CERTAIN PLADIENOLIDE COMPOUNDS AND METHODS OF USE

Abstract

The present disclosure provides novel pladienolide compounds, pharmaceutical compositions containing such compounds, and methods for using the compounds as therapeutic agents. These compounds may be useful in the treatment of cancers, particularly cancers in which agents that target the spliceosome and mutations therein are known to be useful. Also provided herein are methods of treating cancers by administering at least one compound disclosed herein and at least one additional therapy.

Claims

1. A compound chosen from compounds of Formula I: ##STR00607## and pharmaceutically acceptable salts thereof, wherein: n is chosen from 0, 1, 2 or 3; R.sup.1 is chosen from C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups, —NR.sup.9R.sup.10, ##STR00608## groups, ##STR00609## groups, ##STR00610## groups, ##STR00611## groups, ##STR00612## groups, ##STR00613## groups, ##STR00614## groups, and ##STR00615## groups; R.sup.9 is chosen from hydrogen, —NR.sup.11R.sup.12 groups, C.sub.1-C.sub.6 alkyl groups, —(C.sub.1-C.sub.6 alkyl)—CO.sub.2H groups, C.sub.3-C.sub.8 cycloalkyl groups, and C.sub.3-C.sub.8 heterocyclyl groups, wherein the —NR.sup.11R.sup.12 groups, C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups, and C.sub.3-C.sub.8 heterocyclyl groups may be unsubstituted or substituted from 1-3 times with a group independently chosen from C.sub.1-C.sub.6 alkyl groups, —(C.sub.1-C.sub.6 alkyl)—CO.sub.2H groups, hydroxy, halogen groups, and C.sub.1-C.sub.6 alkoxy groups; R.sup.10 is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups; one of either R.sup.2 or R.sup.3 is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups, and the other is chosen from hydrogen, —OR.sup.10, —OC(O)R.sup.10, —OC(O)R.sup.1, and C.sub.1-C.sub.6 alkyl groups; R.sup.4 is chosen from hydrogen and hydroxy; R.sup.5 and R.sup.6 are each independently chosen from C.sub.1-C.sub.6 alkyl groups; R.sub.7 and R.sub.8 are each independently chosen from hydrogen, hydroxy, C.sub.1-C.sub.6 alkoxy groups, and C.sub.1-C.sub.6 alkyl groups; and Y is chosen from phenyl, thiophenyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein Y may be unsubstituted or substituted from 1-3 times with groups independently chosen from oxo groups, C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.5 cycloalkyl groups, hydroxy C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 alkoxy groups, methoxy C.sub.1-C.sub.6 alkyl groups, —NR.sup.11R.sup.12 groups, ##STR00616## wherein R.sup.11 and R.sup.12 are each independently chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups.

2. The compound of claim 1, wherein Y is ##STR00617##

3. The compound of claim 1, wherein Y is optionally substituted phenyl.

4. The compound of claim 1, wherein R.sup.1 is chosen from methyl, ##STR00618## groups, ##STR00619## groups, ##STR00620## groups, ##STR00621## groups, ##STR00622## groups, ##STR00623## groups, ##STR00624## groups, and ##STR00625## groups.

