (s, 3H).13C NMR (126 MHz, CDCl3) δ 201.23, 167.05, 159.00, 151.61, 151.01, 140.49, 133.57, 131.53, 130.20, 129.41, 129.23, 128.66, 114.04, 84.24, 83.11, 81.03, 80.15, 78.76, 74.85, 72.11, 71.60, 58.24, 55.53, 46.63, 42.90, 37.16, 36.64, 35.15, 28.15, 27.87, 25.80, 24.69, 22.40, 20.25, 18.07, 17.98, 14.51, 12.58, 10.09, 6.84, 5.35.19F NMR (376 MHz, CDCl3) δ -84.45 – -84.94 (m), -86.24 (d, J = 37.9 Hz). HRMS (ESI-TOF): m / z: Calcd. For C62H90F2N2O16Si2H+1213.5870, Found, 1213.5887.

[0320] SB-T-12854C2

[0321] Compound 2-7C2 (49 mg, 0.04 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(4 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.5 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 30 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C2 (22 mg, 74%) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.65 – 7.58 (m, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.28 (s, 3H), 6.96 – 6.89 (m, 2H), 6.26 (s, 1H), 6.19 – 6.12 (m, 1H), 5.59 (d, J = 7.0 Hz, 1H), 4.96 (dt, J = 10.4, 3.4 Hz, 2H), 4.88 (d, J = 10.6 Hz, 1H), 4.60 (ddd, J = 24.8, 9.5, 1.7 Hz, 1H), 4.44 – 4.36 (m, 1H), 4.33 – 4.27 (m, 2H), 4.15 (dd, J = 9.1, 637.6 Hz, 1H), 3.83 (s, 3H), 3.78 (d, J = 7.0 Hz, 1H), 3.55 (d, J = 5.8 Hz, 1H), 2.57 (ddd, J = 14.7, 9.6, 6.7 Hz, 1H), 2.39 (s, 3H), 2.33 (dd, J = 15.4, 9.1 Hz, 1H), 2.24 (dd, J = 15.6, 9.1 Hz, 1H), 1.94 – 1.85 (m, 4H), 1.69 (s, 3H), 1.45 (s, 8H), 1.32 (s, 8H), 0.88 (s, 3H), 0.65 (s, 3H).13C NMR (126 MHz, CDCl3) δ 203.72, 170.30, 167.06, 159.11, 154.93, 152.49, 151.30, 141.94, 133.69, 132.58, 131.39, 130.20, 129.34, 129.08, 128.71, 114.03, 84.40, 83.59, 81.01, 80.45, 78.88, 76.65, 76.40, 74.93, 73.11, 72.52, 71.94, 60.42, 58.51, 55.57, 47.92, 45.74, 42.86, 36.64, 35.72, 35.26, 29.72, 28.14, 27.87, 25.96, 22.34, 22.32, 20.95, 14.89, 14.21, 9.57.19F NMR (376 MHz, CDCl3) δ -83.88 (dd, J = 36.5, 24.6 Hz), -85.80 (d, J = 36.6 Hz). HRMS (ESI-TOF): m / z: Calcd. C47H56F2N2O16H+943.3671, Found, 943.3664.

[0322] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C3 [2-7C3]

[0323] Compound 2-5C3 (108 mg, 0.132 mmol) and 1-12 (80 mg, 0.2 mmol) were dissolved in THF(5 mL;), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M THF (0.4 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-7C3 (111 mg, 71% yield) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 2H), 7.66 – 7.59 (m, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.41 – 7.33 (m, 2H), 7.28 – 7.24 (m, 2H), 7.01 (s, 1H), 6.47 (s, 1H), 6.20 (t, J = 9.1 Hz, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.01 – 4.94 (m, 2H), 4.91 (d, J = 10.4 Hz, 1H), 4.57 – 4.46 (m, 3H), 4.34 (d, J = 8.5 Hz, 1H), 4.21 (d, J = 8.5 Hz, 1H), 3.86 (d, J = 7.0 Hz, 1H), 2.60 – 2.49 (m, 1H), 2.49 (s, 3H), 2.38 (d, J = 20.3 Hz, 4H), 2.27 (t, J = 12.5 Hz, 1H), 2.11 (d, J = 1.4 Hz, 3H), 1.98 – 1.88 (m, 1H), 1.73 (s, 5H), 1.32 (s, 8H), 1.31 – 1.14 (m, 16H), 1.13 (d, J = 6.1 Hz, 12H), 0.94 (t, J = 7.9 Hz, 9H), 0.61 (qd, J = 7.9, 4.7 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 202.93, 170.89, 170.02, 167.08, 154.91, 141.24, 135.36, 133.63, 133.41, 130.24, 129.24, 128.70, 128.34, 119.74, 119.73, 84.29, 81.08, 80.19, 78.82, 78.52, 77.29, 77.03, 76.78, 76.54, 74.93, 72.35, 71.82, 58.40, 49.02, 46.81, 43.31, 37.21, 35.39, 28.16, 26.52, 22.42, 22.41, 21.42, 18.06, 17.98, 16.88, 14.37, 12.57, 12.32, 10.11, 6.77, 5.35.19FNMR (376 MHz, CDCl3) δ -83.85 (dd, J = 36.4, 24.5 Hz), -85.77 (d, J = 36.5 Hz). HRMS (ESI-TOF): m / z:Calcd. For C62H90F2N2O15SSi2H+1229.5641, Found, 1229.5708.

[0324] SB-T-12854C3

[0325] Compound 2-7C3 (100 mg, 0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), 64neutralized with saturated NaHCO3(50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C3 (66 mg, 0.07 mmol, 87%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.7 Hz, 2H), 7.67 – 7.59 (m, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.27 – 7.22 (m, 2H), 6.99 (s, 1H), 6.34 (s, 1H), 6.27 (t, J = 9.0 Hz, 1H), 5.70 (d, J = 7.0 Hz, 1H), 5.03 – 4.96 (m, 2H), 4.91 (d, J = 9.9 Hz, 1H), 4.60 (ddd, J = 24.8, 9.6, 1.8 Hz, 1H), 4.48 (ddd, J = 10.9, 6.6, 4.0 Hz, 1H), 4.37 – 4.29 (m, 2H), 4.21 (d, J = 8.5 Hz, 1H), 3.83 (d, J = 7.0 Hz, 1H), 3.57 (d, J = 5.5 Hz, 1H), 2.88 (s, 1H), 2.64 – 2.54 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.39 (d, J = 9.3 Hz, 1H), 2.32 (dd, J = 15.6, 9.1 Hz, 1H), 1.97 – 1.88 (m, 4H), 1.80 (s, 1H), 1.71 (s, 4H), 1.33 (s, 8H), 1.28 (s, 12H), 1.19 (s, 3H).13C NMR (126 MHz, CDCl3) δ 204.97, 172.45, 171.24, 170.33, 167.14, 156.48, 154.93, 142.97, 134.71, 133.74, 133.08, 133.07, 130.24, 129.09, 128.75, 128.15, 119.75, 119.73, 84.51, 81.08, 80.48, 79.17, 76.48, 75.94, 75.08, 73.17, 72.64, 72.31, 60.44, 58.62, 47.96, 45.62, 43.22, 36.64, 35.56, 35.50, 29.72, 28.14, 26.89, 22.34, 22.32, 22.21, 21.08, 16.73, 15.00, 14.21, 9.51.19F NMR (376 MHz, CDCl3) δ -83.85 (dd, J = 36.4, 24.5 Hz), -85.77 (d, J = 36.5 Hz). HRMS (ESI-TOF): m / z: Calcd. For C47H56F2N2O15SH+959.3442, Found, 959.3451.

[0326] 2-Debenzoyl-2-(3-trifluromethoxybenzoyl)-7-triethylsilyl-10-p-acetylphenylcarbamoyl-10-DAB III [2-8C1]

[0327] Compound 1-20b (200 mg, 0.28 mmol) was dissolved in THF (6 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.45 mL) was added dropwise, followed by the dropwise addition of p-acetylphenylisocyanate (65 mg, 0.42 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 67:33) to afford 2-8C1 (208 mg, 0.23 mmol, 89% yield) as a white solid :1H NMR (400 MHz, CDCl3) δ 8.08 – 7.97 (m, 2H), 7.97 – 7.90 (m, 2H), 7.77 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.48 – 7.41 (m, 1H), 6.47 (s, 1H), 5.63 (d, J = 7.0 Hz, 1H), 5.04 – 4.96 (m, 1H), 4.89 (t, J = 8.1 Hz, 1H), 4.54 (dd, J = 10.4, 6.7 Hz, 1H), 4.28 (d, J = 8.2 Hz, 1H), 4.15 (d, J = 3.2 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 2.57 (s, 4H), 2.42 (s, 1H), 2.39 – 2.23 (m, 9H), 1.89 (ddd, J = 14.2, 10.5, 2.0 Hz, 1H), 1.70 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H), 0.91 (t, J = 7.9 Hz, 9H), 0.59 (qd, J = 7.8, 2.1 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 203.87, 197.21, 171.33, 170.67, 165.48, 151.82, 149.27, 145.51, 142.58, 132.22, 132.02, 131.52, 65130.28, 129.83, 128.54, 126.10, 122.19, 121.68, 119.12, 117.98, 84.24, 80.65, 78.70, 77.02, 76.33, 75.22, 72.56, 67.82, 60.46, 58.60, 47.35, 42.68, 38.45, 37.18, 26.75, 26.37, 22.42, 21.04, 20.17, 15.06, 14.17, 9.95, 6.75, 6.67, 5.30, 5.13.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C45H56F3NO13SiH+904.3546, Found, 904.3581.

[0328] 2’-Triisopropylsilyl-7-triethylsilyl- SB-T-1216C105 [2-9C1]

[0329] Compound 2-8C1 (120 mg, 0.13 mmol) and 1-8 (81 mg, 0.2 mmol) were dissolved in THF (3mL;), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.35 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-9C1 (113 mg, 0.083 mmol, 74% yield) as a white solid:1H NMR (400 MHz, CDCl3 ) δ 8.07 (d, J = 7.7 Hz, 1H), 8.00 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.61 – 7.36 (m, 5H), 6.48 (d, J = 6.7 Hz, 1H), 6.10 (d, J = 9.0 Hz, 1H), 5.70 (d, J = 6.9 Hz, 1H), 5.39 – 5.32 (m, 1H), 5.02 – 4.95 (m, 1H), 4.87 (d, J = 9.8 Hz, 1H), 4.52 (dd, J = 10.5, 6.7 Hz, 1H), 4.45 (d, J = 2.6 Hz, 1H), 4.30 (d, J = 8.1 Hz, 1H), 4.19 (dd, J = 8.2, 3.1 Hz, 1H), 3.92 – 3.85 (m, 1H), 2.57 (d, J = 15.5 Hz, 2H), 2.40 (s, 1H), 2.37 (s, 3H), 2.15 – 2.05 (m, 5H), 1.97 – 1.84 (m, 4H), 1.81 – 1.70 (m, 9H), 1.35 (s, 8H), 1.27 – 1.19 (m, 5H), 1.14 (q, J = 3.0 Hz, 22H), 0.93 (td, J = 8.0, 3.7 Hz, 10H), 0.61 (qd, J = 7.9, 3.2 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 171.85, 171.22, 169.79, 165.34, 155.23, 149.20, 142.00, 137.86, 132.95, 131.49, 130.24, 129.84, 129.28, 128.72, 126.01, 122.20, 122.02, 108.22, 84.33, 83.12, 81.02, 79.44, 78.74, 77.24, 76.39, 75.53, 75.28, 72.35, 71.95, 60.43, 58.36, 52.03, 46.80, 43.24, 37.16, 35.41, 28.25, 26.38, 25.73, 25.64, 22.37, 21.31, 21.06, 18.39, 18.05, 18.01, 17.97, 14.45, 14.20, 12.55, 10.04, 6.77, 6.75, 5.35, 1.31.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C66H95F3N2O17Si2H+1301.6194, Found 1301.6180.

[0330] SB-T-1216C105

[0331] Compound 2-9C1 (113 mg, 0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(8 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3(50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl 66acetate = 50:50) to afford SB-T-1216C105 (64 mg, 0.065 mmol, 78%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.07 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (s, 1H), 7.74 – 7.69 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.04 – 7.00 (m, 1H), 6.36 (s, 1H), 6.18 (t, J = 8.6 Hz, 1H), 5.69 (d, J = 7.0 Hz, 1H), 5.36 (d, J = 7.3 Hz, 1H), 5.02 (dd, J = 9.7, 2.2 Hz, 1H), 4.80 – 4.71 (m, 2H), 4.49 (ddd, J = 10.9, 6.7, 4.0 Hz, 1H), 4.31 (d, J = 8.3 Hz, 1H), 4.25 – 4.17 (m, 2H), 3.85 (d, J = 7.0 Hz, 1H), 3.38 (d, J = 7.0 Hz, 1H), 3.08 (d, J = 3.7 Hz, 1H), 2.88 (d, J = 4.0 Hz, 1H), 2.60 (ddd, J = 14.4, 9.6, 6.6 Hz, 1H), 2.49 – 2.38 (m, 1H), 2.37 (s, 3H), 2.07 (s, 2H), 1.98 (d, J = 1.4 Hz, 3H), 1.96 – 1.88 (m, 1H), 1.77 (dd, J = 13.1, 1.4 Hz, 6H), 1.71 (d, J = 5.4 Hz, 4H), 1.65 (s, 2H), 1.37 (s, 9H), 1.31 – 1.26 (m, 3H), 1.20 (s, 2H).13C NMR (126 MHz, CDCl3) δ 204.84, 170.07, 165.50, 149.29, 149.28, 138.16, 131.28, 130.35, 129.33, 128.67, 126.20, 122.18, 120.52, 119.41, 117.62, 108.13, 84.52, 83.11, 81.03, 79.93, 79.26, 76.32, 75.66, 73.68, 72.31, 60.43, 58.60, 51.60, 45.62, 43.14, 35.51, 35.44, 28.21, 26.76, 25.77, 25.68, 22.19, 22.07, 18.41, 15.09, 14.22, 14.21, 9.43.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C51H61F3N2O17H+1039.3494, Found 1039.3511.

