DIMERIC PEPTIDE INHIBITORS OF APOPTOSIS PROTEINS

Abstract

The present technology is directed to compounds, compositions, and methods related to treatment of cancers and viral infections mediated by IAPs. In particular the present compounds and compositions may be used to treat IAP-mediated ovarian cancer and hepatitis B infection.

##STR00001##

Claims

1. A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer of the compound: ##STR00051## wherein X is a bond to the Linker or, when the Linker is attached to positions, 2, 3, or 4 on the pyrrolidine ring, X is selected from ##STR00052## wherein  Y is H or halogen; R.sup.1 and R.sup.3 are independently selected from a substituted or unsubstituted C.sub.1-6 alkyl or a C.sub.3-6 cycloalkyl group; R.sup.2 is H or a substituted or unsubstituted C.sub.1-6 alkyl group; m is 1, 2, 3, 4, 5, or 6; n is 0, 1 or 2; and Linker is selected from the group consisting of ##STR00053##

2. The compound of claim 1 wherein Linker is ##STR00054##

3. The compound of claim 1 wherein n is 1.

4. The compound of claim 1, wherein X is a bond to Linker.

5. The compound of claim 1 wherein Linker is ##STR00055##

6. The compound of claim 1 wherein m is 1, 2 or 3.

7. The compound of claim 1 wherein Linker is ##STR00056##

8. The compound of claim 7 wherein X is a bond to Linker.

9-10. (canceled)

11. The compound of claim 1 wherein Linker is ##STR00057##

12. The compound of claim 11 wherein m is 1, 2 or 3.

13. The compound of claim 1 wherein Linker is attached to the 3 position of the pyrrolidine of the compound of Formula I.

14. The compound of claim 1 wherein X is ##STR00058## and n is 1.

15. The compound of claim 1 wherein X is ##STR00059## and Y is F.

16. The compound of claim 1 wherein R.sup.1 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl group.

17. The compound of claim 1 wherein R.sup.2 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl group.

18. The compound of claim 1 wherein R.sup.3 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl group.

19. The compound of claim 1 wherein the compound is selected from ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##

20. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising an effective amount of the compound of claim 1 for treating a cancer or a viral infection mediated by an IAP.

22. The pharmaceutical composition of claim 21 wherein the cancer or viral infection mediated by an IAP is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

23. A method of treatment comprising administering an effective amount of a compound of claim 1, or administering a pharmaceutical composition comprising an effective amount of a compound of claim 1, to a subject suffering from a cancer or a viral infection mediated by an IAP.

24. The method of claim 23, wherein the cancer or viral infection is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

25. A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer of the compound: ##STR00067## wherein X is a bond to the Linker or, when the Linker is attached to positions, 2, 3, or 4 on the pyrrolidine ring, X is selected from ##STR00068## wherein  Y is H or halogen; R.sup.1 is a C.sub.3-6 cycloalkyl group; R.sup.2 is H or a substituted or unsubstituted C.sub.1-6 alkyl group; R.sup.3 is selected from a substituted or unsubstituted C.sub.1-6 alkyl or a C.sub.3-6 cycloalkyl group; m is 1, 2, 3, 4, 5, or 6; n is 0, 1 or 2; and Linker is ##STR00069##

26. The compound of claim 25 wherein m is 2 or 3.

27. The compound of claim 25 the compound is ##STR00070##

28. A pharmaceutical composition comprising an effective amount of the compound of claim 25 for treating a cancer or a viral infection mediated by an IAP.

29. The pharmaceutical composition of claim 28 wherein the cancer or viral infection mediated by an IAP is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

30. A method of treatment comprising administering an effective amount of a compound of claim 25, or administering a pharmaceutical composition comprising an effective amount of a compound of claim 25, to a subject suffering from a cancer or a viral infection mediated by an IAP.

31. The method of claim 30, wherein the cancer or viral infection is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.

Description

EXAMPLES

General Synthetic and Analytical Details

[0105] All reagents and materials are or were purchased from commercial vendors.

Representative General Synthetic Schemes

[0106] The following compounds were or can be prepared as indicated in the following synthetic schemes using procedures known to those of ordinary skill in the art.

##STR00016## ##STR00017##

Example 1: Synthesis of Compound I (Scheme 1)

[0107] Benzyl (2S)-1-[(2S)-2-[[(tert-butoxy)carbonyl]amino]-2-cyclohexylacetyl]pyrrolidine-2-carboxylate (Compound 1-3): To a solution of (2S)-2-[[(tert-butoxy)carbonyl]amino]-2-cyclohexylacetic acid (5 g, 19.43 mmol), DIEA (15 g, 116.06 mmol) and benzyl (2S)-pyrrolidine-2-carboxylate (9.4 g, 45.80 mmol) in DMF (100 mL) was added HATU (14.8 g, 38.92 mmol) batch-wise at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with 300 mL of EtOAc. The resulting mixture was washed successively with water and brine. The residue was concentrated under vacuum after dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:3, v/v). This resulted in 7.9 g (91%) of the title compound as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=445.3.

[0108] Benzyl (2S)-1-[(2S)-2-amino-2-cyclohexylacetyl]pyrrolidine-2-carboxylate (Compound 1-4): To a solution of Compound 1-3 (7.9 g, 17.77 mmol) in dioxane (50 mL) was added a solution of hydrogen chloride in dioxane (50 mL, 4M). The resulting solution was stirred for 6 h at room temperature. The residue was concentrated under vacuum. This resulted in 6.5 g of the title compound as a white solid. LCMS (ESI, m/z): [M+H].sup.+=345.2.

[0109] Benzyl (2S)-1-[(2S)-2-[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanamido]-2-cyclohexylacetyl]pyrrolidine-2-carboxylate (Compound 1-5): To a solution of (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanoic acid (3.2 g, 15.75 mmol), DIEA (6.1 g, 47.20 mmol) and Compound 1-4 (6.5 g, 18.87 mmol) in DMF (150 mL) was added HATU (7.2 g, 18.94 mmol) batch-wise at room temperature. The resulting mixture was stirred for 3 h at room temperature. The mixture was diluted with 250 mL of EtOAc. The mixture was washed successively with water and brine. The residue was concentrated under vacuum after dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:3, v/v). This resulted in 8.0 g (96%) of the title compound as an orange oil. LCMS (ESI, m/z): [M+H]+=530.3.

[0110] (2S)-1-[(2S)-2-[(2S)-2-[[(tert-Butoxy)carbonyl](methyl)amino]propanamido]-2-cyclohexylacetyl]pyrrolidine-2-carboxylic acid (Compound 1-6): To a solution of Compound 1-5 (9.7 g, 18.31 mmol) in MeOH (150 mL) was added Pd/C (0.97 g). The resulting solution was stirred overnight at room temperature under H.sub.2 atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 6.5 g (81%) of the title compound as a white solid. LCMS (ESI, m/z): [M+H].sup.+=440.3.