5. A compound chosen from compounds of Formula II: ##STR00626## and pharmaceutically acceptable salts thereof, wherein: X is chosen from O, NR′ groups, and CH.sub.2, wherein R′ is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups; R.sup.1 is chosen from methyl, —NR.sup.11R.sup.12 groups, ##STR00627## groups, and ##STR00628## groups, R.sup.10 is chosen from C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups, and halo C.sub.1-C.sub.6 alkyl groups, wherein the C.sub.3-C.sub.8 cycloalkyl groups may be unsubstituted or substituted from 1-3 times with a group independently chosen from C.sub.1-C.sub.6 alkyl groups, hydroxy, halogen groups, and C.sub.1-C.sub.6 alkoxy groups; R.sup.11 and R.sup.12 are each independently chosen from C.sub.1-C.sub.6 alkyl groups; one of either R.sup.2 or R.sup.3 is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups, and the other is chosen from hydrogen, hydroxy and C.sub.1-C.sub.6 alkyl groups; one of either R.sup.4 or R.sup.5 is hydrogen, and the other is chosen from hydrogen, hydroxy, and ##STR00629## R.sup.6 and R.sup.7 are each independently chosen from C.sub.1-C.sub.6 alkyl groups; R.sup.8 and R.sup.9 are each independently chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups; or R.sup.8 and R.sup.9 are taken together to form a cyclopropyl ring; and Y is chosen from C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups, methoxy, and —NR.sup.13R.sup.14 groups, wherein R.sup.13 and R.sup.14 are each independently chosen from hydrogen, C.sub.1-C.sub.6 alkyl groups, and methoxy C.sub.1-C.sub.6 alkyl groups; or R.sup.13 and R.sup.14 may be taken together with the N to form a group chosen from ##STR00630## a morpholine, a piperidine, a thiazolidine, an indole, an indoline, and an isoindoline ring; wherein Y may be unsubstituted or substituted from 1-3 times with a group independently chosen from C.sub.1-C.sub.6 alkyl groups, hydroxy, hydroxy C.sub.1-C.sub.6 alkyl groups, methoxy, methoxy C.sub.1-C.sub.6 alkyl groups, halo, halo C.sub.1-C.sub.6 alkyl groups, —C(O)NH.sub.2, —NHCOO—C.sub.1-C.sub.6 alkyl groups, —COOH, ##STR00631## and —NR.sup.15R.sup.16 groups, wherein R.sup.15 and R.sup.16 are each independently chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups.

6. A compound chosen from compounds of Formula III: ##STR00632## and pharmaceutically acceptable salts thereof, wherein: n is chosen from 0, 1 and 2; m is chosen from 1, 2, and 3; R.sup.1 is chosen from C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups, —NR.sup.11R.sup.12 groups, ##STR00633## groups, ##STR00634## groups, ##STR00635## groups, ##STR00636## groups, ##STR00637## groups, ##STR00638## groups, ##STR00639## groups, ##STR00640## groups, and ##STR00641## groups, R.sup.11 is chosen from hydrogen, —NR.sup.16R.sup.17 groups, C.sub.1-C.sub.6 alkyl groups, —(C.sub.1-C.sub.6 alkyl)—CO.sub.2H groups, —(C.sub.1-C.sub.6 alkyl)—CO.sub.2R.sup.12 groups, —(C.sub.1-C.sub.6 alkyl)—NR.sup.16R.sup.17 groups, C.sub.3-C.sub.8 cycloalkyl groups, and C.sub.3-C.sub.8 heterocyclyl groups, wherein the —NR.sup.11R.sup.12 groups, C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.8 cycloalkyl groups and C.sub.3-C.sub.8 heterocyclyl groups may be unsubstituted or substituted from 1-3 times with a group independently chosen from C.sub.1-C.sub.6 alkyl groups, —(C.sub.1-C.sub.6 alkyl)—CO.sub.2H groups, hydroxy, halogen groups, and C.sub.1-C.sub.6 alkoxy groups; R.sup.12 is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups; one of either R.sup.2 or R.sup.3 is chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups, and the other is chosen from hydrogen, —OR.sup.10, —OC(O)R.sup.10, —OC(O)R.sup.1, and C.sub.1-C.sub.6 alkyl groups; R.sup.4 is hydrogen or hydroxy; R.sup.5 and R.sup.6 are each independently chosen from C.sub.1-C.sub.6 alkyl groups; R.sub.7 and R.sub.8 are each independently chosen from hydrogen, hydroxy, C.sub.1-C.sub.6 alkoxy groups, and C.sub.1-C.sub.6 alkyl groups; and R.sup.9 and R.sup.10 are each independently chosen from hydrogen, C.sub.1-C.sub.6 alkyl groups, hydroxy, and C.sub.1-C.sub.6 alkoxy groups; or, one of R.sup.9 or R.sup.10 is oxo and the other is absent; Z is chosen from C.sub.1-C.sub.6 alkyl groups, —C(O)—C.sub.1-C.sub.6 alkyl groups, —OR.sup.13, and —NR.sup.14R.sup.15 groups, wherein R.sup.13 is chosen from hydrogen, C.sub.1-C.sub.6 alkyl groups, and —C(O)—C.sub.1-C.sub.6 alkyl groups, wherein R.sup.14 and R.sup.15 are each independently chosen from hydrogen, C.sub.1-C.sub.6 alkyl groups, and methoxy C.sub.1-C.sub.6 alkyl groups; or R.sup.14 and R.sup.15 may be taken together with the N to form a group chosen from ##STR00642## a morpholine, a piperidine, a thiazolidine, an indole, an indoline, and an isoindoline ring; wherein Z may be unsubstituted or substituted from 1-3 times with a group independently chosen from C.sub.1-C.sub.6 alkyl groups, C.sub.3-C.sub.5 cycloalkyl groups, hydroxy C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 alkoxy groups, methoxy C.sub.1-C.sub.6 alkyl groups, —NR.sup.16R.sup.17 groups, ##STR00643## wherein R.sup.16 and R.sup.17 are each independently chosen from hydrogen and C.sub.1-C.sub.6 alkyl groups.