[0332] 2-Debenzoyl-2-(3-trifluromethoxybenzoyl)-7-triethylsilyl-10-p-methoxyphenylcarbamoyl-10-DAB III [2-8C2]

[0333] Compound 1-20b (100 mg, 0.135 mmol) was dissolved in THF (3 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.4 mL) was added dropwise, followed by the dropwise addition of p-methoxyphenylisocyanate (30 mg, 0.2 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 67:33) to afford 2-8C2 (97 mg, 0.11 mmol, 82% yield) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.06 (dt, J = 7.8, 1.3 Hz, 1H), 8.04 – 8.00 (m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.8, 1.9 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.91 – 6.84 (m, 2H), 6.45 (s, 1H), 5.63 (d, J = 7.1 Hz, 1H), 5.00 (dd, J = 9.6, 2.0 Hz, 1H), 4.87 (t, J = 8.2 Hz, 1H), 4.54 (dd, J = 10.5, 6.7 Hz, 1H), 4.29 (d, J = 8.3 Hz, 1H), 4.16 (d, J = 2.1 Hz, 1H), 3.95 – 3.88 (m, 1H), 3.80 (s, 4H), 2.56 (ddd, J = 14.2, 9.6, 6.7 Hz, 1H), 2.29 (d, J = 6.1 Hz, 8H), 2.01 (s, 1H), 1.90 (ddd, J = 14.3, 10.6, 2.2 Hz, 1H), 1.72 (s, 3H), 1.19 (d, J = 5.0 Hz, 2H), 1.05 (s, 2H), 0.94 (t, J = 7.9 Hz, 9H), 0.61 (qd, J = 7.7, 3.8 Hz, 6H).13C NMR (126 MHz, ) δ 203.72, 170.72, 165.56, 156.13, 149.28, 144.81, 130.79, 130.26, 128.56, 126.12, 122.21, 121.03, 114.25, 84.27, 80.75, 78.81, 77.30, 77.05, 76.79, 76.38, 75.28, 72.49, 67.91, 60.44, 58.60, 55.50, 47.39, 42.71, 38.21, 37.22, 26.82, 22.46, 21.06, 20.09, 15.02, 14.20, 9.96, 6.78, 5.30.19F NMR (376 MHz, CDCl3) δ - 57.85. HRMS (ESI-TOF): m / z: Calcd. For C51H61F3N2O17H+1031.3995, Found 1031.3992. 67

[0334] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C205 [2-9C2]

[0335] Compound 2-8C2 (97 mg, 0.11 mmol and 1-8 (61 mg, 0.152 mmol) were dissolved in THF(2.5 mL), and cooled to -300C under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.3 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-9C2 (56 mg, 0.055 mmol, 50% yield) as a white solid.1H NMR (500 MHz, , CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.2, 2.4 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.92 – 6.84 (m, 3H), 6.48 (s, 1H), 6.13 – 5.97 (m, 1H), 5.70 (d, J = 7.1 Hz, 1H), 5.35 (d, J = 9.6 Hz, 1H), 4.98 (dd, J = 9.6, 2.2 Hz, 1H), 4.88 – 4.71 (m, 2H), 4.52 (dd, J = 10.5, 6.7 Hz, 1H), 4.44 (d, J = 2.7 Hz, 1H), 4.31 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.89 (d, J = 6.9 Hz, 1H), 3.81 (s, 4H), 2.55 (ddd, J = 14.1, 9.5, 6.5 Hz, 1H), 2.39 (s, 1H), 2.37 (s, 3H), 2.11 (s, 3H), 1.92 (ddd, J = 13.7, 10.5, 4.3 Hz, 1H), 1.83 – 1.74 (m, 7H), 1.72 (s, 4H), 1.35 (s, 8H), 1.24 (t, J = 7.1 Hz, 4H), 1.13 (d, J = 4.4 Hz, 24H), 0.94 (t, J = 7.9 Hz, 11H), 0.61 (tt, J = 7.7, 4.0 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 171.87, 171.18, 169.77, 165.39, 155.21, 149.22, 133.10, 131.48, 130.25, 128.72, 126.03, 122.22, 122.03, 121.32, 119.41, 114.26, 84.34, 81.03, 78.85, 77.29, 77.04, 76.78, 76.41, 75.54, 75.27, 72.31, 71.91, 60.41, 58.32, 55.50, 53.44, 46.80, 43.22, 37.17, 35.36, 31.60, 28.25, 27.71, 26.35, 25.65, 22.67, 22.38, 21.06, 18.40, 18.05, 17.97, 17.85, 14.45, 14.21, 14.13, 12.56, 10.04, 6.78, 5.34, 5.29.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C65H95F3N2O17Si2H+1289.6194, Found 1289.6191.

[0336] SB-T-1216C205

[0337] Compound 2-9C2 (56 mg, 0.055 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(4 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.5 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-1216C205 (32 mg, 0.032 mmol, 85%) as a crystalline white solid:1H NMR (500 MHz, , CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.28 (s, 2H), 6.91 – 6.86 (m, 2H), 6.85 (s, 1H), 6.34 (s, 1H), 6.18 (s, 1H), 5.68 (d, 68J = 7.1 Hz, 1H), 5.35 (d, J = 7.5 Hz, 1H), 5.02 (dd, J = 9.6, 2.2 Hz, 1H), 4.81 – 4.71 (m, 2H), 4.48 (dd, J = 10.9, 6.7 Hz, 1H), 4.31 (d, J = 8.4 Hz, 1H), 4.24 – 4.17 (m, 2H), 3.81 (s, 5H), 2.59 (ddd, J = 14.7, 9.6, 6.6 Hz, 1H), 2.36 (s, 4H), 1.97 (d, J = 1.5 Hz, 3H), 1.92 (ddd, J = 14.6, 10.9, 2.3 Hz, 1H), 1.77 (dd, J = 13.1, 1.4 Hz, 7H), 1.71 (s, 3H), 1.37 (s, 9H), 1.29 (d, J = 9.0 Hz, 4H), 1.21 (s, 2H).13C NMR (126 MHz, CDCl3) δ 205.08, 170.05, 165.49, 155.42, 149.27, 138.12, 131.30, 130.33, 128.67, 126.18, 122.18, 121.20, 120.53, 114.28, 84.56, 81.05, 79.92, 79.27, 77.24, 76.33, 75.70, 73.67, 72.34, 60.43, 58.59, 55.52, 53.44, 51.58, 45.60, 43.16, 35.46, 28.21, 26.78, 25.68, 22.19, 21.07, 18.41, 15.09, 14.21, 9.41.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C50H61F3N2O17H+1020.4028, Found 1020.4033.

[0338] 2-Debenzoyl-2-(3-trifluromethoxybenzoyl)-7-triethylsilyl-10-p-methylthiophenylcarbamoyl-10-DAB III [2-8C3]

[0339] Compound 1-20b (150 mg, 0.2 mmol) was dissolved in THF (4 mL) and cooled to -40 oC underinert conditions. To the mixture LiHMDS, 1.0 M in THF (0.3 mL) was added dropwise, followed by the dropwise addition of p-methylthiophenylisocyanate (43 mg, 0.3 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 67:33) to afford 2-8C3 (128 mg, 0.15 mmol, 76% yield) as a white solid :1H NMR (500 MHz, CDCl3 ) δ 8.05 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (dt, J = 2.6, 1.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.48 – 7.44 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.27 – 7.22 (m, 3H), 6.45 (s, 1H), 5.63 (d, J = 7.1 Hz, 1H), 5.00 (dd, J = 9.7, 2.0 Hz, 1H), 4.90 – 4.83 (m, 1H), 4.54 (dd, J = 10.4, 6.7 Hz, 1H), 4.29 (d, J = 8.3 Hz, 1H), 4.15 (d, J = 8.0 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 2.61 – 2.49 (m, 1H), 2.47 (s, 2H), 2.35 – 2.21 (m, 8H), 1.94 – 1.85 (m, 1H), 1.71 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H), 0.92 (t, J = 8.0 Hz, 9H), 0.60 (qd, J = 7.9, 3.8 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 203.75, 171.28, 170.68, 165.51, 152.14, 149.29, 149.27, 145.04, 135.58, 132.68, 132.30, 131.53, 130.27, 128.63, 128.55, 128.30, 126.75, 126.11, 123.50, 122.21, 121.44, 120.39, 119.62, 119.39, 84.26, 80.71, 78.76, 77.32, 77.27, 77.07, 76.81, 76.36, 75.24, 72.52, 67.88, 60.45, 58.58, 53.45, 47.37, 42.69, 38.31, 37.20, 26.77, 22.44, 21.06, 20.12, 16.85, 16.05, 15.03, 14.19, 9.95, 6.94, 6.88, 6.77, 5.52, 5.30, 5.06, 5.04.19F NMR (376 MHz, CDCl3) δ -57.62. HRMS (ESI-TOF): m / z: Calcd. For C44H56F3NO12SSiH+908.3317, Found 908.3317.

[0340] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C305 [2-9C3]

[0341] Compound 2-8C3 (128 mg, 0.15 mmol) and 1-8 (40 mg, 0.2 mmol) were dissolved in THF (3mL), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M THF (0.3 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and 69upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-9C3 (104 mg, 70% yield) as a white solid:1H NMR (500 MHz, , CDCl3) δ 8.08 (dt, J = 7.8, 1.4 Hz, 1H), 8.02 – 7.98 (m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.50 – 7.45 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.30 – 7.23 (m, 2H), 6.48 (s, 1H), 6.09 (t, J = 9.2 Hz, 1H), 5.70 (d, J = 7.1 Hz, 1H), 5.35 (dt, J = 8.8, 1.7 Hz, 1H), 4.99 (dd, J = 9.6, 2.1 Hz, 1H), 4.86 (d, J = 9.8 Hz, 1H), 4.52 (dd, J = 10.4, 6.6 Hz, 1H), 4.45 (d, J = 2.6 Hz, 1H), 4.30 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.88 (d, J = 7.0 Hz, 1H), 2.50 (s, 1H), 2.48 (s, 2H), 2.40 (s, 1H), 2.37 (s, 3H), 2.11 (d, J = 1.5 Hz, 3H), 2.00 – 1.87 (m, 3H), 1.77 (dd, J = 7.8, 1.4 Hz, 6H), 1.72 (s, 3H), 1.35 (s, 8H), 1.23 (d, J = 11.8 Hz, 5H), 1.13 (d, J = 4.4 Hz, 21H), 0.93 (t, J = 7.9 Hz, 8H), 0.61 (qd, J = 7.9, 4.6 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 203.01, 171.89, 171.21, 169.79, 165.36, 155.22, 149.21, 141.93, 136.35, 133.00, 131.47, 130.26, 128.72, 128.33, 126.03, 122.21, 122.01, 121.46, 119.75, 119.41, 84.33, 81.02, 81.00, 79.44, 78.80, 76.40, 76.12, 75.51, 75.28, 72.34, 71.94, 60.43, 58.35, 52.04, 52.03, 46.78, 43.23, 37.16, 35.38, 28.25, 26.35, 25.65, 22.37, 21.30, 21.06, 18.40, 18.05, 17.98, 16.88, 14.46, 14.21, 12.56, 10.05, 6.77, 5.37, 5.35.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI- TOF): m / z: Calcd. For C63H89F5N2O16SSi2H+1313.5464, Found 1313.5501.

[0342] SB-T-1216C305

[0343] Compound 2-9C3 (90 mg, 0.07 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(7 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.8 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate =50:50) to afford SB-T-1216C305 (56 mg, 0.05 mmol, 90%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.07 (dt, J = 7.8, 1.4 Hz, 1H), 8.01 (s, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.0, 2.4 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.28 – 7.22 (m, 2H), 7.02 (s, 1H), 6.35 (s, 1H), 6.18 (t, J = 8.9 Hz, 1H), 5.68 (d, J = 7.0 Hz, 1H), 5.35 (d, J = 8.4 Hz, 1H), 5.01 (dd, J = 9.7, 2.2 Hz, 1H), 4.75 (d, J = 8.7 Hz, 1H), 4.48 (dd, J = 10.9, 6.7 Hz, 1H), 4.30 (d, J = 8.4 Hz, 1H), 4.24 – 4.16 (m, 2H), 3.85 (d, J = 7.0 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.48 (s, 3H), 2.44 (dd, J = 15.4, 9.1 Hz, 2H), 2.32 (s, 5H), 2.06 (s, 1H), 1.97 (d, J = 1.3 Hz, 3H), 1.94 – 1.87 (m, 1H), 1.77 (dd, J = 12.5, 1.4 Hz, 6H), 1.36 (s, 8H), 1.28 (q, J = 5.3 Hz, 5H), 701.19 (s, 3H).13C NMR (126 MHz, CDCl3) δ 204.99, 171.24, 170.08, 165.47, 155.44, 149.26, 143.61, 138.05, 132.64, 131.29, 130.33, 128.66, 128.15, 126.18, 122.17, 121.45, 120.55, 119.75, 119.40, 84.52, 81.03, 79.95, 79.20, 77.30, 77.25, 77.05, 76.79, 76.32, 76.00, 75.68, 73.67, 72.30, 60.44, 58.58, 51.64, 45.64, 43.15, 35.52, 35.46, 28.21, 26.74, 25.68, 22.18, 22.06, 21.07, 18.40, 16.74, 15.09, 14.21, 9.44.19F NMR (376 MHz, CDCl3) δ -57.85. HRMS (ESI-TOF): m / z: Calcd. For C50H61F3N2O16SH+1035.3767, Found 1035.3774.