[0111] tert-Butyl N-[(1R)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate (Compound 1-8): To a solution of (1R)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-amine (3.1 g, 13.71 mmol) in DCM (20 mL) was added di-tert-butyl dicarbonate (3.16 g, 14.48 mmol). The resulting solution was stirred at room temperature for 6 h. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:10, v/v). This resulted in 4.24 g (95%) of the title compound as a white solid. LCMS (ESI, m/z): [M+H].sup.+=326.1.

[0112] tert-Butyl N-[(1R)-5-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate (Compound 1-9): To a solution of Compound 1-8 (3 g, 9.21 mmol) in dioxane (50 mL) was added piperazine (3.18 g, 36.93 mmol), Pd.sub.2(dba).sub.3 CHCl.sub.3 (510 mg, 0.48 mmol), Xanphos (540 mg, 0.93 mmol) and Cs.sub.2CO.sub.3(8.7 g, 26.61 mmol). The resulting solution was stirred at 100° C. for overnight under N.sub.2. The solids were filtered out. The resulting mixture was diluted with 50 mL of EA. The resulting mixture was washed successively with water and brine. The residue was concentrated under vacuum after dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ACN/H.sub.2O (1:1, v/v). This resulted in 1.16 mg (39%) of the title compound as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=332.2.

[0113] tert-Butyl N-[(1R)-5-[4-[(5R)-5-[[(tert-butoxy)carbonyl]amino]-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate (Compound 1-10): To a solution of Compound 1-8 (1.14 g, 3.49 mmol) in dioxane (15 mL) was added Compound 1-9 (1.16 g, 3.50 mmol), Pd.sub.2(dba).sub.3. CHCl.sub.3 (190 mg, 0.18 mmol), X-Phos (330 mg, 0.69 mmol) and Cs.sub.2CO.sub.3 (2.86 g, 8.75 mmol). The resulting solution was stirred overnight at 100° C. under N.sub.2 atmosphere. The solids were filtered out.

[0114] The resulting mixture was diluted with 15 mL of EA. The resulting mixture was washed successively with water and brine. The residue was concentrated under vacuum after dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:6, v/v). This resulted in 1.3 g (66%) of the title compound as a yellow solid. LCMS (ESI, m/z): [M+H].sup.+=577.4.

[0115] (1R)-5-[4-[(5R)-5-Amino-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1,2,3,4-tetrahydronaphthalen-1-amine (Compound 1-11): To a solution of Compound 1-10 (1.3 g, 2.25 mmol) in dioxane (10 mL) was added a solution of hydrogen chloride in dioxane (10 mL, 4M). The resulting solution was stirred for 1 h at room temperature. The residue was concentrated under vacuum. This resulted in 840 mg (99%) of the title compound as a yellow solid. LCMS (ESI, m/z): [M+H].sup.+=377.3

[0116] tert-Butyl N-[(1S)-1-[[(1S)-2-[(2S)-2-[[(1R)-5-[4-[(5R)-5-[(2S)-1-[(2S)-2-[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanamido]-2-cyclohexylacetyl]pyrrolidine-2-amido]-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]carbamoyl]ethyl]-N-methyl carbamate (Compound 1-12): To a solution of Compound 1-6 (1.75 g, 3.98 mmol), DIEA (1.03 g, 7.97 mmol) and Compound I-11 (500 mg, 1.33 mmol) in DMA (15 mL) was added HATU (1.52 g, 4.00 mmol) batch-wise at room temperature. The resulting mixture was stirred for 30 minutes at room temperature then quenched by adding 15 mL of water. The resulting mixture was extracted with 5×15 mL of EtOAc and the organic layers were combined. The resulting mixture was washed successively with water and brine. The residue was concentrated under vacuum after dried over anhydrous sodium sulfate. The crude product was applied onto a silica gel column with MeOH/DCM (99:1, v/v). This resulted in 963 mg (59%) of the title compound as a light yellow solid. LCMS (ESI, m/z): [M+H].sup.+=1220.

[0117] (2S)-1-[(2S)-2-Cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-N-[(1R)-5-[4-[(5R)-5-[(2S)-1-[(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl] pyrrolidine-2-amido]-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound I): To a solution of Compound 1-12 (963 mg, 0.79 mmol) in DCM (30 mL) was added TFA (3 mL). The resulting solution was stirred for 2 h at room temperature. The residue was concentrated under vacuum. The crude product was applied onto a reversed column with ethyl ACN/H.sub.2O (7:3, v/v). This resulted in 372 mg (46%) of the title compound as a white solid. LCMS (ESI, m/z): [M+H].sup.+=1019.8. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): δ 7.61 (s, 2H), 7.15-7.07 (m, 4H), 6.98-6.95 (m, 4H), 5.14 (s, 2H), 4.63-4.51 (m, 4H), 3.85-3.81 (m, 2H), 3.63-3.53 (m, 2H), 3.10-2.95 (m, 10H), 2.86-2.82 (m, 2H), 2.72-2.66 (m, 2H), 2.57-2.48 (m, 2H), 2.35 (s, 6H), 2.16-2.03 (m, 6H), 1.93-1.76 (m, 8H), 1.66-1.57 (m, 12H), 1.28-1.24 (m, 8H), 1.13-0.88 (m, 10H).

[0118] Following the procedure described above for Scheme 1 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds were prepared.

##STR00018##

[0119] (2S,2′S,29S,34S)—N, N′-((1R,1′R)-5,5′-(Piperazine-1,4-diyl)bis(1,2,3,4-tetrahydronaphthalene-5,1-diyl))bis(1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide) (Compound I-A): LCMS (ESI, m/z): [M+H].sup.+=967.6. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): δ 7.76 (m, 2H), 7.20-6.94 (m, 8H), 5.21-5.07 (m, 2H), 4.63-4.57 (m, 2H), 4.42-4.40 (m, 1H), 3.63-4.40 (m, 4H), 3.01-2.83 (m, 10H), 2.80-2.70 (m, 4H), 2.48-2.32 (m, 8H), 2.18-1.93 (m, 8H), 1.78-1.53 (m, 6H), 1.32-1.30 (m, 3H), 1.21-0.99 (m, 18H), 0.89-0.82 (m, 6H).

##STR00019##

[0120] (2S)-1-[(2S)-2-[(2S)-2-(Methylamino)propanamido]butanoyl]-N-[(1R)-5-[4-[(5R)-5-[(2S)-1-[(2S)-2-[(2S)-2-(methylamino)propanamido]butanoyl]pyrrolidine-2-amido]-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound I-B): LCMS (ESI, m/z): [M+H].sup.+=911.7.

##STR00020##

[0121] (S)-1-((S)-3-Methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-5-(4-((R)-5-((S)-1-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide (Compound I-C): LCMS (ESI, m/z): [M+H].sup.+=939.5.