7. The compound of claim 6, wherein R.sup.1 is chosen from methyl, ##STR00644## groups, ##STR00645## groups, ##STR00646## groups, ##STR00647## groups, ##STR00648## groups, ##STR00649## groups, ##STR00650## groups, ##STR00651## groups, and ##STR00652## groups.

8. A compound chosen from: [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[[(2R,3R)-3-hydroxypentan-2-yl]carbamoyloxy]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-(propylcarbamoyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] pyrrolidine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptyl-4-oxidopiperazin-4-ium-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(dimethylcarbamoyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-(diethylcarbamoyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propan-2-yl)carbamoyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butyl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butan-2-yl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-carbamoyloxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (2R)-2-(methoxymethyl)pyrrolidine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-methoxyethyl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] azetidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (2S)-2-methylpyrrolidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (2S)-2-methylpyrrolidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] piperidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (3R)-3-hydroxypyrrolidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] morpholine-4-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 4-methylpiperazine-1carboxylate; 3-thiazolidinecarboxylic acid [(2R,3E,5E)-6-[(2R,3S,4E,6R,7R,10R)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 1,3-dihydroisoindole-2-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] indole-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-(1-hydroxyethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidine-1-carbonyl)oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 2,3-dihydroindole-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 2-oxa-5-azaspiro[3.4]octane-5-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-[6-[(2R)-1-hydroxypropan-2-yl]pyridin-2-yl]hepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-propan-2-ylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-tert-butylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cyclopentylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(oxan-4-yl)piperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 6-cycloheptyl-2,6-diazaspiro[3.3]heptane-2-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptyl-3-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cyclobutylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] N-methyl-N-(1-methylpiperidin-4-yl)carbamate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] morpholine-4-carboxylate; [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] (1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 8-cycloheptyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methyl-1,4-diazepane-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cyclohexylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] piperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptyl-1,4-diazepane-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(azepan-1-yl)piperidine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)piperidine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10R)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-10-(pyrrolidine-1-carbonyloxy)-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-carbamoylpyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidine-1-carbonyl)oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10R)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-7-hydroxy-3,7-dimethyl-12-oxo-10-(pyrrolidine-1-carbonyloxy)-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; (2R)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienoxy]carbonylpyrrolidine-2-carboxylic acid; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(3-oxopyrrolidine-1-carbonyl)oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 2-oxa-7-azaspiro[3.4]octane-7-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-5-[1-(pyrrolidine-1-carbonyloxymethyl)cyclopropyl]penta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S,4R)-3,4-dihydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; (3S)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienoxy]carbonylpyrrolidine-3-carboxylic acid; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,5-dihydropyrrole-1-carbonyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] 