[0344] 2-Debenzoyl-2-(3-difluromethoxybenzoyl)-7-triethylsilyl-10-p-acetylphenylcarbamoyl-10-DAB III [2-10C1]

[0345] Compound 1-20c (120 mg, 0.16 mmol) was dissolved in THF (3.2 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.4 mL) was added dropwise, followed by the dropwise addition of p-acetylphenylisocyanate (0 mL, 0.636 mmol). The mixture was stirred and monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethylacetate = 67:33) to afford 2-10C1 (132 mg, 0.15 mmol, 92% yield) as a white solid : 1H NMR (400 MHz,CDCl3) δ 8.01 – 7.89 (m, 4H), 7.59 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 15.3, 7.3 Hz, 2H), 7.37 (dd, J = 8.2, 2.5 Hz, 1H), 6.48 (s, 1H), 5.64 (d, J = 7.0 Hz, 1H), 5.04 – 4.97 (m, 1H), 4.89 (t, J = 8.2 Hz, 1H), 4.55 (dd, J = 10.4, 6.7 Hz, 1H), 4.31 (d, J = 8.3 Hz, 1H), 4.16 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 7.0 Hz, 1H), 2.59 (s, 4H), 2.30 (d, J = 2.9 Hz, 8H), 1.90 (ddd, J = 12.9, 10.7, 2.1 Hz, 1H), 1.13 (s, 3H), 1.02 (s, 3H), 0.92 (t, J = 7.9 Hz, 9H), 0.68 – 0.51 (m, 6H).13C NMR (101 MHz, CDCl3) δ 203.55, 197.06, 171.25, 170.78, 165.89, 151.73, 151.00, 145.31, 142.42, 132.33, 132.16, 131.30, 130.18, 129.84, 127.21, 125.10, 121.01, 117.93, 115.57, 112.96, 84.25, 80.72, 78.72, 77.37, 77.25, 77.05, 76.73, 76.40, 75.09, 72.54, 67.91, 60.44, 58.64, 47.34, 42.71, 38.39, 37.21, 26.82, 26.41, 22.51, 21.06, 20.18, 15.06, 14.20, 9.96, 6.77, 5.33.19F NMR (376 MHz, CDCl3) δ -81.01 (d, J = 12.0 Hz), -81.21 (d, J = 11.8 Hz). HRMS (ESI-TOF): m / z: Calcd. For C45H57F2NO13SiH+886.364, Found 886.3646.

[0346] 2’-Triisopropylsilyl-7-triethylsilyl- SB-T-1216C106 [2-11C1]

[0347] Compound 2-10C1 (132 mg, 0.15 mmol) and 1-8 (90 mg, 0.22 mmol) were dissolved in THF(3 mL), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.4 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in 71vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) toafford 2-11C1 (131 mg, 0.1 mmol, 69% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J= 8.2, 6.2 Hz, 3H), 7.89 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.36 (dd, J = 8.1, 2.4 Hz, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.13 (t, J = 9.2 Hz, 1H), 5.69 (d, J = 7.1 Hz, 1H), 5.34 (d, J = 8.6 Hz, 1H), 4.98 (d, J = 9.3 Hz, 1H), 4.87 (d, J = 9.8 Hz, 1H), 4.78 (t, J = 9.5 Hz, 1H), 4.53 (dd, J = 10.5, 6.6 Hz, 1H), 4.46 (d, J = 2.8 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.87 (d, J = 6.9 Hz, 1H), 2.59 (s, 3H), 2.57 – 2.50 (m, 1H), 2.39 (s, 5H), 2.11 (s, 3H), 1.91 (td, J = 11.5, 6.1 Hz, 2H), 1.77 (d, J = 8.0 Hz, 6H), 1.32 (s, 8H), 1.21 (s, 5H), 1.12 (d, J = 4.1 Hz, 22H), 0.93 (t, J = 7.9 Hz, 9H), 0.68 – 0.53 (m, 6H).13C NMR (101 MHz, CDCl3) δ 202.78, 196.97, 171.86, 171.21, 169.93, 165.74, 155.21, 151.65, 151.23, 142.30, 142.09, 136.26, 132.88, 132.39, 131.25, 130.19, 129.83, 127.23, 124.72, 122.04, 120.24, 118.32, 118.04, 115.73, 113.14, 84.29, 80.96, 79.39, 79.38, 78.84, 77.38, 77.06, 76.74, 76.41, 75.44, 75.30, 72.34, 71.76, 60.42, 58.35, 46.74, 43.22, 37.15, 35.40, 28.23, 26.40, 25.68, 22.48, 21.38, 21.04, 18.48, 18.04, 17.97, 14.43, 14.19, 12.55, 10.06, 6.76, 5.37.19F NMR (376 MHz, CDCl3) δ -80.45 (dd, J = 167.1, 73.9 Hz), -81.83 (dd, J = 167.2, 72.8 Hz). HRMS (ESI-TOF): m / z: Calcd. For C66H96F2N2O17Si2H+1283.6288, Found 1283.6272.

[0348] SB-T-1216C106

[0349] Compound 2-11C1 (131 mg, 0.1 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(10 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-1216C106 (89 mg, 0.09 mmol, 89%) as a crystalline white solid:1H NMR (400 MHz, CDCl3) δ 8.00 – 7.88 (m, 4H), 7.51 (t, J = 8.0 Hz, 3H), 7.43 – 7.35 (m, 2H), 7.28 (s, 1H), 6.37 (s, 1H), 6.21 (t, J = 8.9 Hz, 1H), 5.68 (d, J = 7.1 Hz, 1H), 5.36 (d, J = 8.2 Hz, 1H), 5.05 – 4.98 (m, 1H), 4.86 – 4.72 (m, 2H), 4.49 (dd, J = 11.0, 6.6 Hz, 1H), 4.33 (d, J = 8.4 Hz, 1H), 4.26 – 4.16 (m, 2H), 3.85 (d, J = 7.0 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 4H), 1.98 (s, 3H), 1.91 (dtd, J = 14.8, 11.6, 3.9 Hz, 1H), 1.77 (d, J = 8.6 Hz, 6H), 1.71 (s, 3H), 1.34 (s, 8H), 1.28 (s, 4H), 1.18 (s, 3H).13C NMR (101 MHz, CDCl3) δ 204.82, 197.01, 173.29, 171.22, 170.19, 165.85, 155.46, 151.22, 143.74, 141.65, 138.02, 132.73, 132.52, 131.04, 130.27, 129.83, 127.22, 124.95, 120.56, 118.28, 115.69, 113.09, 84.47, 80.98, 79.92, 79.22, 77.24, 76.34, 76.26, 75.57, 73.69, 72.25, 60.43, 58.59, 51.50, 45.65, 43.15, 35.59, 35.48, 28.21, 26.77, 26.45, 25.71, 7222.28, 22.14, 21.07, 18.48, 15.05, 14.21, 9.50.19F NMR (376 MHz, CDCl3) δ -80.48 (dd, J = 166.7, 74.0 Hz), -81.99 (dd, J = 166.7, 72.5 Hz). HRMS (ESI-TOF): m / z: Calcd. For C51H62F2N2O17H+1013.4089, Found 1013.4105.

[0350] 2-Debenzoyl-2-(3-trifluromethoxybenzoyl)-7-triethylsilyl-10-p-methoxyphenylcarbamoyl-10-DAB III [2-10C2]

[0351] Compound 1-20c (110 mg, 0.15 mmol) was dissolved in THF (3 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.25 mL) was added dropwise, followedby the dropwise addition of p-methoxyphenylisocyanate (34 mg, 0.225 mmol). The mixture was stirred andmonitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 67:33) to afford 2-10C2 (95 mg, 0.11 mmol, 74% yield) as a white solid:1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.38 – 7.34 (m, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.44 (s, 1H), 5.62 (d, J = 7.0 Hz, 1H), 5.03 – 4.96 (m, 1H), 4.85 (t, J = 8.2 Hz, 1H), 4.53 (dd, J = 10.4, 6.7 Hz, 1H), 4.34 – 4.25 (m, 1H), 4.14 (p, J = 7.7 Hz, 2H), 3.91 (d, J = 6.9 Hz, 1H), 3.79 (s, 3H), 2.61 – 2.48 (m, 1H), 2.48 – 2.42 (m, 1H), 2.31 – 2.20 (m, 7H), 1.98 – 1.83 (m, 2H), 1.72 (d, J = 16.7 Hz, 3H), 1.15 – 1.06 (m, 3H), 1.02 – 0.87 (m, 11H), 0.67 – 0.49 (m, 6H).13C NMR (101 MHz, CDCl3) δ 171.27, 170.73, 165.88, 151.01, 144.88, 142.08, 134.99, 132.40, 131.35, 130.15, 127.19, 125.03, 120.96, 118.20, 115.59, 114.22, 112.99, 84.28, 80.72, 80.66, 78.82, 78.74, 77.38, 77.06, 76.75, 76.41, 75.16, 72.50, 67.87, 60.44, 58.58, 57.92, 55.48, 47.38, 46.95, 42.71, 42.69, 38.33, 37.22, 26.84, 26.74, 22.49, 21.05, 20.08, 15.20, 14.99, 14.19, 9.96, 6.78, 6.76, 5.29, 5.18.19F NMR (376 MHz, CDCl3) δ -80.42 – -81.10 (dd), -81.10 – -81.70 (dd). HRMS (ESI-TOF): m / z: Calcd. For C44H57F2NO13SiH+874.3640, Found 874.3642.

[0352] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C206 [2-11C2]

[0353] Compound 2-10C2 (95 mg, 0.11 mmol) and 1-8 (61 mg, 0.15 mmol) were dissolved in THF(2.5 mL), and cooled to -30oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-11C2 (90 mg, 0.07 mmol 71% yield) as a white solid:1H NMR (400 MHz, 73CDCl3) δ 7.98 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41 – 7.31 (m, 3H), 6.88 (d, J = 8.9 Hz, 3H), 6.49 (d, J = 9.8 Hz, 1H), 6.13 (t, J = 9.2 Hz, 1H), 5.70 (d, J = 7.0 Hz, 1H), 5.35 (d, J = 8.7 Hz, 1H), 5.02 – 4.95 (m, 1H), 4.86 (d, J = 9.8 Hz, 1H), 4.79 (d, J = 8.8 Hz, 1H), 4.56 – 4.43 (m, 2H), 4.33 (d, J = 8.3 Hz, 1H), 4.23 – 4.15 (m, 1H), 3.88 (d, J = 7.1 Hz, 1H), 3.81 (s, 3H), 2.61 – 2.49 (m, 1H), 2.39 (s, 4H), 2.06 (s, 2H), 1.92 (ddd, J = 13.5, 10.7, 2.3 Hz, 2H), 1.80 – 1.70 (m, 10H), 1.33 (s, 9H), 1.26 (d, J = 7.2 Hz, 4H), 1.23 (s, 3H), 1.13 (d, J = 4.0 Hz, 18H), 1.12 – 1.06 (m, 4H), 0.94 (t, J = 7.9 Hz, 10H), 0.61 (qd, J = 7.8, 2.9 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 171.81, 171.17, 169.88, 165.78, 155.20, 151.25, 136.21, 133.17, 131.30, 130.18, 127.25, 124.70, 122.08, 120.22, 118.35, 115.75, 114.26, 84.34, 81.01, 78.91, 77.25, 76.43, 75.49, 75.27, 72.29, 71.76, 60.41, 58.29, 55.49, 46.77, 43.22, 37.17, 35.37, 28.24, 26.38, 25.69, 22.48, 21.05, 18.48, 18.05, 17.98, 14.39, 14.20, 12.56, 10.07, 6.78, 5.34.19F NMR (376 MHz, CDCl3) δ -80.46 (dd, J = 166.9, 73.8 Hz), -82.00 (dd, J = 166.8, 72.5 Hz). HRMS (ESI-TOF): m / z: Calcd. For C65H96F2N2O17Si2NH4+1288.6554, Found 1288.6557.

[0354] SB-T-1216C206

[0355] Compound 2-11C2 (90 mg, 0.07 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(7 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (1 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-1216C206 (47 mg, 0.05 mmol, 80% yield) as a crystalline white solid:1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.1, 2.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 6.93 – 6.84 (m, 3H), 6.33 (s, 1H), 6.21 (s, 1H), 5.68 (d, J = 7.0 Hz, 1H), 5.35 (d, J = 8.4 Hz, 1H), 5.01 (dd, J = 9.7, 2.2 Hz, 1H), 4.83 (d, J = 8.9 Hz, 1H), 4.77 (td, J = 8.7, 2.6 Hz, 1H), 4.48 (dd, J = 10.9, 6.7 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 4.26 – 4.17 (m, 2H), 3.84 (d, J = 7.0 Hz, 1H), 3.81 (s, 3H), 2.58 (ddd, J = 15.6, 9.6, 6.6 Hz, 1H), 2.38 (s, 5H), 1.96 (s, 3H), 1.95 – 1.85 (m, 2H), 1.81 – 1.72 (m, 7H), 1.34 (s, 8H), 1.28 (t, J = 7.1 Hz, 4H), 1.19 (s, 2H).13C NMR (101 MHz, CDCl3) δ 205.12, 173.22, 170.15, 165.86, 155.43, 151.23, 143.43, 137.97, 132.82, 132.80, 131.09, 130.25, 127.21, 124.90, 121.19, 120.58, 120.16, 118.29, 115.70, 114.26, 113.11, 84.56, 81.02, 79.89, 79.29, 77.36, 77.25, 77.05, 76.73, 76.35, 75.66, 73.68, 72.30, 60.43, 58.55, 55.51, 51.47, 45.59, 43.15, 35.47, 28.21, 26.81, 25.71, 22.28, 22.15, 21.06, 18.48, 15.03, 14.21, 9.45.19F NMR (376 MHz, CDCl3) δ -80.46 (dd, J = 74166.9, 73.8 Hz), -82.00 (dd, J = 166.8, 72.5 Hz) HRMS (ESI-TOF): m / z: Calcd. For C50H62F2N2O17H+1001.4089, Found 1001.4144.