##STR00021## ##STR00022## ##STR00023##

Example 2: Synthesis of Compound II (Scheme 2)

[0122] (2S,4S)-4-[3-(tert-Butoxy)-3-oxopropoxy]pyrrolidine-2-carboxylic acid (Compound II-2): To a solution of Compound IV-3 (1.8 g, 3.86 mmol) in MeOH (25 mL) was added Pd/C (185 mg). The resulting mixture was stirred at room temperature for 3 h under H.sub.2 atmosphere. After the reaction was completed, the mixture was filtered. The filtrate was evaporated in vacuo to afford the title compound (1 g, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=260.1.

[0123] (2S,4S)-1-[(Benzyloxy)carbonyl]-4-[3-(tert-butoxy)-3-oxopropoxy]pyrrolidine-2-carboxylic acid (Compound II-3): To a solution of Compound II-2 (1.0 g, 3.86 mmol) in DCM (20 mL) was added DIEA (1.0 g, 7.74 mmol). The resulting mixture was stirred at room temperature for 30 min. Then a solution of benzyl carbonochloridate (990 mg, 5.80 mmol) in DCM (5 mL) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated to afford the title compound (1.5 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H].sup.+=394.2.

[0124] (2S,4S)-Dibenzyl 4-(3-tert-butoxy-3-oxopropoxy)pyrrolidine-1,2-dicarboxylate (Compound II-4): To a solution of Compound II-3 (1.5 g, 3.81 mmol) in DMF (25 mL) was added K.sub.2CO.sub.3 (1.2 g, 8.39 mmol), KI (63 mg, 0.38 mmol) and (bromomethyl)benzene (1.9 g, 11.40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:1, v/v) to afford the title compound (1.2 g, 65%) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=484.2.

[0125] 3-[[(3S,5S)-1,5-bis[(Benzyloxy)carbonyl]pyrrolidin-3-yl]oxy]propanoic acid (Compound II-5): To a solution of Compound II-4 (1.2 g, 2.48 mmol) in DCM (50 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to afford the title compound (1.02 g, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=428.2.

[0126] (2S,4S)-Dibenzyl 4-(3-hydroxypropoxy)pyrrolidine-1,2-dicarboxylate (Compound II-6): To a solution of Compound II-5 (1.0 g, 2.38 mmol) in THF (30 mL) was added BH.sub.3.THF (12 mL) dropwise at 0° C. under N.sub.2 atmosphere. The resulting mixture was stirred at room temperature for 16 h under N.sub.2 atmosphere. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/EtOAc (1:1, v/v) to afford the title compound (880 mg, 89%) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=414.2.

[0127] (2S,4S)-Dibenzyl 4-(3-(methylsulfonyloxy)propoxy)pyrrolidine-1,2-dicarboxylate (Compound II-7): To a solution of Compound II-6 (880 mg, 2.13 mmol) in DCM (10 mL) was added TEA (237 mg, 2.34 mmol). The resulting mixture was stirred at room temperature for 30 min. Then methanesulfonyl chloride (268 mg, 2.34 mmol) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with H.sub.2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title compound (1.07 g, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=492.2.

[0128] (2S,4S)-Dibenzyl 4-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxylate (Compound II-8): To a solution of Compound II-7 (1.1 g, 2.34 mmol) in CH.sub.3CN (10 mL) was added tert-butyl piperazine-1-carboxylate (1.2 g, 6.56 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (13:1, v/v) to afford the title compound (1.2 g, 99%) as an orange oil.

[0129] LCMS (ESI, m/z): [M+H].sup.+=582.3.

[0130] (2S,4S)-Dibenzyl 4-(3-(piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxylate (Compound II-9): To a solution of Compound II-8 (1.2 g, 2.15 mmol) in DCM (20 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to afford the title compound (970 mg, crude) as an orange oil. LCMS (ESI, m/z): [M+H].sup.+=482.3.

[0131] (2S,2'S,4S,4'S)-Tetrabenzyl 4,4′-(3,3′-(piperazine-1,4-diyl)bis(propane-3,1-diyl))bis(oxy)dipyrrolidine-1,2-dicarboxylate (Compound 11-10): To a solution of Compound II-9 (970 mg, 2.01 mmol) in CH.sub.3CN (7 mL) was added Compound II-7 (825 mg, 1.68 mmol). The resulting mixture was stirred at 60° C. for 48 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (9:1, v/v) to afford the title compound (824 mg, 56%) as an orange oil. LCMS (ESI, m/z): [M+H].sup.+=877.4.

[0132] (2S,4S)-4-[3-[4-(3-[[(3S,5S)-5-Carboxypyrrolidin-3-yl]oxy]propyl)piperazin-1-yl]propoxy]pyrrolidine-2-carboxylic acid (Compound 11-11): To a solution of Compound II-10 (824 mg, 0.94 mmol) in MeOH (10 mL) was added Pd/C (100 mg). The resulting mixture was stirred at room temperature for 16 h under H.sub.2 atmosphere. After the reaction was completed, the mixture was filtered. The filtrate was evaporated in vacuo to afford the title compound (400 mg, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=429.3.

[0133] (2S,4S)-1-[(tert-Butoxy)carbonyl]-4-[3-[4-(3-[[(3S,5S)-1-[(tert-butoxy)carbonyl]-5-carboxypyrrolidin-3-yl] oxy] propyl)piperazin-1-yl]propoxy]pyrrolidine-2-carboxylic acid (Compound 11-12): To a solution of Compound II-11 (400 mg, 0.93 mmol) in DCM (7 mL) was added TEA (207.8 mg, 2.05 mmol). The resulting mixture was stirred at room temperature for 30 min. Then a solution of di-tert-butyl dicarbonate (448.2 mg, 2.05 mmol) in DCM was added dropwise to the mixture at 0° C. The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with H.sub.2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was purified by flash column chromatography with DCM/MeOH (10:1, v/v) to afford the title compound (220 mg, 37%) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=629.4.

[0134] tert-Butyl (2S,4S)-4-[3-[4-(3-[[(3S,5S)-1-[(tert-butoxy)carbonyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]oxy]propyl)piperazin-1-yl] propoxy]-2-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] carbamoyl] pyrrolidine-1-carboxylate (Compound 11-13): To a solution of Compound 11-12 (220 mg, 0.35 mmol) in DMF (7 mL) was added HATU (399.1 mg, 1.05 mmol), DIEA (271.3 mg, 2.10 mmol) and (1R)-1,2,3,4-tetrahydronaphthalen-1-amine (154.5 mg, 1.05 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (12:1, v/v) to afford the title compound (280 mg, 90%) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=887.6.

[0135] (2S,4S)—N-[(1R)-1,2,3,4-Tetrahydronaphthalen-1-yl]-4-[3-[4-(3-[[(3S,5S)-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]oxy]propyl)piperazin-1-yl]propoxy]pyrrolidine-2-carboxamide (Compound 11-14): To a solution of Compound 11-13 (280 mg, 0.31 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to afford the title compound (125 mg, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=687.5.