3-azabicyclo[3.1.0]hexane-3-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrazin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(3-methylpyridin-2-yl)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyridin-2-yl)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-4-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyrimidin-2-yl)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(6-pyrrolidin-1-ylpyridin-2-yl)hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] N,N-dimethylcarbamate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] pyrrolidine-1-carboxylate; [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (3R)-3-hydroxypyrrolidine-1-carboxylate; [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] N,N-dimethylcarbamate; [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-[2-[(3S)-3-triethylsilyloxypyrrolidin-1-yl]pyrimidin-4-yl]hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-[(3R)-3-hydroxypyrrolidin-1-yl]pyrimidin-4-yl]hepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-(1-phenyltetrazol-5-yl)oxypyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]amino]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[methyl(pyrrolidine-1-carbonyl)amino]hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(4-cyclopropyltriazol-1-yl)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-methoxycarbonyloxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-9-methoxy-6-methyl-9-oxonona-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; 4-cycloheptyl-1-piperazinecarboxylic acid [(2R,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-7-[oxo(1-pyrrolidinyl)methoxy]hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] ester; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxyl ate; [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-azacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2R,3E,5E)-2-methyl-6-[(2S,3S,4E,6R)-3-methyl-6-[(4-methylpiperazine-1-carbonyl)amino]-12-oxo-1-oxacyclododec-4-en-2-yl]hepta-3,5-dienyl] pyrrolidine-1-carboxylate; [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (2R,3R)-3-hydroxy-2-methylpentanoate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-7-methyl-6-pyridin-2-ylocta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R)-3-acetyloxypentan-2-yl]oxiran-2-yl]-6-hydroxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-methyl-8-phenyl octa-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-phenylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-thiophen-2-ylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-phenylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-(6-methoxypyridin-2-yl)hepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-[6-(2-methylpropoxy)pyridin-2-yl]hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-pyridin-2-ylocta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-7-pyridin-2-ylhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E,6R)-6-hydroxy-6-methyl-8-phenylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhexa-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhexa-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-8-(4-hydroxyphenyl)-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-phenylocta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[2-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[4-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[3-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6S)-6-hydroxy-6-methyl-7-[(2R,3R)-3-[(2S)-3-oxopentan-2-yl]oxiran-2-yl]hepta-2,4-dien-2-yl]-3,7-dimethyl-10,12-dioxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6E,8S)-8-pyridin-2-ylnona-2,4,6-trien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methyl-4-oxidopiperazin-4-ium-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(4-fluoropiperidin-1-yl)piperidine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(4,4-difluoropiperidin-1-yl)piperidine-1-carboxylate; (4S,7S,8S,9E,11S,12S)-4,7,8-trihydroxy-7,11-dimethyl-12-[(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-9-en-2-one; [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3- hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((S,2E,4E)-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate;[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-7-yl] piperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] piperazine-1-carboxylate; [(2S,3S,4E,6S,7R,10R)-7-ethoxy-10-hydroxy-2-[(2E,4E,6R)-6-hydroxy-7-[(2R,3R)-3-[(2S,3S)-3- hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-7-yl] piperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] piperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] N-methyl-N[2-(methylamino)ethyl]carbamate; [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] N-methyl-N[2-(dimethylamino)ethyl]carbamate; 3-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3- hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]oxycarbonyl]piperazin-2-yl]propanoic acid; 4-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3- hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]oxycarbonyl]piperazin-1-yl]butanoic acid; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl4-propylpiperazine-1-carboxylate; (2R,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((2S,6R,E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-4-en-2-yl)-3,7-di methyl-12-oxooxacyclododec-4-en-7-yl4-(2-hydroxyethyl)piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl4-methylpiperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl4-(2-aminoethyl)piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-(R,2E,4E)-6-hydroxy-7-(2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-(R,2E,4E)-6-hydroxy-7-(2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; and pharmaceutically acceptable salts thereof.