[0356] 2-Debenzoyl-2-(3-Difluromethoxybenzoyl)-7-triethylsilyl-10-p-methylthiophenylcarbamoyl-10-DAB III [2-10C3]

[0357] Compound 1-20c (110 mg, 0.15 mmol) was dissolved in THF (3 mL) and cooled to -40 oCunder inert conditions. To the mixture LiHMDS, 1.0 M in THF (0.25 mL) was added dropwise, followedby the dropwise addition of p-methylthiophenylisocyanate (37 mg, 0.225 mmol). The mixture was stirredand monitored by TLC (hexanes:ethyl acetate = 70:30). Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 X 80 mL). The organic layers were collected and combined, washed with brine (2 X 60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 67:33) to afford 2-10C3 (105 mg, 0.12 mmol, 80% yield) as a white solid.

[0358] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-1216C306 [2-11C3]

[0359] Compound 2-10C3 (105 mg, 0.12 mmol) and (+)-3 (73 mg, 0.182 mmol) were dissolved inTHF (2.5), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.2 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethylacetate = 70:30) to afford 2-11C3 (98 mg,0.083 mmol, 74% yield) as a white solid: 1H NMR (400 MHz,, CDCl3) δ 7.98 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 (td, J = 6.2, 3.1 Hz, 3H), 7.28 (d, J = 3.3 Hz, 2H), 6.99 (s, 1H), 6.77 (d, J = 73.5 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.13 (t, J = 9.1 Hz, 1H), 5.70 (d, J = 7.0 Hz, 1H), 5.35 (d, J = 8.6 Hz, 1H), 4.98 (d, J = 9.2 Hz, 1H), 4.86 (d, J = 9.8 Hz, 1H), 4.79 (d, J = 9.3 Hz, 1H), 4.57 – 4.44 (m, 2H), 4.33 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.88 (d, J = 7.0 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.48 (s, 3H), 2.38 (d, J = 10.1 Hz, 5H), 2.11 (s, 3H), 1.97 – 1.86 (m, 1H), 1.77 (d, J = 7.1 Hz, 6H), 1.72 (s, 3H), 1.33 (s, 8H), 1.22 (d, J = 4.8 Hz, 7H), 1.13 (d, J = 4.1 Hz, 20H), 1.10 (d, J = 4.5 Hz, 2H), 0.93 (t, J = 7.9 Hz, 10H), 0.61 (qd, J = 7.8, 2.5 Hz, 7H).13C NMR (101 MHz, CDCl3) δ 202.90, 171.82, 171.18, 169.90, 165.78, 155.20, 151.25, 141.85, 136.21, 135.40, 133.05, 131.28, 130.19, 128.33, 127.25, 124.72, 122.07, 120.24, 118.33, 115.74, 113.15, 84.32, 80.99, 79.40, 78.90, 77.36, 77.25, 77.05, 76.73, 76.43, 76.08, 75.47, 75.28, 72.31, 71.76, 60.41, 58.32, 51.95, 46.76, 43.23, 37.16, 35.37, 28.24, 26.40, 25.69, 22.48, 21.37, 21.05, 18.48, 18.05, 17.98, 16.88, 14.41, 14.21, 12.56, 7510.07, 6.77, 5.35.19F NMR (376 MHz, CDCl3) δ -80.41 (dd, J = 167.0, 74.0 Hz), -81.82 (dd, J = 167.1, 72.8 Hz). HRMS (ESI-TOF): m / z: Calcd. For C65H96F2N2O16SSi2H+1287.606, Found 1287.6066.

[0360] SB-T-1216C306

[0361] Compound 2-11C3 (98 mg, 0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(8 mL total) and cooled to 0 OC under inert conditions. To the mixture excess HF, 70% in pyridine (0.8 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3(50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-1216C306 (69 mg, 0.07 mmol, 87% yield) as a crystalline white solid:1H NMR (500 MHz, , CDCl3) δ 7.96 (dt, J = 7.8, 1.4 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.40 – 7.32 (m, 3H), 7.30 – 7.21 (m, 3H), 7.08 (s, 1H), 6.34 (s, 1H), 6.20 (t, J = 8.8 Hz, 1H), 5.67 (d, J = 7.1 Hz, 1H), 5.35 (d, J = 8.6 Hz, 1H), 5.01 (dd, J = 9.7, 2.3 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.77 (td, J = 8.8, 2.8 Hz, 1H), 4.48 (ddd, J = 10.9, 6.6, 4.0 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.23 (dd, J = 6.8, 2.8 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.84 (d, J = 7.0 Hz, 1H), 3.46 (d, J = 6.8 Hz, 1H), 2.94 (s, 1H), 2.63 – 2.54 (m, 1H), 2.48 (s, 3H), 2.38 (s, 5H), 1.98 – 1.89 (m, 4H), 1.87 (dd, J = 14.2, 4.4 Hz, 2H), 1.77 (dd, J = 9.9, 1.4 Hz, 6H), 1.70 (s, 3H), 1.34 (s, 8H), 1.27 (s, 3H), 1.18 (s, 2H).13C NMR (126 MHz, CDCl3) δ 205.06, 173.26, 171.26, 170.18, 165.85, 155.45, 151.22, 143.52, 143.51, 137.97, 132.71, 132.71, 131.07, 130.26, 128.15, 127.21, 124.91, 120.57, 120.15, 119.75, 117.77, 115.70, 113.62, 84.53, 80.99, 79.89, 79.24, 77.31, 77.06, 76.81, 76.34, 75.98, 75.63, 73.68, 72.26, 60.45, 58.54, 51.47, 51.46, 45.62, 43.14, 35.51, 28.21, 26.78, 25.71, 22.28, 22.14, 21.07, 18.48, 16.74, 15.03, 14.21, 9.48.19F NMR (376 MHz, CDCl3) δ -80.47 (dd, J = 166.8, 74.0 Hz), -81.99 (dd, J = 166.7, 72.5 Hz). HRMS (ESI-TOF): m / z: Calcd. For C50H62F2N2O16SH+1017.3861, Found 1017.388.

[0362] 2’-Triisopropylsilyl-7-triethylsilyl- SB-T-12854C105 [2-12C1]

[0363] Compound 2-8C1 (100 mg, 0.11 mmol) and 1-12 (66 mg, 0.162 mmol) were dissolved in THF(2.5 mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.3 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to 76afford 2-12C1 (83 mg,0.06 mmol, 83% yield) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.4, 6.1 Hz, 3H), 7.50 – 7.44 (m, 2H), 6.48 (s, 1H), 6.15 (t, J = 9.0 Hz, 1H), 5.69 (d, J = 7.2 Hz, 1H), 4.98 (dd, J = 9.7, 2.0 Hz, 2H), 4.56 – 4.45 (m, 3H), 4.31 (d, J = 8.4 Hz, 1H), 4.19 (d, J = 8.4 Hz, 1H), 3.87 (d, J = 7.0 Hz, 1H), 2.59 (s, 3H), 2.58 – 2.51 (m, 1H), 2.41 – 2.31 (m, 5H), 2.12 (d, J = 1.5 Hz, 3H), 1.97 – 1.87 (m, 2H), 1.72 (s, 3H), 1.49 – 1.42 (m, 1H), 1.32 (s, 9H), 1.24 – 1.17 (m, 7H), 1.14 (p, J = 4.0 Hz, 24H), 0.93 (t, J = 7.9 Hz, 10H), 0.61 (qd, J = 7.9, 4.1 Hz, 7H).13C NMR (126 MHz, CDCl3) δ 202.91, 197.01, 171.25, 170.99, 169.97, 165.52, 154.88, 151.66, 149.29, 142.25, 141.71, 133.08, 132.43, 131.31, 130.34, 129.85, 128.61, 126.09, 125.28, 122.31, 121.45, 119.39, 118.01, 92.19, 84.27, 81.00, 80.10, 78.76, 78.35, 77.30, 77.05, 76.79, 76.38, 76.27, 75.45, 74.91, 72.60, 72.39, 71.91, 60.79, 60.44, 58.41, 49.05, 46.77, 43.26, 37.14, 36.65, 35.29, 28.11, 26.40, 24.69, 23.39, 22.21, 21.33, 21.05, 18.04, 17.96, 17.91, 17.84, 14.42, 14.19, 14.02, 12.79, 12.55, 12.11, 10.05, 6.74, 5.59, 5.35, 5.33, 5.12.19F NMR (376 MHz, CDCl3) δ -57.97, -84.69 (dd, J = 38.1, 24.8 Hz), - 86.30 (d, J = 38.2 Hz). HRMS (ESI-TOF): m / z: Calcd. For C64H89F5N2O17Si2H+1309.5693, Found 1309.5691.

[0364] SB-T-12854C105

[0365] Compound 2-12C1 (83 mg, 0.06 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(6 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.6 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C105 (52 mg, 0.05 mmol, 84% yield) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 (dd, J = 15.9, 8.8 Hz, 3H), 7.42 (s, 1H), 6.37 (s, 1H), 6.23 (t, J = 8.9 Hz, 1H), 5.68 (d, J = 7.1 Hz, 1H), 5.04 – 4.96 (m, 2H), 4.88 (t, J = 9.7 Hz, 1H), 4.66 – 4.56 (m, 1H), 4.48 (dq, J = 11.6, 5.2 Hz, 1H), 4.31 (dd, J = 10.5, 6.8 Hz, 2H), 4.19 (d, J = 8.4 Hz, 1H), 3.85 (d, J = 7.1 Hz, 1H), 3.70 – 3.46 (m, 1H), 2.81 (d, J = 9.9 Hz, 1H), 2.59 (s, 3H), 2.38 (d, J = 13.4 Hz, 4H), 1.99 – 1.88 (m, 4H), 1.83 (s, 1H), 1.77 (s, 1H), 1.72 (s, 3H), 1.33 (s, 9H), 1.27 (d, J = 3.3 Hz, 4H), 1.19 (s, 3H).13C NMR (126 MHz, CDCl3) δ 204.73, 197.08, 172.52, 171.26, 170.30, 165.62, 154.91, 149.33, 143.32, 141.64, 132.73, 131.15, 130.41, 129.85, 128.59, 126.24, 122.31, 121.45, 119.39, 84.45, 80.99, 80.41, 79.16, 77.29, 77.04, 76.79, 76.30, 76.19, 75.63, 73.17, 72.59, 72.26, 60.45, 58.59, 48.10, 45.69, 43.15, 36.64, 35.62, 35.39, 28.09, 26.78, 7726.45, 24.69, 22.10, 21.07, 15.03, 14.20, 9.50.19F NMR (376 MHz, CDCl3) δ -57.97, -84.69 (dd, J = 38.1, 24.8 Hz), -86.30 (d, J = 38.2 Hz). HRMS (ESI-TOF): m / z: Calcd. For C49H55F5N2O17H+1039.3494, Found 1039.3511.

[0366] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C205 [2-12C2]

[0367] Compound 2-8C2 (90 mg, 0.1 mmol) and 1-12 (61 mg, 0.152 mmol) were dissolved in THF(2 mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-12C2 (86 mg,0.07 mmol, 70% yield) as a white solid:1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.2, 2.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.02 (s, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.46 (s, 1H), 6.15 (s, 1H), 5.69 (d, J = 7.1 Hz, 1H), 5.01 – 4.95 (m, 2H), 4.89 (d, J = 11.7 Hz, 1H), 4.56 – 4.45 (m, 3H), 4.31 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.90 – 3.82 (m, 1H), 3.81 (s, 3H), 2.55 (ddd, J = 14.3, 9.7, 6.6 Hz, 1H), 2.37 (s, 3H), 2.36 – 2.30 (m, 2H), 2.11 (s, 3H), 1.97 – 1.86 (m, 2H), 1.72 (s, 3H), 1.68 – 1.42 (m, 2H), 1.32 (s, 9H), 1.26 – 1.20 (m, 5H), 1.13 (t, J = 5.1 Hz, 23H), 0.94 (t, J = 7.9 Hz, 10H), 0.69 – 0.53 (m, 6H).13C NMR (126 MHz, CDCl3) δ 203.13, 171.22, 170.93, 169.92, 165.54, 156.22, 154.88, 152.51, 149.29, 141.28, 133.38, 131.36, 130.64, 130.32, 129.55, 128.61, 126.06, 123.51, 122.33, 121.45, 121.30, 119.40, 114.56, 114.26, 92.16, 84.31, 81.04, 80.09, 78.82, 78.36, 77.30, 77.05, 76.79, 76.40, 75.95, 75.52, 74.89, 72.34, 71.92, 60.42, 58.34, 55.49, 49.03, 46.81, 43.25, 37.16, 36.65, 35.28, 28.11, 26.39, 24.69, 23.38, 22.21, 21.27, 21.05, 18.05, 17.96, 17.91, 17.85, 14.40, 14.20, 12.79, 12.55, 12.32, 10.05, 7.92, 6.76, 5.56, 5.32, 5.09.19F NMR (376 MHz, CDCl3) δ -57.96, -84.59 – -84.88 (m), -86.35 (d, J = 38.3 Hz). HRMS (ESI-TOF): m / z: Calcd. For C63H89F5N2O17Si2H+1297.5693, Found 1297.5699.