[0136] Benzyl N-[(1S)-1-[[(1S)-2-[(2S,4S)-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]propanamido]-2-cyclohexylacetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]oxy]propyl)piperazin-1-yl]propoxy]-2-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]carbamoyl]ethyl]-N-methylcarbamate (Compound 11-15): To a solution of Compound IV-16 (205.5 mg, 0.55 mmol) in DMF (5 mL) was added HATU (207.6 mg, 0.55 mmol), DIEA (141.1 mg, 1.09 mmol) and Compound 11-14 (125 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h.

[0137] The mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1:13, v/v) to afford the title compound (218 mg, 85%) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=1404.1.

[0138] (2S,4S)-1-[(2S)-2-Cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] propyl)piperazin-1-yl] propoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II): To a solution of Compound 11-15 (218 mg, 0.16 mmol) in MeOH (8 mL) was added Pd/C (20 mg). The resulting mixture was stirred at room temperature for 5 h under H.sub.2 atmosphere. After the reaction was completed, the mixture was filtered. The filtrate was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19×250 mm, 5 um; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 42% B in 7 min; 254/220 nm; Rt: 7 min to afford the title compound (20 mg, 10%) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=1135.8. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.35-7.25 (m, 2H), 7.14-7.09 (m, 6H), 5.10-4.90 (m, 3H), 4.52-4.46 (m, 3H), 4.21-4.02 (m, 3H), 3.90-3.86 (m, 4H), 3.80-3.40 (m, 7H), 3.31-2.88 (m, 7H), 2.81-2.75 (m, 6H), 2.66-2.59 (m, 6H), 2.45-2.02 (m, 5H), 1.99-1.61 (m, 24H), 1.53-1.50 (m, 4H), 1.47 (d, J=6.8 Hz, 2H), 1.25-1.13 (m, 10H).

[0139] Following the procedure described above for Scheme 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds were prepared.

##STR00024##

[0140] (2S,4S)-1-[(2S)-2-[(2S)-2-(Methylamino)propanamido] propanoyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-2-[(2S)-2-(methylamino)propanamido]propanoyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propyl)piperazin-1-yl]propoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-A):

[0141] LCMS (ESI, m/z): [M+H].sup.+=1000.3. .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.25-7.91 (m, 2H), 7.85-7.82 (m, 2H), 7.21-7.04 (m, 8H), 4.95-4.80 (m, 2H), 4.61-4.52 (m, 2H), 4.28-4.20 (m, 2H), 4.13-3.89 (m, 4H), 3.74-3.17 (m, 6H), 2.98-2.83 (m, 2H), 2.80-2.58 (m, 4H), 2.47-1.93 (m, 20H), 1.91-1.49 (m, 14H), 1.25-1.14 (m, 6H), 1.05 (d, J=6.6 Hz, 6H).

##STR00025##

[0142] (2S,4S)-1-[(2S)-2-[(2S)-2-(Methylamino)propanamido] butanoyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-2-[(2S)-2-(methylamino)propanamido]butanoyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propyl)piperazin-1-yl]propoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-B):

[0143] LCMS (ESI, m/z): [M+H].sup.+=1027.7. .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.29-7.83 (m, 4H), 7.36-7.19 (m, 2H), 7.18-7.02 (m, 6H), 5.00-4.83 (m, 2H), 4.55-4.23 (m, 4H), 4.14-3.94 (m, 4H), 3.47-3.37 (m, 6H), 3.00-2.83 (m, 2H), 2.80-2.61 (m, 4H), 2.41-2.10 (m, 20H), 1.91-1.40 (m, 18H), 1.06 (d, J=6.9 Hz, 6H), 0.86-0.81 (m, 6H).

##STR00026##

[0144] (2S,4S)-1-[(2S)-3-Methyl-2-[(2S)-2-(methylamino)propanamido] butanoyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-3-methyl-2-[(2S)-2-(methylamino)propanamido]butanoyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propyl)piperazin-1-yl]propoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-C):

[0145] LCMS (ESI, m/z): [M+H].sup.+=1055.6. .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.48-7.28 (m, 2H), 7.21-7.04 (m, 6H), 5.10-5.02 (m, 2H), 4.55-4.41 (m, 4H), 4.22-4.11 (m, 4H), 3.70-3.59 (m, 2H), 3.59-3.38 (m, 5H), 3.22-3.09 (m, 2H), 2.85-2.72 (m, 4H), 2.54-2.35 (m, 13H), 2.31 (s, 6H), 2.24-2.05 (m, 4H), 2.04-1.65 (m, 12H), 1.29-1.17 (m, 6H), 1.11-0.95 (m, 12H).

##STR00027##

[0146] (2S,4S)-1-[(2S)-3,3-Dimethyl-2-[(2S)-2-(methylamino)propanamido] butanoyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-3,3-dimethyl-2-[(2S)-2-(methylamino)propanamido]butanoyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] carbamoyl] pyrrolidin-3-yl] oxy]propyl)piperazin-1-yl] propoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-D):

[0147] LCMS (ESI, m/z): [M+H].sup.+=1084.4. .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.09-8.00 (m, 1H), 7.89-7.81 (m, 2H), 7.51-7.47 (m, 1H), 7.38-7.21 (m, 2H), 7.20-7.01 (m, 6H), 5.02-4.79 (m, 2H), 4.49-4.46 (m, 1H), 4.39-4.28 (m, 3H), 4.15-4.02 (m, 3H), 4.01-3.89 (m, 1H), 3.69-3.59 (m, 1H), 3.49-3.35 (m, 5H), 3.02-2.90 (m, 2H), 2.79-2.65 (m, 4H), 2.48-2.20 (m, 13H), 2.19-2.02 (m, 9H), 1.93-1.48 (m, 14H), 1.15-0.89 (m, 24H).

##STR00028##

[0148] (S,S,2S,2'S,4S,4'S)-4,4′-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(oxy))bis(l-((S)-2-cyclopentyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide) (Compound II-E): LCMS (ESI, m/z): [M+H].sup.+=1107.6.

##STR00029##

[0149] (2S,4S)-1-[(2S)-2-Cyclopropyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-cyclopropyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] propyl)piperazin-1-yl] propoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-F):

[0150] LCMS (ESI, m/z): [M+H].sup.+=1051.7. .sup.1H NMR (300 MHz, DMSO-d.sub.6; ppm): δ 8.25-7.99 (m, 2H), 7.88-7.60 (m, 2H), 7.34-7.03 (m, 8H), 4.99-4.83 (m, 2H), 4.52-4.21 (m, 4H), 4.11-3.65 (m, 4H), 3.49-3.31 (m, 6H), 2.98-2.81 (m, 2H), 2.79-2.66 (m, 4H), 2.45-2.11 (m, 19H), 2.05-1.89 (m, 3H), 1.87-1.75 (m, 4H), 1.74-1.48 (m, 8H), 1.20-1.02 (m, 8H), 0.49-0.19 (m, 8H).