9. The compound of any one of claims 1-8, wherein said compound is stereomerically pure.

10. A pharmaceutical composition comprising a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9.

11. The pharmaceutical composition of claim 10, wherein said composition is formulated for intravenous, oral, subcutaneous, or intramuscular administration.

12. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11.

13. The method of claim 12, wherein said cancer is chosen from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, cholangiocarcinoma, and lung cancer.

14. The method of claim 13, wherein said cancer is chosen from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

15. The method of claim 13, wherein said cancer is myelodysplastic syndrome.

16. The method of claim 13, wherein said cancer is chronic lymphocytic leukemia.

17. The method of claim 13, wherein said cancer is chronic myelomonocytic leukemia

18. The method of claim 13, wherein said cancer is acute myeloid leukemia.

19. The method of claim 13, wherein said cancer is colon cancer.

20. The method of claim 13, wherein said cancer is pancreatic cancer.

21. The method of claim 13, wherein said cancer is endometrial cancer.

22. The method of claim 13, wherein said cancer is ovarian cancer.

23. The method of claim 13, wherein said cancer is breast cancer.

24. The method of claim 13, wherein said cancer is uveal melanoma.

25. The method of claim 13, wherein said cancer is gastric cancer.

26. The method of claim 13, wherein said cancer is cholangiocarcinoma.

27. The method of claim 13, wherein said cancer is lung cancer.

28. The method of any one of claims 12-27, wherein said cancer is positive for one or more mutations in a spliceosome gene or protein.

29. The method of claim 28, wherein said spliceosome gene or protein is chosen from splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), serine/arginine-rich splicing factor 2 (SRSF2), zinc finger (CCCH type) RNA-binding motif and serine/arginine rich 2 (ZRSR2), pre-mRNA-processing-splicing factor 8 (PRPF8), U2 small nuclear RNA auxiliary factor 2 (U2AF2), splicing factor 1 (SF1), splicing factor 3a subunit 1 (SF3A1), PRP40 pre-mRNA processing factor 40 homolog B (PRPF40B), RNA binding motif protein 10 (RBM10), poly(rC) binding protein 1 (PCBP1), crooked neck pre-mRNA splicing factor 1 (CRNKL1), DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), peptidyl-prolyl cis-trans isomerase-like 2 (PPIL2), RNA binding motif protein 22 (RBM22), small nuclear ribonucleoprotein Sm D3 (SNRPD3), probable ATP-dependent RNA helicase DDX5 (DDX5), pre-mRNA-splicing factor ATP-dependent RNA helicase DHX15 (DHX15), and polyadenylate-binding protein 1 (PABPC1).

30. The method of claim 29, wherein said spliceosome gene or protein is Splicing Factor 3B subunit 1 (SF3B1).

31. The use of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, in the preparation of a medicament for the treatment of cancer.

32. The use of claim 31, wherein said cancer is chosen from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, cholangiocarcinoma, and lung cancer.

33. The use of claim 32, wherein said cancer is chosen from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

34. The use of claim 32, wherein said cancer is myelodysplastic syndrome.

35. The use of claim 32, wherein said cancer is chronic lymphocytic leukemia.

36. The use of claim 32, wherein said cancer is chronic myelomonocytic leukemia

37. The use of claim 32, wherein said cancer is acute myeloid leukemia.

38. The use of claim 32, wherein said cancer is colon cancer.

39. The use of claim 32, wherein said cancer is pancreatic cancer.

40. The use of claim 32, wherein said cancer is endometrial cancer.

41. The use of claim 32, wherein said cancer is ovarian cancer.

42. The use of claim 32, wherein said cancer is breast cancer.

43. The use of claim 32, wherein said cancer is uveal melanoma.

44. The use of claim 32, wherein said cancer is gastric cancer.

45. The use of claim 32, wherein said cancer is cholangiocarcinoma.

46. The use of claim 32, wherein said cancer is lung cancer.

47. The use of any one of claims 31-46, wherein said cancer is positive for one or more mutations in a spliceosome gene or protein.