[0368] SB-T-12854C205

[0369] Compound 2-12C2 (86 mg, 0.07 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(7 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.7 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3(50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done 78by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C205 (61 mg, 0.061 mmol, 91% yield) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.3, 2.5 Hz, 1H), 7.35 – 7.27 (m, 3H), 6.91 – 6.84 (m, 3H), 6.33 (s, 1H), 6.24 (d, J = 11.3 Hz, 1H), 5.67 (d, J = 7.0 Hz, 1H), 5.01 (dd, J = 9.7, 2.3 Hz, 1H), 4.95 (d, J = 9.2 Hz, 1H), 4.88 (d, J = 10.0 Hz, 1H), 4.60 (ddd, J = 24.7, 9.7, 1.7 Hz, 1H), 4.48 (ddd, J = 10.9, 6.7, 3.9 Hz, 1H), 4.34 – 4.26 (m, 2H), 4.19 (d, J = 8.4 Hz, 1H), 3.85 (d, J = 7.1 Hz, 1H), 3.81 (s, 3H), 3.54 (d, J = 5.8 Hz, 1H), 2.98 – 2.94 (m, 1H), 2.64 – 2.54 (m, 1H), 2.38 (d, J = 9.6 Hz, 5H), 1.98 – 1.86 (m, 4H), 1.71 (d, J = 4.4 Hz, 5H), 1.33 (s, 8H), 1.28 (d, J = 4.5 Hz, 3H), 1.20 (s, 2H).13C NMR (126 MHz, CDCl3) δ 205.00, 172.50, 171.23, 170.25, 165.64, 156.54, 154.87, 153.48, 149.32, 131.20, 130.39, 128.59, 126.21, 122.33, 121.45, 121.21, 119.40, 114.28, 84.54, 81.04, 80.41, 79.26, 77.29, 77.04, 76.78, 76.32, 75.71, 73.15, 72.66, 72.32, 60.44, 58.58, 55.52, 48.04, 45.61, 43.16, 35.48, 35.38, 28.09, 26.85, 22.11, 21.07, 15.03, 14.21, 9.44.19F NMR (376 MHz, CDCl3) δ - 57.95, -83.57 – -84.30 (m), -85.78 (d, J = 35.8 Hz). HRMS (ESI-TOF): m / z: Calcd. For C48H55F5N2O17H+1027.3494, Found 1027.353.

[0370] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C305 [2-12C3]

[0371] Compound 2-8C3 (90 mg, 0.1 mmol) and 1-12 (61 mg, 0.15 mmol) were dissolved in THF (2mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-12C3 (105 mg,0.08 mmol, 81% yield) as a white solid.1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 7.9, 2.4 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.30 – 7.24 (m, 3H), 6.47 (s, 1H), 6.15 (t, J = 9.3 Hz, 1H), 5.69 (d, J = 7.1 Hz, 1H), 5.01 – 4.94 (m, 2H), 4.56 – 4.45 (m, 3H), 4.32 (d, J = 8.3 Hz, 1H), 4.19 (d, J = 8.4 Hz, 1H), 3.88 (d, J = 7.0 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.49 (s, 3H), 2.38 – 2.30 (m, 3H), 2.12 (d, J = 1.6 Hz, 3H), 1.97 – 1.88 (m, 2H), 1.78 – 1.73 (m, 2H), 1.73 (s, 3H), 1.32 (s, 9H), 1.31 – 1.18 (m, 8H), 1.14 (t, J = 5.0 Hz, 23H), 0.94 (d, J = 8.0 Hz, 10H), 0.61 (qd, J = 7.9, 4.9 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 202.87, 170.96, 169.95, 165.57, 154.88, 149.30, 141.44, 135.34, 133.26, 131.33, 130.34, 128.62, 128.33, 126.10, 124.87, 122.34, 121.46, 119.74, 119.40, 84.29, 81.04, 80.11, 78.84, 78.80, 77.29, 77.03, 76.78, 76.39, 76.06, 75.49, 74.90, 72.35, 71.91, 58.37, 49.02, 46.79, 43.98, 43.26, 41.30, 37.16, 36.65, 35.27, 28.12, 26.44, 24.69, 24.04, 23.36, 22.20, 21.32, 18.05, 17.96, 16.87, 14.41, 12.56, 12.32, 10.06, 6.76, 5.35.19F NMR (376 MHz, CDCl3) δ -57.94, -83.04 – 79-84.91 (m), -85.79 (d, J = 35.9 Hz). HRMS (ESI-TOF): m / z: Calcd. For C63H89F5N2O16SSi2H+1313.5464, Found 1313.5468.

[0372] SB-T-12854C305

[0373] Compound 2-12C3 (105 mg,0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(8 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.8 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3(50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C305 (69 mg, 0.07 mmol, 88% yield) as a crystalline white solid:1H NMR (400 MHz, CDCl3 ) δ 8.07 (d, J = 7.7 Hz, 1H), 8.01 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.1, 2.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.31 – 7.21 (m, 3H), 7.06 (s, 1H), 6.34 (s, 1H), 6.22 (t, J = 9.0 Hz, 1H), 5.67 (d, J = 7.0 Hz, 1H), 5.05 – 4.97 (m, 2H), 4.87 (t, J = 9.6 Hz, 1H), 4.67 – 4.53 (m, 1H), 4.48 (dd, J = 10.9, 6.7 Hz, 1H), 4.34 – 4.26 (m, 2H), 4.19 (d, J = 8.3 Hz, 1H), 3.84 (d, J = 7.0 Hz, 1H), 2.59 (ddd, J = 15.6, 9.6, 6.6 Hz, 1H), 2.48 (s, 3H), 2.37 (d, J = 14.0 Hz, 5H), 1.96 (s, 3H), 1.90 (dt, J = 16.8, 4.4 Hz, 1H), 1.71 (s, 3H), 1.33 (s, 8H), 1.27 (s, 3H), 1.18 (s, 2H).13C NMR (101 MHz, CDCl3) δ 204.90, 172.48, 170.28, 165.62, 154.91, 149.32, 143.09, 134.70, 132.91, 131.19, 130.39, 128.59, 128.12, 126.20, 122.31, 121.71, 119.78, 119.14, 84.51, 81.04, 80.42, 79.19, 77.36, 77.25, 77.05, 76.73, 76.31, 75.69, 73.16, 72.60, 72.27, 60.45, 58.56, 45.67, 43.15, 35.55, 35.40, 28.10, 26.79, 22.11, 22.08, 21.06, 16.71, 15.02, 14.20, 9.47.19F NMR (376 MHz, CDCl3) δ -57.94, -83.04 – -84.91 (m), -85.79 (d, J = 35.9 Hz). HRMS (ESI-TOF): m / z: Calcd. For C48H55F5N2O16SH+1043.3265, Found 1043.3296.

[0374] 2’-Triisopropylsilyl-7-triethylsilyl- SB-T-12854C106 [2-13C1]

[0375] Compound 2-10C1 (97 mg, 0.1 mmol) and 1-12 (61 mg, 0.15 mmol) were dissolved in THF(2 mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-13C1 (104 mg,0.08 mmol, 78% yield) as a white solid1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 7.9, 5.2 Hz, 3H), 7.91 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 19.8, 8.2 Hz, 3H), 7.41 – 7.34 (m, 2H), 6.80 (s, 801H), 6.48 (s, 1H), 6.21 (t, J = 9.1 Hz, 1H), 5.69 (d, J = 7.1 Hz, 1H), 5.02 – 4.89 (m, 3H), 4.58 – 4.44 (m, 3H), 4.35 (d, J = 8.4 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.87 (d, J = 7.0 Hz, 1H), 2.59 (s, 2H), 2.59 – 2.50 (m, 2H), 2.40 (s, 3H), 2.38 – 2.31 (m, 1H), 2.26 (dd, J = 15.6, 9.0 Hz, 1H), 2.14 – 2.09 (m, 3H), 1.93 (ddd, J = 13.7, 10.6, 2.2 Hz, 2H), 1.86 (s, 1H), 1.45 (d, J = 14.5 Hz, 1H), 1.28 (s, 7H), 1.23 (d, J = 3.1 Hz, 7H), 1.21 – 1.07 (m, 22H), 0.93 (t, J = 7.9 Hz, 9H), 0.61 (qd, J = 7.9, 2.2 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 202.73, 196.94, 170.87, 170.16, 165.96, 151.64, 142.18, 141.61, 133.14, 132.48, 131.04, 130.26, 129.85, 127.15, 124.94, 119.41, 118.01, 117.99, 84.26, 80.99, 80.17, 78.91, 77.36, 77.04, 76.72, 76.39, 76.22, 75.42, 74.91, 72.34, 71.69, 60.42, 58.37, 48.93, 46.76, 43.26, 37.14, 35.31, 28.09, 26.50, 26.41, 22.63, 22.29, 21.46, 18.05, 17.97, 17.87, 14.36, 14.21, 12.56, 10.10, 6.75, 5.36.19F NMR (376 MHz, CDCl3) δ - 80.58 (dd, J = 167.9, 74.6, 5.8 Hz), -83.08 (dd, J = 167.7, 72.0 Hz), -84.72 (dd, J = 38.2, 25.1 Hz), -86.16 (d, J = 38.3 Hz). HRMS (ESI-TOF): m / z: Calcd. For C64H90F4N2O17Si2H+1291.5787, Found 1291.5811.

[0376] SB-T-12854C106

[0377] Compound 2-13C1 (104 mg, 0.08 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(8 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.8 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C106 (59 mg, 0.06 mmol, 86%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 8.00 – 7.89 (m, 4H), 7.52 (t, J = 8.2 Hz, 3H), 7.43 – 7.36 (m, 2H), 7.28 (s, 1H), 6.36 (s, 1H), 6.26 (t, J = 9.1 Hz, 1H), 5.68 (d, J = 7.1 Hz, 1H), 5.01 (dt, J = 9.6, 4.7 Hz, 2H), 4.92 (t, J = 9.9 Hz, 1H), 4.61 (ddd, J = 24.7, 9.6, 1.7 Hz, 1H), 4.53 – 4.45 (m, 1H), 4.38 – 4.29 (m, 2H), 4.19 (d, J = 8.4 Hz, 1H), 3.85 (d, J = 7.1 Hz, 1H), 3.54 (d, J = 5.5 Hz, 1H), 2.83 – 2.78 (m, 1H), 2.59 (s, 4H), 2.42 (s, 3H), 2.38 (d, J = 9.8 Hz, 1H), 2.35 – 2.25 (m, 1H), 1.98 – 1.88 (m, 4H), 1.80 (s, 1H), 1.73 (d, J = 12.0 Hz, 5H), 1.28 (dd, J = 11.5, 2.5 Hz, 12H), 1.18 (s, 3H).13C NMR (126 MHz, CDCl3) δ 204.73, 197.07, 171.25, 170.40, 170.39, 166.01, 154.93, 152.74, 151.34, 143.22, 132.74, 130.88, 130.32, 129.85, 127.13, 125.07, 119.69, 118.18, 115.69, 84.46, 80.96, 80.44, 80.43, 79.24, 77.29, 77.04, 76.79, 76.31, 76.15, 75.57, 73.11, 72.59, 72.22, 60.45, 58.56, 47.94, 45.64, 43.15, 35.58, 35.43, 28.07, 26.82, 26.46, 22.19, 22.18, 21.08, 14.97, 14.21, 9.54.19F NMR (376 MHz, CDCl3) δ -80.58 (dd, J = 167.9, 74.6, 5.8 Hz), -83.08 (dd, J = 167.7, 72.0 Hz), -84.72 (dd, J = 38.2, 25.1 Hz), -86.16 (d, J = 38.3 Hz). HRMS (ESI-TOF): m / z: Calcd. For C49H56F4N2O17H+1021.3588, Found 1021.3615. 81

[0378] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C206 [2-13C2]

[0379] Compound 2-10C2 (61 mg, 0.07 mmol) and 1-12 (41 mg, 0.1 mmol) were dissolved in THF(1.5 mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.11 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O ( 20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-13C2 (60 mg, 0.04 mmol, 57% yield) as a white solid1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 7.9, 2.4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 6.92 – 6.84 (m, 2H), 6.80 (s, 1H), 6.46 (s, 1H), 6.21 (t, J = 9.0 Hz, 1H), 5.69 (d, J = 7.1 Hz, 1H), 4.97 (t, J = 7.9 Hz, 2H), 4.57 – 4.43 (m, 3H), 4.35 (d, J = 8.3 Hz, 1H), 4.17 (dd, J = 19.7, 7.7 Hz, 1H), 3.81 (s, 4H), 2.55 (ddd, J = 15.6, 9.6, 6.7 Hz, 1H), 2.40 (s, 4H), 2.25 (d, J = 10.9 Hz, 1H), 2.10 (s, 3H), 1.98 – 1.87 (m, 1H), 1.73 (s, 3H), 1.65 (s, 1H), 1.58 (d, J = 6.5 Hz, 1H), 1.50 – 1.39 (m, 2H), 1.28 (s, 9H), 1.23 (s, 4H), 1.13 (dd, J = 5.7, 3.4 Hz, 25H), 0.95 (t, J = 7.9 Hz, 10H), 0.62 (qd, J = 7.8, 2.8 Hz, 7H).13C NMR (101 MHz, CDCl3) δ 202.73, 166.02, 133.42, 131.08, 130.25, 127.15, 124.92, 122.84, 121.31, 114.28, 84.30, 81.03, 80.13, 79.03, 77.35, 77.23, 77.03, 76.71, 76.40, 75.48, 72.27, 71.66, 68.23, 60.66, 58.30, 55.51, 48.94, 46.79, 43.25, 37.16, 35.27, 28.09, 26.48, 21.93, 21.44, 21.06, 18.06, 17.97, 14.32, 12.56, 10.11, 6.78, 5.34.19F NMR (376 MHz, CDCl3) δ -79.57 – -81.59 (m), -83.12 (dd, J = 168.1, 71.9 Hz), -84.05 – -85.67 (m), -86.20 (d, J = 38.0 Hz).