##STR00030##

[0151] (2S,4S)-1-[(2S)-3-Methyl-2-[(2S)-2-(methylamino)propanamido] pentanoyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-3-methyl-2-[(2S)-2-(methylamino)propanamido]pentanoyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propyl)piperazin-1-yl]propoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-G):

[0152] LCMS (ESI, m/z): [M+H].sup.+=1083.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6; ppm): δ 8.10-7.39 (m, 4H), 7.32-6.93 (m, 8H), 4.98-4.85 (m, 2H), 4.51-4.38 (m, 2H), 4.37-4.21 (m, 2H), 4.20-3.58 (m, 5H), 3.48-3.39 (m, 4H), 3.29-3.24 (m, 1H), 3.00-2.88 (m, 2H), 2.79-2.65 (m, 4H), 2.48-2.02 (m, 21H), 1.90-1.25 (m, 19H), 1.19-0.98 (m, 8H), 1.95-1.71 (m, 12H).

##STR00031##

[0153] (2S,4S)-1-[(2S)-2-Cyclobutyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-cyclobutyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] propyl)piperazin-1-yl] propoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound II-H):

[0154] LCMS (ESI, m/z): [M+H].sup.+=1080.4. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.21-7.95 (m, 2H), 7.94-7.61 (m, 2H), 7.36-7.19 (m, 2H), 7.18-7.00 (m, 6H), 4.98-4.81 (m, 2H), 4.72-4.55 (m, 2H), 4.51-4.38 (m, 1H), 4.32-4.18 (m, 2H), 4.09-3.89 (m, 4H), 3.49-3.35 (m, 5H), 3.01-2.88 (m, 2H), 2.78-2.55 (m, 6H), 2.40-2.11 (m, 20H), 1.99-1.49 (m, 28H), 1.18-1.02 (m, 6H).

##STR00032## ##STR00033##

Example 3: Synthesis of Compound III (Scheme 3)

[0155] Compound III may be prepared according to Scheme 3. The Boc-Pro amide (HI-2) is formed from the reaction of Boc-Pro with ammonia and a coupling agent (e.g., carbonyl diimidazole) in water or other suitable solvent. Thiazole ester III-4 may be formed by reacting amide III-3 with P.sub.2S.sub.8 to form the intermediate thioamide II-3, followed by reaction with ethyl 2-oxo-3-bromo-propionate. Hydrolysis of the ethyl ester with (e.g., LiOH) and coupling with N, O-dimethyl hydroxylamine to form the hydroxamate (with e.g., HBTU or other suitable amine coupling reagents) provides the N-Boc hydroxamate III-6. Subsequent reaction with a 4-fluorophenyl Grignard reagent in a suitable solvent (e.g., THF) leads to flurophenylketone III-7. Exposure of compound III-7 to piperazine results in formation the bivalent precursor, III-8. The latter compound may be N-deprotected with acid (e.g., HCl or TFA) which may then be subjected to sequential peptide synthesis conditions to install, e.g., cyclohexylglycine and alanine amino acid derivatives and provide compound III as shown in Scheme 3.

##STR00034## ##STR00035## ##STR00036## ##STR00037##

Example 4: Synthesis of Compound IV (Scheme 4)

[0156] (2S, 4S)-Dibenzyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (Compound IV-2): To a solution of (2S, 4S)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (9.5 g, 35.74 mmol) in DMF (100 mL) was added K.sub.2CO.sub.3 (10.8 g, 78.63 mmol) and KI (0.6 g, 3.57 mmol). Then BnBr (18.2 g, 107.21 mmol) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc. The resulted mixture was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:1, v/v) to afford the title compound (10.0 g, 78%) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=356.3.

[0157] (2S,4S,E)-Dibenzyl-4-(3-tert-butoxy-3-oxoprop-1-enyloxy)pyrrolidine-1,2-dicarboxylate (Compound IV-3): To a solution of Compound IV-2 (10.0 g, 28.17 mmol) in DCM (150 mL) was added DMAP (6.8 g, 56.34 mmol). Then tert-butyl prop-2-ynoate (4.3 g, 33.80 mmol) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DCM. The resulted mixture was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:1, v/v) to afford the title compound (9.0 g, 66%) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=482.2.

[0158] (E)-3-((3S, 5S)-1,5-bis(Benzyloxycarbonyl)pyrrolidin-3-yloxy)acrylic acid (Compound IV-4): To a solution of Compound IV-3 (4.8 g, 10.08 mmol) in DCM (30 mL) was added TFA (4 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H.sub.2O and extracted with DCM. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in vacuo to afford the title compound (4.3 g, crude) as a yellow oil. LCMS (ESI, m/z): [M+H].sup.+=426.1.

[0159] (2S,4S,E)-Dibenzyl-4-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-oxoprop-1-enyloxy)pyrrolidine-1,2-dicarboxylate (Compound IV-5): To a solution of Compound IV-4 (2.0 g, 4.70 mmol) in DMF (20 mL) was added HATU (2.2 g, 5.64 mmol) and DIEA (1.8 g, 14.10 mmol) at 0° C. After stirring for 30 min at 0° C., tert-butyl piperazine-1-carboxylate (1.0 g, 5.64 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (10:1, v/v) to afford the title compound (1.8 g, 64%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=594.3.

[0160] (2S,4S,E)-Dibenzyl-4-(3-oxo-3-(piperazin-1-yl)prop-1-enyloxy)pyrrolidine-1,2-dicarboxylate (Compound IV-6): To a solution of Compound IV-5 (1.7 g, 2.96 mmol) in DCM (20 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 1 h. The pH value of the mixture was adjusted to 7 with NaOH (2 N). The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title compound (1.5 g, crude) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=494.3.

[0161] (2S,2'S,4S,4'S)-Tetrabenzyl-4,4′-(1E,1′E)-3,3′-(piperazine-1,4-diyl)bis(3-oxoprop-1-ene-3,1-diyl)bis(oxy)dipyrrolidine-1,2-dicarboxylate (Compound IV-7): To a solution of Compound IV-4 (1.0 g, 2.47 mmol) in DMF (20 mL) was added HATU (1.1 g, 2.96 mmol) and DIEA (956.9 mg, 7.40 mmol) at 0° C. After stirring for 30 min, Compound IV-6 (1.5 g, 3.04 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (10:1, v/v) to afford the title compound (1.0 g, 45%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=901.3.

[0162] (2S,4S)-4-{3-[4-(3-{[(3S,5S)-5-Carboxypyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}pyrrolidine-2-carboxylic acid (Compound IV-8): To a solution of Compound IV-7 (732 mg, 0.83 mmol) in MeOH (10 mL) was added Pd/C (172.9 mg, 1.62 mmol). The resulting mixture was stirred at room temperature for 16 h under H.sub.2 atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under vacuum to afford the title compound (300 mg, crude) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=457.2.

[0163] (2S,4S)-1-[(tert-Butoxy)carbonyl]-4-{3-[4-(3-{[(3S,5S)-1-[(tert-butoxy)carbonyl]-5-carboxypyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}pyrrolidine-2-carboxylic acid (Compound IV-9): To a solution of Compound IV-8 (508 mg, 1.22 mmol) in DCM (10 mL) was added Et.sub.3N (2.0 mL) and Boc.sub.2O (534.3 mg, 2.45 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (10:1, v/v) to afford the title compound (650 mg, 81%) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=657.2.