48. The use of claim 47, wherein said spliceosome gene or protein is chosen from splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), serine/arginine-rich splicing factor 2 (SRSF2), zinc finger (CCCH type) RNA-binding motif and serine/arginine rich 2 (ZRSR2), pre-mRNA-processing-splicing factor 8 (PRPF8), U2 small nuclear RNA auxiliary factor 2 (U2AF2), splicing factor 1 (SF1), splicing factor 3a subunit 1 (SF3A1), PRP40 pre-mRNA processing factor 40 homolog B (PRPF40B), RNA binding motif protein 10 (RBM10), poly(rC) binding protein 1 (PCBP1), crooked neck pre-mRNA splicing factor 1 (CRNKL1), DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), peptidyl-prolyl cis-trans isomerase-like 2 (PPIL2), RNA binding motif protein 22 (RBM22), small nuclear ribonucleoprotein Sm D3 (SNRPD3), probable ATP-dependent RNA helicase DDX5 (DDX5), pre-mRNA-splicing factor ATP-dependent RNA helicase DHX15 (DHX15), and polyadenylate-binding protein 1 (PABPC1).

49. The use of claim 48, wherein said spliceosome gene or protein is Splicing Factor 3B subunit 1 (SF3B1).

50. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11; and at least one additional therapy.

51. The method of claim 50, wherein the at least one additional therapy comprises at least one, at least two, at least three, at least four, or at least five additional therapies.

52. The method of claim 50, wherein the administered amount of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, and/or the at least one additional therapy is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90%, relative to a standard dosage of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, and/or the at least one additional therapy.

53. The method of any one of claims 50 to 52, wherein the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, and/or the at least one additional therapy is administered at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less frequently, relative to a standard dosing regimen of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, and/or the at least one additional therapy.

54. The method of any one of claims 50 to 53, wherein the administered amount and/or dosage of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, and/or the at least one additional therapy results in lower systemic toxicity and/or improved tolerance.

55. The method of claim 50, wherein administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is initiated before administration of the at least one additional therapy.

56. The method of claim 50, wherein administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is initiated after administration of the at least one additional therapy.

57. The method of claim 50, wherein administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is initiated concurrently with administration of the at least one additional therapy.

58. The method of any one of claims 50 to 57, wherein administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is repeated at least once after initial administration.

59. The method of claim 58, wherein the amount of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, used for repeated administration is reduced relative to the amount used for initial administration.

60. The method of claim 58, wherein the amount of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, used for repeated administration is reduced relative to a standard dosage of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11.

61. The method of claim 58, wherein the amount of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, used for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90%, relative to a standard dosage of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11.

62. The method of any one of claims 50 to 61, wherein administration of the at least one additional therapy is repeated at least once after initial administration.

63. The method of claim 62, wherein the amount of the at least one additional therapy used for repeated administration is reduced relative to the amount used for initial administration.

64. The method of claim 62, wherein the amount of the at least one additional therapy used for repeated administration is reduced relative to a standard dosage of the at least one additional therapy.

65. The method of claim 62, wherein the amount of the at least one additional therapy used for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90%, relative to a standard dosage of the at least one additional therapy.

66. The method of any one of claims 50 to 65, wherein repeated administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is concurrent with repeated administration of the at least one additional therapy.

67. The method of any one of claims 50 to 65, wherein repeated administration of the compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or claim 11, is sequential or staggered with repeated administration of the at least one additional therapy.

68. The method of any one of claims 50 to 67, wherein the at least one additional therapy comprises administering a checkpoint inhibitor.

69. The method of claim 68, wherein the subject is intolerant, non-responsive, or poorly responsive to the checkpoint inhibitor when administered alone.