[0380] SB-T-12854C206

[0381] Compound 2-13C2 (60 mg, 0.04 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(4 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.5 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C206 (35 mg, 0.035 mmol, 87%) as a crystalline white solid:1H NMR (700 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.43 – 7.30 (m, 3H), 7.25 (d, J = 8.3 Hz, 2H), 7.04 (s, 1H), 6.79 (t, J = 73.1 Hz, 1H), 6.33 (s, 1H), 6.26 (t, J = 9.2 Hz, 1H), 5.67 (d, J = 7.1 Hz, 1H), 5.01 (dt, J = 8.7, 4.3 Hz, 2H), 4.92 (d, J = 9.8 Hz, 1H), 4.64 – 4.56 82(m, 1H), 4.49 (dd, J = 11.0, 6.7 Hz, 1H), 4.35 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 2.3 Hz, 1H), 4.19 (d, J = 8.5 Hz, 1H), 3.84 (d, J = 7.1 Hz, 1H), 2.59 (ddd, J = 15.6, 9.8, 6.7 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 2H), 2.38 (d, J = 9.8 Hz, 1H), 2.30 (dd, J = 15.4, 8.9 Hz, 1H), 1.95 (s, 3H), 1.70 (s, 3H), 1.43 (d, J = 16.7 Hz, 1H), 1.28 (d, J = 9.2 Hz, 13H), 1.18 (s, 3H), 0.95 – 0.80 (m, 2H).13C NMR (126 MHz, CDCl3) δ 205.00, 172.52, 170.34, 166.03, 156.45, 154.89, 151.38, 142.96, 130.92, 130.31, 127.14, 125.04, 121.20, 121.20, 119.68, 114.29, 114.28, 84.55, 81.01, 81.01, 80.42, 79.35, 77.29, 77.04, 76.78, 76.33, 75.64, 73.08, 73.07, 72.69, 72.27, 60.43, 58.55, 55.52, 47.91, 45.56, 43.16, 35.42, 29.72, 28.07, 26.89, 22.20, 21.07, 14.97, 14.21, 9.48.19F NMR (376 MHz, CDCl3) δ -80.58 (dd, J = 167.7, 74.7 Hz), -83.15 (dd, J = 167.8, 72.0 Hz), -83.75 – - 84.11 (m), -85.70 (d, J = 36.2 Hz). HRMS (ESI-TOF): m / z: Calcd. For C48H56F4N2O17H+1009.3588, Found 1009.3597.

[0382] 2’-Triisopropylsilyl-7-triethylsilyl-SB-T-12854C306 [2-13C3]

[0383] Compound 2-10C3 (92 mg, 0.1 mmol) and 1-12 (61 mg, 0.15 mmol) were dissolved in THF(2 mL), and cooled to -40oC under inert conditions. To the mixture was added LiHMDS, 1M in THF (0.25 mL), dropwise. The reaction was monitored at low temperature by TLC (hexanes:ethyl acetate = 70:30), and upon completion was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was then allowed to warm to room temperature, diluted with H2O (20 mL) and extracted with ethyl acetate (3 X 20 mL). The organic layer was then washed with brine (3 X 20 mL), dried over MgSO4, and concentrated in vacuo. Purification was done by column chromatography on silica gel (hexanes:ethyl acetate = 70:30) to afford 2-13C3 (88 mg,0.07 mmol, 70% yield) as a white solid.

[0384] SB-T-12854C306

[0385] Compound 2-13C3 (88 mg, 0.07 mmol) was dissolved in a 1:1 mixture of acetonitrile:pyridine(7 mL total) and cooled to 0oC under inert conditions. To the mixture excess HF, 70% in pyridine (0.7 mL), was added dropwise. The reaction was stirred at room temperature and monitored by TLC (hexanes:ethyl acetate = 50:50). Upon completion the reaction was quenched with 10% aqueous citric acid (10 mL), neutralized with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was collected, washed with saturated CuSO4 solution (3 X 50 mL), water (60 mL) and brine (3 X 60 mL). The extract was then dried over anhydrous MgSO4, concentrated in vacuo. Purification was done by column chromatography on silica gel with increasing amounts of ethyl acetate in hexanes (hexanes:ethyl acetate = 50:50) to afford SB-T-12854C306 (47 mg, 0.05 mmol, 84%) as a crystalline white solid:1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.91 (t, J = 1.9 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.1, 2.5 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.28 – 7.22 (m, 2H), 6.99 (s, 1H), 6.94 (s, 0H), 6.80 (s, 1H), 6.65 (s, 0H), 6.33 (s, 1H), 6.26 (t, J = 9.1 Hz, 1H), 5.67 (d, J = 7.1 Hz, 1H), 5.00 (td, J = 11.6, 5.5 Hz, 2H), 4.92 (d, J = 9.9 Hz, 1H), 4.60 (ddd, J = 24.7, 9.5, 1.7 Hz, 1H), 4.49 (ddd, J = 11.0, 6.6, 4.0 Hz, 1H), 834.35 (d, J = 8.4 Hz, 1H), 4.31 (dd, J = 5.5, 2.3 Hz, 1H), 4.19 (d, J = 8.3 Hz, 1H), 3.84 (d, J = 7.1 Hz, 1H), 3.51 (d, J = 5.5 Hz, 1H), 2.89 (s, 1H), 2.59 (ddd, J = 14.6, 9.8, 6.7 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 3H), 2.40 – 2.35 (m, 1H), 2.35 – 2.25 (m, 1H), 1.97 – 1.93 (m, 3H), 1.93 – 1.87 (m, 1H), 1.73 (s, 1H), 1.71 (s, 3H), 1.42 (s, 1H), 1.28 (d, J = 5.3 Hz, 11H), 1.18 (s, 2H).13C NMR (126 MHz, CDCl3) δ 204.92, 172.50, 170.38, 166.01, 156.54, 154.93, 151.34, 143.01, 133.00, 130.92, 130.31, 128.14, 127.13, 125.05, 119.73, 117.78, 115.70, 113.63, 84.52, 80.99, 80.43, 79.27, 77.30, 77.05, 76.79, 76.32, 75.88, 75.63, 73.10, 72.63, 72.22, 58.53, 47.93, 45.61, 43.15, 35.50, 35.42, 34.68, 31.94, 29.72, 29.38, 28.22, 28.19, 28.08, 26.83, 22.71, 22.19, 16.71, 14.96, 14.14, 9.51.19F NMR (376 MHz, CDCl3) δ -80.58 (dd, J = 167.7, 74.7 Hz), -83.15 (dd, J = 167.8, 72.0 Hz), -83.75 – -84.11 (m), -85.70 (d, J = 36.2 Hz). HRMS (ESI-TOF): m / z: Calcd. For C48H56F4N2O16SH+1025.3359, Found 1025.33711. DISCUSSION

[0386] Paclitaxel (PTX) and docetaxel (DTX) are two of the most extensively used chemotherapeuticdrugs in clinic for the treatment of various cancers, particularly for ovarian, lung, and breast cancers in the last quarter century. Over the past three decades, Ojima et al. conducted systematic SAR studies on PTX leading to the development of 2ndgeneration (with modifications at C10, C3′ and C3′N), 3rdgeneration (with modifications at C2, C10, C3′ and C3′N) and difluorovinyl (DFV) taxoids (with modification at C4’) which exhibit 2–3 orders of magnitude higher potency than PTX and DTX against various drug-resistant cancer cell lines expressing the multidrug-resistance (MDR) phenotype. However, these chemotherapeutic agents display low to no tumor specificity leading to high levels of systemic toxicity inducing organ dysfunction or failures at times. Thus, there is an increasing demand for the development of novel taxoid anticancer agents with superior pharmacological properties and potency against various types of cancer, in particular drug-resistant and metastatic cancers. Ojima et al. previously reported C-10 site being crucial for the recognition and binding by P-glycoprotein (P-gp). These interactions can be minimized by incorporating carbamate modifiers at C-10 position without affecting binding to microtubules.

[0387] According to recent findings by Yan et al., installing a para acetylphenylcarbamoyl group atthe C-10 position of docetaxel (DTX-AI) led to a drastic improvement in the in vivo survival rate of the mice (100%) as compared to DTX (0%) upon an 8 week long-term therapy (Hela tumor treatment) suggesting enhanced safety and low systemic toxicity of DTX-AI. The present disclosure reports a series of new 2nd / 3rdgeneration taxoids and their corresponding DFV taxoids as novel anticancer agents bearing para substituted phenyl carbamoyl group at C-10 and 3-OCF3 / 3-OCHF2at C-2 benzoate. The biological evaluation of these novel taxoids for their potency against drug-sensitive and drug-resistant cancer cell lines, as well as their selectivity to human cancer cell lines over normal cell lines, is discussed below. 84

[0388] The previous designed third-generation taxoids exhibited remarkable in vitro potency across abroad spectrum of human cancer cell lines. Against drug-sensitive lines, including A549 (lung), HT29 (colon), Vcap (prostate), and PC3 (metastatic prostate), the taxoids displayed subnanomolar IC50 values. More significantly, they demonstrated 2–4 orders of magnitude greater potency against highly drug- resistant cell lines, such as LCC6-MDR and DLD-1, compared to paclitaxel as illustrated in Table 1. These findings indicate their potential to overcome MDR mechanisms mediated by P-glycoprotein (Pgp) and other ABC transporters (Kalani 2023).

[0389] Table 1. In vitro cytotoxicity data of selected 2nd / 3rd generation taxoids against drug sensitiveand drug-resistant cancer cell lines Taxoid A549 HT29 Vcap PC3 MCF-7 LCC6-MDR DLD-1 p: e,e, LCC6-MDR: Multidrug-resistant (Pgp+) human breast cancer cell line.

[0390] Table 2. Cytotoxicity of 2nd and 3rd generation taxoids against drug sensitive cancer and non-cancerous cell lines along with selectivity index towards cancer cell. Taxoids Cytotoxicity (IC50 nM) Selectivity Index (SI) M: Non- cancerous lung fibroblast cell line, SI= (IC50against WI38) / (IC50against MCF-7 or MDA-MB-231) 85

[0391] Despite their exceptional potency, the present disclosure revealed a critical limitation: the lackof inherent tumor selectivity. When tested against non-cancerous cell lines, these taxoids displayed comparable cytotoxicity, highlighting poor selectivity profiles. This lack of discrimination between healthy and malignant cells suggests that while these taxoids are highly cytotoxic, they may still cause significant off-target toxicity in clinical settings. The findings emphasize the need for further modifications to enhance tumor specificity, such as incorporating targeting ligands or selective delivery systems (Karolina 2022, Sychra, 2024 and Daniel 2024).

[0392] The previous designed third-generation taxoids demonstrate impressive cytotoxicity and theability to overcome MDR in cancer cells. However, their limited selectivity toward tumor cells raises concerns regarding potential off-target toxicity (Table 2). The present disclosure presents new taxoids with improved tumor-specific targeting while maintaining their potent anticancer properties. These modifications could enhance therapeutic efficacy and reduce adverse effects, ultimately improving clinical outcomes (Karolina 2022, Sychra, 2024 and Daniel 2024).

[0393] Design of novel C-10 phenylcarbamoyl taxoids

[0394] The long-standing problem of chemotherapy is the lack of tumor-specific treatments.Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects, such as hair loss and damage to the liver, kidney, and bone marrow. Paclitaxel (PTX) and docetaxel (DTX) are two of the most extensively used chemotherapeutic drugs in clinic for the treatment of various cancers, particularly for ovarian, lung, and breast cancers in the last quarter century.

[0395] Over the past three decades, Ojima et al. conducted systematic SAR studies on PTX leading tothe development of 2ndgeneration (with modifications at C10, C3′ and C3′N), 3rdgeneration (with modifications at C2, C10, C3′ and C3′N) and difluorovinyl (DFV) taxoids (with modification at C4’) which exhibit 2–3 orders of magnitude higher potency than PTX and DTX against various drug-resistant cancer cell lines expressing the multidrug-resistance (MDR) phenotype. However, these chemotherapeutic agents display low to no tumor specificity leading to high levels of systemic toxicity inducing organ dysfunction or failures at times. In order to deliver the cytotoxic payload selectively to the tumor, complex tumor targeted drug delivery system (TTDD) need to be designed, requiring long synthesis (Ojima 2007 and Ojima 2012). Thus, there is an increasing demand for the development of novel taxoid anticancer agents with superior pharmacological properties and potency against various types of cancer, in particular drug- resistant and metastatic cancers and possessing inherent tumor selectivity. Ojima et al. previously reported C-10 site being crucial for the recognition and binding by P-glycoprotein (P-gp). These interactions can be 86minimized by incorporating carbamate modifiers at C-10 position without affecting binding to microtubules (Ojima 1996).

[0396] Yan et al. describes the synthesis of 10-O-4-ketonephenylcarbamatedocetaxel (a novelderivative of docetaxel, DTX) through the modification of the C10 position of the DTX scaffold using 4- acetylphenyl carbamate. The compound’s safety profile, anticancer efficacy, and potential to overcome multidrug resistance (MDR) were evaluated in vitro across a range of normal and tumor cell lines. Additionally, the mechanism underlying its activity was investigated. In vivo, the present disclosure further assessed its safety, short-term and long-term antitumor effects, as well as its impact on tumor recurrence using cervical and non-small cell lung cancer xenograft models in nude mice. Installing a para acetylphenylcarbamoyl group at the C-10 position of docetaxel (DTX-AI) led to a drastic improvement in the in vivo survival rate of the mice (100%) as compared to DTX (0%) upon an 8 week long-term therapy (Hela tumor treatment) suggesting enhanced safety and low systemic toxicity of DTX-AI (Figure 2-2A). DTX-AI demonstrates exceptionally high effectiveness against both DTX-sensitive and DTX-resistant tumor cells in vitro (Figure 2-2B) . However, it shows reduced sensitivity to normal cells, making DTX- AI safer than DTX (Figure 2-2C) (Ojima 2012).

[0397] Chemotherapeutic agents display low to no tumor specificity leading to high levels of systemictoxicity inducing organ dysfunction or failures at times. Complex tumor targeted drug delivery systems need to be designed to deliver the payload selectively to cancer cells. Thus, there is an increasing need to develop novel taxoids having inherent selectivity towards cancer cells over normal cells. To address this, the present disclosure conducted a SAR study exploring previously unexplored p-phenylcarbamoyl group at C-10 and 3-OCF3 / 3-OCHF2 at C-2 benzoate as novel 2nd / 3rdgeneration taxoids and corresponding C 3’ difluorovinyl (DFV) taxoids as novel anticancer agents. A library of 18 novel taxoids bearing C-10 (p- acetylphenyl, p-methoxyphenyl and p-methylthiophenyl) carbamoyl analogs were designed and synthesized (9-13 steps) by means of the β-lactam synthon method via modified 10 deacetylbaccatin III derivatives (Figure 3A, 3B, 3C and 3D).