[0164] tert-Butyl (2S,4S)-4-{3-[4-(3-{[(3S,5S)-1-[(tert-butoxy)carbonyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}-2-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidine-1-carboxylate (Compound IV-10): To a solution of Compound IV-9 (650 mg, 0.99 mmol) in DMF (20 mL) was added HATU (903.2 mg, 2.38 mmol) and DIEA (767.5 mg, 5.94 mmol) at 0° C. After stirring for 30 min, (R)-1,2,3,4-tetrahydronaphthalen-1-amine (349.7 mg, 2.38 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1:10, v/v) to afford the title compound (320 mg, 35%) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=915.6.

[0165] (2S,4S)-4-{3-Oxo-3-[4-(3-{[(3S,5S)-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]propoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-11): To a solution of Compound IV-10 (100 mg, 0.11 mmol) in DCM (10 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 1 h. The pH value of the mixture was adjusted to 7 with NaOH (2 N). The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title compound (72 mg, 92%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=715.3.

[0166] Benzyl N-[(1S)-1-{[(1S)-2-[(2S,4S)-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-2-[(2S)-2-{[(benzyloxy)carbonyl](methyl)amino}propanamido]-2-cyclohexylacetyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}-2-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]carbamoyl}ethyl]-N-methylcarbamate (Compound IV-17): To a solution of Compound IV-16 (289.6 mg, 0.77 mmol) in DMF (20 mL) was added HATU (351 mg, 0.93 mmol) and DIEA (129.2 mg, 2.31 mmol) at 0° C. After stirring for 30 min, Compound IV-11 (275 mg, 0.36 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1:10, v/v) to afford the title compound (70 mg, 5%) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=1431.5.

[0167] (2S,4S)-1-[(2S)-2-Cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV): To a solution of Compound IV-17 (70 mg, 0.05 mmol) in MeOH (10 mL) was added Pd/C (30 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 16 h under H.sub.2 atmosphere. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: 1) Column: XSelect CSH C18 Column 19×150, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 11% B to 33% B in 7 min; 254/220 nm; Rt: 6.8 min 2) Column: XSelect CSH C18 Column 19×150.5 um; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 55% B in 12 min; 254/220 nm; Rt: 10 min to afford the title compound (4.6 mg, 8%) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=1163.5. .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.16 (s, 2H), 8.15-7.99 (m, 1H), 7.85-7.40 (m, 1H), 7.52-7.48 (m, 1H), 7.25-7.06 (m, 5H), 4.99-4.81 (m, 2H), 4.31-4.01 (m, 5H), 3.12-2.98 (m, 2H), 3.61-3.32 (m, 3H), 2.23-2.08 (m, 6H), 1.83-1.58 (m, 15H), 1.16-0.96 (m, 12H).

[0168] (S)-tert-Butyl-2-(benzyloxycarbonylamino)-2-cyclohexylacetate (Compound IV-13): To a solution of (S)-2-(benzyloxycarbonylamino)-2-cyclohexylacetic acid (400 mg, 1.37 mmol) in toluene (10 mL) was added di-tert-butoxy-N, N-dimethylmethanamine (1.2 g, 5.90 mmol). The resulting mixture was stirred at 110° C. for 16 h under N.sub.2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1:10, v/v) to afford the title compound (246 mg, 51.6%) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=347.3.

[0169] (S)-tert-Butyl 2-amino-2-cyclohexylacetate (Compound IV-14): To a solution of Compound IV-13 (246 mg, 0.75 mmol) in MeOH (10 mL) was added Pd/C (120 mg, 1.23 mmol). The resulting mixture was stirred at room temperature for 16 h under H.sub.2 atmosphere. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum to afford the title compound (170 mg, crude) as a colorless oil. LCMS (ESI, m/z): [M+H].sup.+=214.3.

[0170] (S)-tert-Butyl-2-((S)-2-((benzyloxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetate (Compound IV-15): To a solution of (S)-2-((benzyloxycarbonyl)(methyl)amino)propanoic acid (189.1 mg, 0.80 mmol) in DMF (20 mL) was added HATU (363.6 mg, 0.96 mmol) and DIE A (309 mg, 2.39 mmol) at 0° C. After stirring for 30 min, Compound IV-14 (170 mg, 0.80 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1:10, v/v) to afford the title compound (340 mg, 98%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=433.3.

[0171] (S)-2-((S)-2-((Benzyloxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetic acid (Compound IV-16): To a solution of Compound IV-15 (340 mg, 0.79 mmol) in DCM (20 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title compound (290 mg, crude) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=377.2.

[0172] Following the procedure described above for Scheme 4 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds were prepared.

##STR00038##

[0173] (2S,4S)-1-[(2S)-2-[(2S)-2-(Methylamino)propanamido]propanoyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-[(2S)-2-(methylamino)propanamido]propanoyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]oxy]propanoyl)piperazin-1-yl]-3-oxopropoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-A):

[0174] LCMS (ESI, m/z): [M+H].sup.+=1027.6. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.39-7.29 (m, 1H), 7.29-7.20 (m, 1H), 7.19-7.01 (m, 6H), 5.15-4.95 (m, 2H), 4.68-4.34 (m, 4H), 4.28-4.09 (m, 2H), 3.99-3.36 (m, 13H), 3.20-2.95 (m, 3H), 2.87-2.65 (m, 4H), 2.60-2.36 (m, 5H), 2.36-2.22 (m, 6H), 2.22-2.09 (m, 3H), 2.08-1.63 (m, 8H), 1.47-1.12 (m, 10H), 1.10-1.00 (m, 2H).

##STR00039##

[0175] (2S, 4S)-1-[(2S)-2-[(2S)-2-(Methylamino)propanamido]butanoyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-[(2S)-2-(methylamino)propanamido]butanoyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]oxy]propanoyl)piperazin-1-yl]-3-oxopropoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-B):

[0176] LCMS (ESI, m/z): [M+H].sup.+=1055.7. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.39-7.16 (m, 2H), 7.16-7.07 (m, 6H), 5.15-5.03 (m, 2H), 4.58-4.50 (m, 3H), 4.37-4.18 (m, 3H), 4.04-3.95 (m, 2H), 3.88-3.36 (m, 11H), 3.21-3.10 (m, 2H), 3.07-2.97 (m, 1H), 2.87-2.71 (m, 4H), 2.58-2.24 (m, 11H), 2.23-2.11 (m, 4H), 2.10-1.62 (m, 13H), 1.28-1.17 (m, 4H), 1.09-0.98 (m, 8H).