70. The method of claim 68, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3, and/or KIR.

71. The method of claim 68, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40, and/or GITR.

72. The method of claim 70 or claim 71, wherein the checkpoint inhibitor comprises a cytotoxic T-lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor.

73. The method of claim 72, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

74. The method of claim 73, wherein the anti-CTLA4 antibody is ipilimumab.

75. The method of claim 70 or claim 71, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor.

76. The method of claim 75, wherein the PD1 inhibitor is an anti-PD1 antibody.

77. The method of claim 76, wherein the anti-PD1 antibody is nivolumab.

78. The method of claim 75, wherein the PD1 inhibitor is an anti-PDL1 antibody.

79. The method of claim 78, wherein the anti-PDL1 antibody is atezolizumab.

80. The method of claim 70 or claim 71, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

81. The method of claim 80, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

82. The method of claim 81, wherein the anti-CTLA4 antibody is ipilimumab.

83. The method of claim 80 or claim 81, wherein the PD1 inhibitor is an anti-PD1 antibody.

84. The method of claim 83, wherein the anti-PD1 antibody is nivolumab.

85. The method of claim 80 or claim 81, wherein the PD1 inhibitor is an anti-PDL1 antibody.

86. The method of claim 85, wherein the anti-PDL1 antibody is atezolizumab.

87. The method of any one of claims 50 to 67, wherein the at least one additional therapy comprises administering a cytokine or cytokine analog.

88. The method of claim 87, wherein the subject is intolerant, non-responsive, or poorly responsive to the cytokine or cytokine analog when administered alone.

89. The method of claim 87, wherein the cytokine or cytokine analog comprises a T-cell enhancer.

90. The method of claim 87, wherein the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ, and/or TNFα.

91. The method of any one of claims 50 to 67, wherein the at least one additional therapy comprises administering engineered tumor-targeting T-cells.

92. The method of any one of claims 50 to 91, wherein the subject has a non-synonymous mutational burden of about 150 mutations or less.

93. The method of any one of claims 50 to 92, wherein the subject has a non-synonymous mutational burden of about 100 mutations or less.

94. The method of any one of claims 50 to 93, wherein the subject has a non-synonymous mutational burden of about 50 mutations or less.

95. The method of any one of claims 50 to 94, wherein the cancer is a hematological malignancy or a solid tumor.

96. The method of claim 95, wherein the hematological malignancy is chosen from a B-cell malignancy, a leukemia, a lymphoma, and a myeloma.

97. The method of claim 95 or claim 96, wherein the hematological malignancy is chosen from acute myeloid leukemia and multiple myeloma.

98. The method of claim 95, wherein the solid tumor is chosen from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.

99. The method of any one of claims 50 to 94, wherein the cancer is chosen from myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, cholangiocarcinoma, and lung cancer.

100. A method of inducing at least one neoantigen, comprising contacting a neoplastic cell with a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, thereby inducing production of at least one neoantigen.

101. The method of claim 100, wherein the neoplastic cell is present in an in vitro cell culture.

102. The method of claim 100 or claim 101, wherein the neoplastic cell is obtained from a subject.

103. The method of claim 100, wherein the neoplastic cell is present in a subject.

104. The method of any one of claims 100 to 103, wherein the neoplastic cell is derived from a hematological malignancy or a solid tumor.

105. The method of claim 104, wherein the hematological malignancy is selected from a B-cell malignancy, a leukemia, a lymphoma, and a myeloma.

106. The method of claim 104 or claim 105, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

107. The method of claim 104, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.

108. A method of inducing at least one neoantigen and/or a T-cell response in a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11.

109. A method of treating a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt according to any one of claims 1-9, or a pharmaceutical composition according to claim 10 or claim 11, wherein administration of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition, induces at least one neoantigen and/or a T-cell response.

110. The method of claim 109, wherein the amount of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition, administered is reduced due to induction of at least one neoantigen and/or a T-cell response, relative to a standard dosage of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition.

111. The method of claim 110, wherein the administered amount of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition, is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90%, relative to a standard dosage of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition.