[0398] In vitro cytotoxicity evaluation of C-10 carbamoyl analogs of taxoids

[0399] The cytotoxic activity of the newly synthesized C-10 carbamoyl taxoid analogs was assessedacross a panel of cancerous and non-cancerous cell lines to evaluate both potency and selectivity. The panel included drug-sensitive cell lines such as PC-3 (prostate adenocarcinoma), MCF-7 (breast adenocarcinoma), and HeLa (cervical carcinoma), alongside drug-resistant lines, including MDA-MB-231 (triple-negative breast cancer), DLD-1 (colorectal adenocarcinoma), and an MDR variant of MCF-7. To assess the selectivity profile, the non-cancerous WI-38 cell line, composed of diploid fibroblasts derived from normal lung tissue, was included as a control. 87

[0400] MCF-7 cells, which originate from breast cancer, initially respond to therapy but are prone todeveloping multidrug resistance (MDR), making them a valuable model for studying resistance mechanisms. PC-3 cells, derived from prostate cancer, are commonly used to evaluate drug efficacy against androgen-independent tumors. The MDA-MB-231 line, originating from pleural effusion of breast adenocarcinoma, represents triple-negative breast cancer (TNBC), characterized by the absence of ER, PR, and HER2 expression. Its inherent resistance to standard treatments makes it a key model for exploring therapies targeting aggressive, drug-resistant breast cancers. HeLa cells, derived from cervical carcinoma, exhibit epithelial-like morphology and are broadly used as a model for evaluating anticancer agents due to their general sensitivity to treatment. DLD-1 cells, established from colorectal adenocarcinoma, display varying responses to chemotherapeutics, with some subpopulations acquiring resistance, making them useful for studying resistance mechanisms in colorectal cancer. Finally, WI-38 cells, being non-malignant, serve as a reference model to assess the compounds' selectivity and potential cytotoxicity against normal human cells.

[0401] The results of the cytotoxicity assays, summarized in Table 3, provide insight into thetherapeutic potential and selectivity, summarized in Table 4 of the C-10 carbamoyl taxoid analogs against both sensitive and resistant cancer cell lines.

[0402] Table 3. In vitro cytotoxicity evaluation of novel 2nd / 3rd generation taxoids against drugsensitive , drug resistant cancer and non-cancerous cell lines. MCF-7 Hela PC3 DLD-1 MDA-MB-231 WI-38 Taxoids88MCF-7 Hela PC3 DLD-1 MDA-MB-231 WI-38 Taxoids (nM) (nM) (nM) (nM) (nM) (nM) 3 .2 .70 2 2 2 4 0 0metastatc prostate cancer ce ne, WI-38: umanung brobast ce ne 89

[0403] In the MCF-7 cell line, SB-T-12854C1 and SB-T-1216C106 exhibited IC50 values of 0.28 nM,indicating potent inhibition. SB-T-1216C206 showed the lowest IC50at 0.19 nM, demonstrating even stronger inhibition compared to the reference compound SBT-1214. Overall, most compounds showed higher cytotoxicity towards MCF-7 cells, with SB-T-1216C105 showing the least inhibition with an IC50of 2.2 nM.

[0404] For HeLa cells, SB-T-1216C3, SB-T-1216C205, SB-T-1216C206, and SB-T-12854C305showed higher cytotoxicity compared to SBT-1214. Notably, SB-T-12854C1 and SB-T-12854C2 displayed very low IC50 values, making them standout as the most effective compounds in inhibiting HeLa cells. SB- T-12854C306 had the highest IC50 at 1.3 nM, slightly higher than paclitaxel (1.12 nM).

[0405] In PC-3 cells, SB-T-1216C205, SB-T-1216C206, SB-T-1216C306, SB-T-12854C205, andSB-T-12854C106 showed lower IC50 values compared to SBT-1214. Impressively, SB-T 1216C2, SB-T- 12854C1, SB-T-12854C206, and SB-T-12854C306 demonstrated the highest inhibition with IC50 values ranging from 0.03 to 0.09 nM, significantly lower than SBT-1214 (0.37 nM).

[0406] Despite being a drug-resistant cell line, most compounds showed very low IC50 values rangingfrom 0.18 to 1.5 nM in DLD-1 cells. SB-T-1216C105 had a higher IC50 of 14.27 nM, indicating lower inhibition compared to SBT-1214 (1.3 nM) but similar to paclitaxel (18.41 nM).

[0407] Compounds generally showed higher IC50 values in MDA-MB-231 cells compared to othercell lines. Nevertheless, SB-T-1216C105 (0.74 nM), SB-T-1216C206 (0.87 nM), SB-T 12854C205 (0.56 nM), and SB-T-12854C106 (0.18 nM) demonstrated good potency with lower IC50 values compared to the reference taxoid SBT-1214 (1.08 nM).

[0408] As anticipated for a non-cancerous cell line, the tested compounds generally exhibited lowercytotoxicity against WI-38 cells. Notably, SB-T-1216C206 (IC50 = 693.17 nM), SB-T-12854C105 (460.89 nM), SB-T-12854C205 (215.04 nM), and SB-T-12854C305 (199.75 nM) displayed significantly higher IC50 values compared to SB-T-1214 (6.32 nM) and paclitaxel (6.88 nM), indicating reduced toxicity toward normal cells.

[0409] Among the analogs, SB-T-1216C2 demonstrated pronounced cytotoxicity against PC-3 cells,suggesting its potential as a targeted agent for prostate cancer. SB-T-12854C1 exhibited substantial activity against both HeLa and PC-3 cells, indicating its dual efficacy in cervical and prostate cancers. SB-T- 12854C2 displayed potent cytotoxic effects specifically against HeLa cells, highlighting its selectivity for cervical cancer. SB-T-1216C205 showed strong activity against DLD-1 cells, suggesting potential utility in colon cancer therapy. 90

[0410] SB-T-1216C206 exhibited broad-spectrum cytotoxicity, effectively targeting MCF-7, DLD-1,and MDA-MB-231 cells, indicating its therapeutic potential across breast, colon, and triple-negative breast cancers. Similarly, SB-T-12854C205 displayed marked cytotoxic effects against both MDA-MB-231 and DLD-1 cells, suggesting promise for treating triple-negative breast and colorectal cancers. SB-T- 12854C106 demonstrated dual efficacy by inhibiting both HeLa and MDA-MB-231 cell lines, indicating potential for cervical and triple-negative breast cancer treatment. Additionally, SB-T-12854C206 and SB- T-12854C306 exhibited notable cytotoxicity against PC-3 cells, further supporting their relevance for prostate cancer therapy.

[0411] These findings underscore the diverse cytotoxic profiles of the C-10 carbamoyl taxoid analogs,revealing their potential as selective anticancer agents. SB-T-1216C206, in particular, emerges as a promising candidate due to its broad-spectrum activity against multiple cancer types, including breast, colon, and triple-negative breast cancers. Further in vitro and in vivo studies are necessary to validate these results and elucidate the underlying mechanisms of action, paving the way for potential clinical translation.

[0412] Tumor specificity of the novel C-10 carbamoyl analogs of taxoids

[0413] The selectivity indexes (SI) for the C-10 carbamoyl taxoid analogs were determined bycalculating the ratio of the IC50 values in the non-cancerous WI-38 cell line to those in the respective cancer cell lines. This metric provides insight into the compounds' selectivity, indicating their preferential cytotoxicity towards cancer cells over normal cells. The summarized SI values are presented in Table 4

[0414] Table 4. Selectivity index (SI) of novel 2nd / 3rd generation taxoids towards cancer cell line overnon-cancerous / normal cell line.

[0415] Selectivity Indices Based on MTT assay

[0416] SI = IC50 in WI-38 / IC50 in cancer cell lineSI (MDA- Taxoids SI (MCF-7) SI (Hela) SI (PC3) SI (DLD-1)91SI (MDA- Taxoids SI (MCF-7) SI (Hela) SI (PC3) SI (DLD-1) MB-231) M ela: hua cevca cace ce e, -: u a ug-essa coo cace ce e, : u a postate cancer cell line.

[0417] The newly designed C-10 carbamoyl taxoid analogs exhibit remarkable selectivity towardscancer cells, achieving selectivity indices (SI) exceeding 1500—substantially higher than those of paclitaxel and SB-T-1214, both of which display SI values below 20 across all tested drug-sensitive cancer cell lines. This pronounced disparity highlights the superior cancer cell specificity of the novel analogs, effectively sparing normal cells from cytotoxic effects. 92

[0418] Among the tested compounds, SB-T-1216C206 demonstrates the highest selectivity index,largely due to its significantly elevated IC50 value in the WI-38 cell line, which serves as a model for normal human fibroblasts. This indicates that SB-T-1216C206 exhibits notably lower cytotoxicity toward normal cells while retaining potent anticancer activity. In general, the selectivity indices are markedly higher when comparing the IC50 values against WI-38 cells, as opposed to cancer cell lines such as PC-3 (prostate cancer) or DLD-1 (colorectal cancer).

[0419] Cancer is a multifaceted disease characterized by uncontrolled cell proliferation and thepotential to form tumors, which may be benign or malignant. It arises due to a combination of genetic mutations and environmental factors, disrupting the normal cell cycle and promoting invasive growth. Common cancer types, including breast, prostate, lung, and colorectal cancers, account for a significant portion of new cases and cancer-related mortality annually. While traditional treatment modalities—such as chemotherapy, radiation, immunotherapy, and targeted therapies—have improved patient outcomes, they remain challenged by issues of toxicity, side effects, and the emergence of drug resistance. Taxanes, such as paclitaxel, docetaxel, and cabazitaxel, are widely used chemotherapeutics that inhibit cell division by stabilizing microtubules. However, their clinical utility is often hampered by limitations in solubility and the development of resistance, necessitating the search for more effective therapeutic strategies.

[0420] To address these challenges, the cytotoxicity of novel C-10 carbamoyl taxoid analogs wasevaluated against a diverse panel of cancer cell lines, comprising both drug-sensitive (PC-3, MCF-7, HeLa) and drug-resistant (MDA-MB-231, DLD-1, MDR-MCF-7) models, along with the non-cancerous WI-38 fibroblast cell line to assess selectivity. MCF-7 cells, derived from breast cancer, initially respond to chemotherapy but frequently develop multidrug resistance (MDR). PC-3 cells, originating from prostate adenocarcinoma, serve as a model for androgen-independent prostate cancer. MDA-MB-231 cells represent triple-negative breast cancer (TNBC), a particularly aggressive and treatment-resistant subtype lacking ER, PR, and HER2 expression. HeLa cells, derived from cervical carcinoma, are widely used for evaluating anticancer agents due to their epithelial-like morphology and sensitivity to chemotherapy. DLD-1 cells, established from colorectal adenocarcinoma, exhibit variable drug responses and are frequently used for studying resistance mechanisms in colorectal cancer. The WI-38 cell line, composed of normal lung fibroblasts, was employed as a non-cancerous control to evaluate the selectivity of the novel analogs.

[0421] The analogs in the present disclosure demonstrated potent cytotoxicity across multiple cancercell lines with SB-T-1216C206 exhibiting broad-spectrum activity against MCF-7, DLD-1, and MDA-MB- 231 cells, indicating its potential for treating breast, colon, and triple-negative breast cancers. SB-T-1216C2 and SB-T-12854C1 displayed strong activity against PC-3 and HeLa cells, suggesting promise for prostate and cervical cancer therapy. Notably, these compounds exhibited high selectivity indices, particularly SB- 93T-1216C206, which demonstrated strong anticancer potency while sparing normal cells, indicating a favorable therapeutic window. In addition, any novel C-10 carbamoyl taxoid analogs that has a selectivity index (S.I.) exceeds 10 in Table 4 is to be considered cancer selective. Therefore, all 18 C-10 carbamoyl taxoid analogs are considered cancer selective. Among these, an S.I. exceeds 100 is preferentially cancer selective. C-10 carbamoyl taxoid analogs of SB-T-1216C205, SB-T-1216C305, SB-T-1216C106, SB-T- 1216C306, SB-T-12854C105, SB-T-12854C205, and SB-T-12854C306 are all promising cytotoxic agents with wide therapeutic window. 94REFERENCES 1. Wang, C.; Wang, X.; Sun, Y.; Taouil, A. K.; Yan, S.; Botchkina, G. I.; Ojima, I. Design, Synthesis and SAR Study of 3rd-Generation Taxoids Bearing 3-CH3, 3-CF3O and 3-CHF2O Groups at the C2- Benzoate Position. Bioorganic Chemistry 2020, 95, 103523.https: / / doi.org / 10.1016 / j.bioorg.2019.103523. 2 Iwao Ojima; Chen J; Sun L; Borella C. P.; Wang, T.; Miller, M. L.; Lin, S.; Geng, X.; Kuznetsova,.; Qu, C.; Ga ager, .; ao, .; anar , I.; Xia, S.; Susan Band Horwitz; Jon Mallen‐St. Clair; Guerriero, J. L.; Dafna Bar‐Sagi; Veith, J.; Pera, P. Design, Synthesis, and Biological Evaluation of New- Generation Taxoids. Journal of Medicinal Chemistry 2008, 51 (11), 3203–3221.https: / / doi.org / 10.1021 / jm800086e. 3. Wang, C.; Chen, L.; Sun, Y.; Guo, W.; Taouil, A. 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Claims

1. CLAIMS What is claimed is:

1. A compound having the structure:R1O R3O O O O , wherein R1 is -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, -NH-heterocycloalkyl, -NH-alkyl-aryl, -NH- alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, -NH-alkynyl- heteroaryl, -NH-alkyl-cycloalkyl, -NH-alkenyl-cycloalkyl, -NH-alkynyl-cycloalkyl, -NH-alkyl- heterocycloalkyl, -NH-alkenyl-heterocycloalkyl, or -NH-alkynyl-heterocycloalkyl; R2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R3 is -H or alkyl; and R4 is alkyl, alkenyl, -CHF2, or -CF3; and wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted.