##STR00040##

[0177] (2S,4S)-1-[(2S)-2-Cyclopropyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-{3-[4-(3-{[(3S,5S)-1-[(2S)-2-cyclopropyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}pyrrolidin-3-yl]oxy}propanoyl)piperazin-1-yl]-3-oxopropoxy}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-C):

[0178] LCMS (ESI, m/z): [M+H].sup.+=1081.6. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.42-7.21 (m, 2H), 7.16-7.07 (m, 6H), 5.15-5.03 (m, 3H), 4.87-4.56 (m, 2H), 4.32-4.12 (m, 4H), 4.02-3.89 (m, 2H), 3.87-3.37 (m, 11H), 3.19-3.07 (m, 2H), 2.84-2.72 (m, 4H), 2.58-2.31 (m, 6H), 2.30-2.18 (m, 8H), 2.06-1.72 (m, 8H), 1.22-1.18 (m, 8H), 0.54-0.42 (m, 8H).

##STR00041##

[0179] (2S, 4S)-1-[(2S)-3-Methyl-2-[(2S)-2-(methylamino)propanamido]butanoyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-3-methyl-2-[(2S)-2-(methylamino)propanamido]butanoyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] propanoyl)piperazin-1-yl]-3-oxopropoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-D):

[0180] LCMS (ESI, m/z): [M+H].sup.+=1083.5. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.45-7.25 (m, 2H), 7.15-7.10 (m, 4H), 7.09-7.07 (m, 2H), 5.06-5.03 (m, 2H), 4.70-4.52 (m, 2H), 4.50-4.43 (m, 4H), 4.29-4.16 (m, 2H), 4.12-4.03 (m, 2H), 3.79-3.65 (m, 7H), 3.64-3.37 (m, 5H), 3.22-3.12 (m, 2H), 2.87-2.71 (m, 4H), 2.57-2.38 (m, 6H), 2.32 (s, 6H), 2.27-2.15 (m, 4H), 2.07-1.70 (m, 8H), 1.24 (d, J=7.2 Hz, 6H), 1.04 (d, J=6.4 Hz, 6H), 0.99-0.96 (m, 6H).

##STR00042##

[0181] (S,S,2S,2'S,4S,4'S)-4,4′-((Piperazine-1,4-diylbis(3-oxopropane-3,1-diyl))bis(oxy))bis(1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide) (Compound IV-E): LCMS (ESI, m/z): [M+H].sup.+=1111.7.

##STR00043##

[0182] (S,S,2S,2'S,4S,4'S)-4,4′-((Piperazine-1,4-diylbis(3-oxopropane-3,1-diyl))bis(oxy))bis(l-((S)-2-cyclopentyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide) (Compound IV-F): LCMS (ESI, m/z): [M+H].sup.+=1137.7.

##STR00044##

[0183] (2S,4S)-1-[(2S)-2-Cyclobutyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-[3-[4-(3-[[(3S,5S)-1-[(2S)-2-cyclobutyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] propanoyl)piperazin-1-yl]-3-oxopropoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide (Compound IV-G):

[0184] LCMS (ESI, m/z): [M/2+H].sup.+=555.4. .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.39-7.22 (m, 2H), 7.21-7.03 (m, 6H), 5.10-5.00 (m, 2H), 4.77-4.64 (m, 2H), 4.59-4.42 (m, 2H), 4.25-4.16 (m, 2H), 4.03-3.82 (m, 4H), 3.80-3.68 (m, 5H), 3.63-3.52 (m, 2H), 3.51-3.33 (m, 3H), 3.27-3.09 (m, 2H), 2.89-2.70 (m, 6H), 2.59-2.19 (m, 14H), 2.01-1.66 (m, 22H), 1.34-1.17 (m, 6H).

##STR00045## ##STR00046##

Example 5: Synthesis of Compound V (Scheme 5)

[0185] 2-[2-[(4-Methylbenzenesulfonyl)oxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (Compound V-2): To a solution of 2-(2-hydroxyethoxy)ethan-1-ol (10.5 g, 98.94 mmol) in DCM (300.0 mL) was added DMAP (4.7 g, 38.47 mmol) and TEA (20.3 g, 200.61 mmol). Then 4-methylbenzene-1-sulfonyl chloride (40.3 g, 211.393 mmol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was evaporated in vacuo. The residue was purified by flash column chromatography with DCM/MeOH (99:1, v/v) to afford the title compound (32.1 g, 78%) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=415.1

[0186] (2S,4S)-1-[(Benzyloxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (Compound V-4): To a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid hydrochloride (10.1 g, 60.38 mmol) in H.sub.2O (100.0 mL) was added NaHCO.sub.3 (18.1 g, 215.46 mmol). Then a solution of benzyl carbonochloridate (12.6 g, 73.86 mmol) in THF (100.0 mL) was added dropwise to the mixture at 0° C. under N.sub.2. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was extracted with Et.sub.2O. The pH value of the aqueous phase was adjusted to 3-4 with HCl (1M). The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in vacuo to afford the title compound (7.2 g, crude) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=266.1

[0187] (2S,4S)-1-[(Benzyloxy)carbonyl]-4-[2-(2-[[(3S,5S)-1-[(benzyloxy)carbonyl]-5-carboxypyrrolidin-3-yl]oxy]ethoxy)ethoxy]pyrrolidine-2-carboxylic acid (Compound V-5): To a solution of Compound V-4 (1.9 g, 7.16 mmol) in THF (70.0 mL) was added NaH (832 mg, 20.80 mmol, 60%) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 30 min. Then a solution of Compound V-2 (1.9 g, 4.60 mmol) in THF (20.0 mL) was added dropwise to the mixture at 0° C. The mixture was stirred at room temperature for 2 days. The pH value of the mixture was adjusted to 4 with HCl (1 mol/L) and then evaporated in vacuo. The residue was purified by reverse phase flash column chromatography with CH.sub.3CN/H.sub.2O (60:40, v/v) to afford the title compound (680 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H].sup.+=601.3

[0188] Benzyl (2S,4S)-4-[2-(2-[[(3S,5S)-1-[(benzyloxy)carbonyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] carbamoyl] pyrrolidin-3-yl] oxy] ethoxy)ethoxy]-2-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidine-1-carboxylate (Compound V-6): To a mixture of Compound V-5 (680 mg, 1.13 mmol), (1R)-1,2,3,4-tetrahydronaphthalen-1-amine (519 mg, 3.52 mmol) and DIEA (1.5 mL, 8.61 mmol) in DMF (10.0 mL) was added HATU (2.4 g, 6.41 mmol) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 2 h. After the reaction was completed, the mixture was purified by reverse phase flash column chromatography with CH.sub.3CN/H.sub.2O (80:20, v/v) to afford the title compound (671.6 mg, 69%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=859.4.

[0189] (2S,4S)—N-[(1R)-1,2,3,4-Tetrahydronaphthalen-1-yl]-4-[2-(2-[[(3S,5S)-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] carbamoyl] pyrrolidin-3-yl]oxy]ethoxy)ethoxy]pyrrolidine-2-carboxamide (Compound V-7): To a solution of Compound V-6 (781 mg, 0.91 mmol) in MeOH (20.0 mL) was added Pd/C (610 mg, 5.73 mmol). The mixture was stirred at room temperature for 16 h under H.sub.2. After the reaction was completed, the reaction mixture was filtered. The filtrate was evaporated in vacuo to afford the title compound (460 mg, crude) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=591.4.

[0190] Benzyl N-[(1S)-1-[[(1S)-2-[(2S,4S)-4-[2-(2-[[(3S,5S)-1-[(2S)-2-[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]propanamido]-2-cyclohexylacetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] carbamoyl] pyrrolidin-3-yl] oxy] ethoxy)ethoxy]-2-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]carbamoyl]ethyl]-N-methylcarbamate (Compound V-8): To a mixture of Compound V-7 (400 mg, 0.67 mmol), Compound IV-16 (493.6 mg, 1.31 mmol) and DIEA (1.3 mL, 7.46 mmol) in DMF (10.0 mL) was added HATU (888.1 mg, 2.34 mmol) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with H.sub.2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with DCM/MeOH (94:6, v/v) and then purified by reverse phase flash column chromatography with CH.sub.3CN/H.sub.2O (98:2, v/v) to afford the title compound (630 mg, 71%) as a light yellow oil. LCMS (ESI, m/z): [M+H].sup.+=1307.7.

[0191] (2S,4S)-1-[(2S)-2-Cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-4-[2-(2-[[(3S,5S)-1-[(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl] oxy] ethoxy)ethoxy]-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl] pyrrolidine-2-carboxamide (Compound V): To a solution of Compound V-8 (630 mg, 0.48 mmol) in MeOH (20.0 mL) was added Pd/C (781 mg, 7.34 mmol). The mixture was stirred at room temperature for 16 h under H.sub.2. After the reaction was completed, the reaction mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 30×250 mm, 5 um; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 53% B to 69% B in 9 min; 254 nm; Rt: 8.55 min to afford the title compound (23.8 mg, 5%) as an off-white solid. LCMS (ESI, m/z): [M+H].sup.+=1040.3. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4, ppm): δ 7.39-7.29 (m, 2H), 7.17-7.06 (m, 6H), 5.12-5.00 (m, 2H), 4.50-4.45 (m, 4H), 4.22-4.12 (m, 4H), 3.75-3.41 (m, 10H), 3.15-3.09 (m, 2H), 2.90-2.70 (m, 4H), 2.37-2.16 (m, 9H), 2.05-1.57 (m, 20H), 1.22-1.04 (m, 17H).

##STR00047## ##STR00048##

##STR00049## ##STR00050##

Example 6: Synthesis of Selected Bivalent Compounds

[0192] Following the procedures described above for Scheme 1, Scheme 2, Scheme 4 or Scheme 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds in Scheme 6 may be prepared.

Example 7: Synthesis of Selected Bivalent Compounds

[0193] Following the procedure described above for Scheme 2-5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the compounds shown in Scheme 7 may be prepared.

Example 8: Biological Activity

Assay Protocol

[0194] IAPs are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins. This protocol establishes three binding assays for XIAP Bir3 domain, cIAP1 and cIAP2 using FP (Fluorescence polarization) technology. The fluorescence probe used is a synthetic peptide conjugated to 5-carboxyfluorescein (AbuRPFK-5FAM). The fluorescence polarization value (mP) was detected by Envision, which was used to reflect the binding degree of protein and fluorescent marker. Reagents and equipment used in the assay are listed below, followed by the protocol.

TABLE-US-00001 Number Name Vendor Cat# 1 HEPES Life Technologies 15630-080 2 NaCl Sigma S5886 3 Triton X-100 Sigma T8787 4 XIAP-BIR3 Reaction Biology APT-11-374 5 cIAP1-BIR3 Reaction Biology APT-11-370 6 cIAP2-BIR3 Reaction Biology APT-11-372 7 AbuRPF-K(5-Fam)-NH2(SM5F) NJ Peptide 8 DMSO MP 196055 9 Topseal A PerkinElmer E5341 10 ProxiPlate-384 F Plus PerkinElmer 6008260 11 V96 MicroWell Plates nunc 249944 12 384-well plates corning 3657 13 Envision Perkin Elmer 2104 14 Centrifuge Eppendorf 5810R [0195] a) Prepare 100 times of the final cpd concentration in appropriate tube and transfer 5 uL compound (“cpd”) to 45 μL 1× reaction buffer with 10% DMSO. [0196] b) The final reference cpd concentration is 10000, 3333.3, 1111.1, 370.4, 123.4, 41.2, 13.7, 4.57, 1.52, 0.51, 0.17 and 0 nM. So the 100 times of the concentration is 1000, 333.3, 111.1, 37.04, 12.34, 4.12, 1.0.46, 0.15, 0.05, 0.017 and 0 μM. The final test cpds concentration is 3333.3, 1111.1, 370.4, 123.4, 41.2, 13.7, 4.57, 1.52, 0.51, 0.17, 0.057 and 0 nM. So the 100 times of the concentration is 333.3, 111.1, 37.04, 12.34, 4.12, 1.0.46, 0.15, 0.05, 0.017, 0.0057 and 0 μM [0197] c) Add 8 μL/well each dose enzyme to 384 well microplate (ProxiPlate-384 F Plus, 6008260) using multichannel pipette, prepared in step 2.1.1.2 [0198] d) Centrifuge at 1000 rpm. [0199] e) Add 2 μL/well cpd to 384 well microplate (ProxiPlate-384 F Plus, 6008260) using multichannel pipette, prepared in step a). [0200] f) Centrifuge at 1000 rpm. RT, 15 min. [0201] g) Start the assay by adding 10 uL/well substrate (prepared in step 2.1.1.3) to the same 384 well microplate using multichannel pipette [0202] h) Centrifuge at 1000 rpm. [0203] i) Cover the assay plate and incubate for 60 min at 25° C. [0204] j) Read on Envision 2104 for mP and plot the IC.sub.50s with mP values. [0205] k) Data analysis: IC50s were determined based on a non-linear regression analysis of data collected.

Biological Data

[0206] Compounds of the present technology as described herein were or are tested according to the protocol above and show or are expected to show IC50 values equal to or below 1 uM in one or more of the above assays. Certain compounds exhibit or are expected to exhibit IC.sub.50s of 100 nM or less, and others exhibit or are expected to exhibit IC.sub.50s of 10 nM or less in one or more of the above binding assays. Exemplary results are shown in Table 1 for selected compounds.

TABLE-US-00002 TABLE 1 IC.sub.50 (nm) IC.sub.50 (nm) IC.sub.50 (nm) XIAP-BIR3 cIAP1-BIR3 cIAP2-BIR3 binding binding binding Compound assay assay assay I B A B I-A C A B I-B C A B I-C B A B II B A B II-A C A B II-B B A A II-C A A A II-D B A B II-F C A B II-G A A A II-H B A B IV B A B IV-A C A B IV-B C A B IV-C C A A IV-D B A B IV-G B A B V B A A A: 0.1-10 nM B: >10 nM-100 nM C: >100 nM-1 uM

EQUIVALENTS

[0207] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0208] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0209] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified.

[0210] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0211] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0212] All publications, patent applications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0213] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.