2. The compound of claim 1, wherein any one of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,or heterocycloalkyl is (a) unsubstituted, or(b) substituted with one or more of halogen, -OCF3, -CHF2, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl; preferably, substituted with one or more of -H, -F, -Cl, -Br, -CN, -OCF3, -CHF2, C1-C6alkyl, C1-C6alkoxy, C1-C6acyl, or C1-C6alkylthio; more preferably, substituted with one or more of -F, C1-C6alkyl, -OCF3, - CHF2, C1-C6alkoxy, C1-C6alkylthio, or -C1-C6alkanoyl.

973. The compound of any one of claims 1-2, wherein R1 is -NH-aryl, -NH-heteroaryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, -NH-alkynyl-aryl, -NH-alkyl-heteroaryl, -NH-alkenyl-heteroaryl, or -NH-alkynyl- heteroaryl; preferably, R1is -NH-aryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, or -NH-alkynyl-aryl; more preferably, R1is -NH-aryl, -NH-alkyl-aryl, -NH-alkenyl-aryl, or -NH-alkynyl-aryl, and wherein aryl is a substituted aryl; more preferably, R1is -NH-aryl.

4. The compound of any one of claims 1-3, wherein R1 has the structure:, wherein R5, R6, R7, R8, and R9 are eagen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl; preferably, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6acyl, or C1-C6alkylthio; more preferably, R5, R6, R7, R8, and R9are each independently -H, C1-C6alkoxy, -C1-C6alkylthio, or C1-C6alkanoyl.

5. The compound of any one of claims 1-4, wherein R1 has the structure:.

6. Thearyl.

7. The compound of any one of claims 1-6, wherein R2 has the structure:98, wherein R10, R11, R12, R13, and R14are each independently -H, halogen, -CHF2, -CH2F, -CF3, -O-CHF2, -O- CH2F, -O-CF3, -S-CHF2, -S-CH2F, -S-CF3, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cyano, or azido; preferably, R10, R11, R12, R13, and R14 are each independently -H, -F, -Cl, -Br, -CHF2, -CH2F, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, -S-CH2F, or -S- CF3; more preferably, R10, R11, R12, R13, and R14 are each independently -H, -O-CHF2, -O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F; more preferably, R10, R11, R12, R13, and R14 are each independently -H, -O-CHF2, or -O-CF3.

8. The compound of any one of claims 1-7, wherein R2 has the structure:.

9. The compound of any one o6 alkyl; preferably, R3 is -H or methyl;more preferably, R3is -H.

10. The compound of any one of claims 1-9, wherein R4 is alkenyl, -CHF2, or -CF3.

11. The compound of any one of claims 1-10, wherein R4 has the structure:, wherein R15, R16, and R17are each independenty , aogen, or alkyl; preferably, R15, R16and R17are each independently -H, -F, or methyl.

12. The compound of any one of claims 1-11, wherein R4 is 2-methylprop-2-enyl or 2,2-difluorovinyl.9913. The compound of any one of claims 1-12, wherein R4 has the structure:.

14. The compound of claim 1 h, , R1O O R O3O O O NH O R4 OO H OH OOH OOAcR14R10R13R11, or R12, preferably, the compound has the structure: , or , 100more preferably, the compound has the structure: , cture:.

15. Theco pou o ca av g e s ucue:, , 101, , , , , , 102, , , , , , 103, , ,or ; preferably, the compound has the structure: ,,104, , ,, or; 105more preferably, the compound has the structure: .16., mpound has the structure:,106, ,, ,, or .

17. A composition comprising the compound of any one of claims 1-16 and a pharmaceutically acceptablecarrier or pharmaceutically active agent; preferably, the composition is a pharmaceutical composition. 10718. A method of inhibiting the growth of cancer cells in a subject, wherein the method comprisesadministering an effective amount of the compound of claims 1-16 or the composition of claim 17 to the subject.

19. The method of claim 18, wherein the effective amount of the compound of claims 1-16 or thecomposition of claim 17 inhibits the growth of more cancer cells than normal cells in the subject; preferably, inhibits 10-10000 times more cancer cells than normal cells; more preferably, inhibits 100- 10000 times more cancer cells than normal cells; more preferably, inhibits 1000-10000 times more cancer cells than normal cells.

20. The method of claim 19, wherein the effective amount of the compound of claim 16 inhibits the growthof more cancer cells than normal cells in the subject; preferably, inhibits 10-10000 times more cancer cells than normal cells; more preferably, inhibits 100-10000 times more cancer cells than normal cells; more preferably, inhibits 1000-10000 times more cancer cells than normal cells.

21. A method of treating cancer in a subject, wherein the method comprises administering an effectiveamount of the compound of claims 1-16 or the composition of claim 17 to the subject.

22. The method of any one of claims 18-21, wherein the method further comprises administering ananticancer therapy.

23. The method of claim 22, wherein(a) the subject is receiving the anticancer therapy prior to administering the compound or thecomposition; (b) the anticancer therapy and the compound or the composition are administered sequentially;(c) the anticancer therapy and the compound or the composition are administered simultaneously;(d) the compound or the composition is administered orally, intravenously, subcutaneously , orintraperitoneally; or (e) the anticancer therapy is taxane.

24. The method of any one of claims 18-23, wherein(a) the cancer is prostate cancer, skin cancer, breast cancer, hepatocellular carcinoma, cervicalcancer, ovarian cancer, lung cancer, or colon cancer, or (b) the subject is a mammal, preferably, the mammal is human.

25. Use of the compound of claims 1-16 or the composition of claim 17 in inhibiting the growth of cancercells or treating cancer. 10826. The compound of claims 1-16 or the composition of claim 17 for use in inhibiting the growth of cancercells or treating cancer.

27. A process for producing the compound of any one of claims 1-16, the process comprises:(a) reacting a compound of Formula I:II: (b)ormula III:109(Formula III), wherein R5, R6, R7, R8, and R9 are each independently -H, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, acyl, alkylthio, heteroaryl, heteroaryloxy, cyano; amino, alkylamino, arylamino, heteroarylamino, heterocyclylamino, dialkylamino, diarylamino, diheteroarylamino, diheterocyclylamino or alkanoyl; preferably, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, or C1-C6 alkylthio; R10, R11, R12, R13, and R14 are each independently -H, -CHF2, -CH2F, -CF3, -O-CHF2, -O-CH2F, - O-CF3, -S-CHF2, -S-CH2F, -S-CF3, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cyano, or azido; preferably, R10, R11, R12, R13, and R14 are each independently -H, -F, -Cl, -Br, -CHF2, - CH2F, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, -O-CHF2, -O-CH2F, -O-CF3, -S- CHF2, -S-CH2F, or -S-CF3; more preferably, R10, R11, R12, R13, and R14 are each independently -H, -O-CHF2, - O-CH2F, -O-CF3, -S-CHF2, or -S-CH2F; more preferably, R10, R11, R12, R13, and R14 are each independently -H, -O- CHF2, or -O-CF3; and R15, R16, and R17are each independently H, halogen, or alkyl; preferably, R15, R16and R17< / sub>are -H, -F or methyl.

28. The process of claim 27, wherein(i) step (a) is conducted in the presence of a base; preferably, the base is an organic base, morepreferably, the base is a strong, non-nucleophilic base; more preferably, the base is an amide base; more preferably, the base is lithium bis(trimethylsilyl)amide (LiHMDS); 110(ii) step (a) is conducted in the presence of a solvent; preferably, the solvent is an organicsolvent; more preferably, the solvent is a heterocyclic compound; more preferably, the solvent is tetrahydrofuran (THF);(iii) step (a) is conducted at a temperature from -900C to -100C; preferably, from -800C to -200C; more preferably, from -700C to -300C; more preferably, from -600C to -300C; more preferably, from -500C to -300C; more preferably, from -450C to -350C; more preferably, at -40<sup>0C;(iv) step (a) is conducted at a period from 40 to180 minutes; preferably, from 40 to 160 minutes;more preferably, from 40 to 140 minutes; more preferably, from 40 to 120 minutes; more preferably, from 60 to 120 minutes;(v) step (b) is conducted in the presence of an acid; preferably, the acid is an inorganic base,more preferably, the acid is a strong, corrosive base; more preferably, the acid is hydrogen fluoride (HF);(vi) step (b) is conducted in the presence of one or more solvents; preferably, the one or moresolvents is an organic solvent; more preferably, the one or more solvents is pyridine and acetonitrile (MeCN);(vii) step (b) is conducted at a temperature from -300C to 300C; preferably, from -200C to 300C;more preferably, from -100C to 300C; more preferably, from -50C to 300C; more preferably, from 00C to 25<sup>0C;(viii) step (b) is conducted at a period of 10-40 hours; preferably, at 10-30 hours; morepreferably, at 15-25 hours; more preferably, at 18-24 hours; more preferably, at 21 hours; and / or(ix) Formula III has the structure:. 11129. The process of any one of claims 27-28, wherein the compound of Formula I is produced from(a) reacting a compound of Formula (IV):(Formula IV) with a protecting agentf Formula V: (Formula V); and<img src='' class="img-anchor img-center" img-id="IMGF000113_0002" / >(b) reacting Formul to produce the compound of Formula I.

30. The process of claim 29,w ere ni) the protecting agent contains a trimethylsilyl group; preferably, the protecting agent istrimethylsilyl fluoride or trimethylsilyl chloride; more preferably, the protecting agent is trimethylsilyl chloride; ii) step (a) is conducted in the presence of an organic compound; preferably, the organiccompound is a heterocyclic organic compound, more preferably, the heterocyclic organic compound has a five-membered aromatic ring; more preferably, the organic compound is imidazole; 112iii) step (a) is conducted in the presence of a solvent; preferably, the solvent is an organic solvent;more preferably, the solvent is dimethylformamide (DMF); iv) step (a) is conducted at a temperature from -300C to 300C; preferably, from -200C to 300C;more preferably, from -100C to 300C; more preferably, from -50C to 300C; more preferably, from 00C to 25<sup>0C; v) step (a) is conducted at a period from 10 to 60 minutes; preferably, from 10 to 50 minutes;more preferably, from 20 to 50 minutes; more preferably, from 30 to 50 minutes; more preferably, of 40 minutes; vi) step (b) is conducted in the presence of a base; preferably, the base is an organic base, morepreferably, the base is a strong, non-nucleophilic base; more preferably, the base is an amide base; more preferably, the base is lithium bis(trimethylsilyl)amide (LiHMDS); vii) step (b) is in the presence of a solvent; preferably, the solvent is an organic solvent; morepreferably, the solvent is heterocyclic; more preferably, the solvent is tetrahydrofuran (THF); viii) step (b) is conducted at a temperature from -900C to -100C; preferably, from -800C to -200C;more preferably, from -700C to -300C; more preferably, from -600C to -300C; more preferably, from -500C to -300C; more preferably, from -450C to -350C; more preferably, at -400< / sup>C; and / or ix) step (b) is conducted at a period from 10 to 60 minutes; preferably, from 10 to 50 minutes;more preferably, from 10 to 40 minutes; more preferably, from 20 to 35 minutes; more preferably, of 30 minutes.

31. A compound according to formula I:<img src='' class="img-anchor img-center" img-id="IMGF000114_0001" / >wherein: X is selected from O and S; 113R1is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and C0-6alkyl- unsubstituted or substituted with one or more substituents selected from halogen, C0-6alkyl-, C0-6alkyl-O-, C0-6alkyl-CO-, C0-6alkyl-S-, C0-6alkyl-NH-, aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl; Y1and Y2are each independently selected from halogen, C0-6alkyl-, and C0-6alkyl-O-; Z is selected from CF3-C0-6alkyl-O-, CHF2-C0-6alkyl-O-, C0-6alkyl-O-, C0-6alkyl-CO-, and C0-6alkyl-S-; and R2is C0-6< / sub>alkyl-.

32. The compound according to claim 31, wherein R1 is selected from aryl and heteroaryl unsubstitutedor substituted with one or more substituents selected from C1-3alkyl-O-, C1-3alkyl-CO-, and C1-3< / sub>alkyl- S-.

33. The compound according to claim 31, wherein X is selected from C1-3alkyl-O-, C1-3alkyl-CO-, andC1-3alkyl-S-.

34. The compound according to any one of the preceding claims, wherein Y1 and Y2 are each independentlyselected from fluorine, chlorine, bromine, methyl, ethyl, and propyl.

35. The compound according to any one of the preceding claims, wherein Z is selected fromtrifluoromethoxy and difluoromethoxy.

36. The compound according to any one of the preceding claims, wherein the stereochemistry at the C-10position is R or S.

37. A pharmaceutical composition comprising a compound according to claim 35 and a pharmaceuticallyacceptable carrier.

38. A method of treating cancer in a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound according to formula I: 114(I) wherein:X is selected from halogen, Co-ealkyl-, Co-salkyl-O-, Co-ealkyl-CO-, Co-ealkyl-S-, Co-ealkyl -NH-, and, heteroaryl, cycloalkyl, cycloheteroalkyl;Y1and Y2are each independently selected from halogen, Co-ealkyl-, Co-ealkyl-O-; andZ is selected from CFo-Co-ealkyl-O-, CHF2-Co-ealkyl-0-. Co-ealkyl-O-, Co-ealkyl-CO-, Co-ealkyl-S-.

39. The method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 37 in combination with another anticancer agent.

40. The method according to claims 38 and 39, wherein the cancer is selected from ovarian cancer, breast cancer, lung cancer, colon cancer, and cervical cancer.

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