112. The method of any one of claims 109 to 111, wherein the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition, is administered at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less frequently, relative to a standard dosing regimen of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition.

113. The method of any one of claims 109 to 111, wherein the administered amount and/or dosage of the compound and/or pharmaceutically acceptable salt, or pharmaceutical composition, results in lower systemic toxicity and/or improved tolerance.

114. The method of any one of claims 108 to 113, further comprising administering at least one additional therapy.

Description

EXAMPLES 1-205

[0524] General: Microwave heating was done using a Biotage Emrys Liberator or Initiator microwave. Column chromatography was carried out using an Isco Rf200d. Solvent removal was carried out using either a BUchi rotary evaporator or a Genevac centrifugal evaporator. Preparative LC/MS was conducted using a Waters autopurifier and 19×100 mm XTerra 5 micron MS C18 column under acidic mobile phase condition. NMR spectra were recorded using a Varian 400 MHz spectrometer.

[0525] When the term “inerted” is used to describe a reactor (e.g., a reaction vessel, flask, glass reactor, and the like) it is meant that the air in the reactor has been replaced with an essentially moisture-free or dry, inert gas (such as nitrogen, argon, and the like).

[0526] General methods and experimentals for preparing compounds of the present disclosure are set forth below. In certain cases, a particular compound is described by way of example. However, it will be appreciated that in each case a series of compounds of the present disclosure were prepared in accordance with the schemes and experimentals described below.

[0527] The following abbreviations are used herein: [0528] COMU: (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate [0529] DMAP: 4-(Dimethylamino)pyridine [0530] DMP: Dess Martin Periodinane [0531] EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide [0532] KHMDS: Potassium bis(trimethylsilyl)amide [0533] LCMS: Liquid chromatography—mass spectrometry [0534] Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium(0) [0535] TBAF: Tetrabutylammonium fluoride [0536] TBSCl: tert-Butyldimethylsilyl chloride [0537] TBSOTf: tert-Butyldimethylsilyl trifluoromethanesulfonate [0538] TESCl: Chlorotriethylsilane [0539] THF: Tetrahy drofuran [0540] TLC: Thin-layer chromatography [0541] pTsOH: p-Toluenesulfonic acid [0542] PPTS: Pyridinium p-toluenesulfonate

[0543] Materials: The following compounds are commercially available and/or can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, disclosed compounds can be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0544] LCMS information: Mobile phases: A (0.1% formic acid in H.sub.2O) and B (0.1% formic acid in acetonitrile). Gradient: B 5%.fwdarw.95% in 1.8 minutes. Column: Acquity BEH C18 column (1.7 um, 2.1×50 mm).

[0545] U.S. Pat. Nos. 7,884,128 and 7,816,401, both entitled: Process for Total Synthesis of Pladienolide B and Pladienolide D, describe methods known in the art for synthesis of Pladienolide B and D. Synthesis of Pladienolide B and D may also be performed using methods known in the art and described in Kanada et al., “Total Synthesis of the Potent Antitumor Macrolides Pladienolide B and D,” Angew. Chem. Int. Ed. 46:4350-4355 (2007). Kanada et al. and PCT application publication WO 2003/099813, entitled: Novel Physiologically Active Substances, describe methods known in the art for the synthesis of E7107 (Compound 45 of WO '813) from Pladienolide D (11107D of WO '813). A corresponding U.S. Pat. No. is 7,550,503 to Kotake et al.

[0546] Exemplified Synthesis of Compounds [0547] Compounds 1-60 (Table I) were prepared by the method of Scheme 1.

##STR00117##

General Protocol for the Synthesis of Compounds 1-60:

[0548] Step 1: A solution of pladienolide D (A, 5.3 g, 9.7 mmol, 1.0 equiv.) under nitrogen in DMF (80 mL, 0.1M) at 0° C. was treated with imidazole (4.6 g, 67.8 mmol, 7.0 equiv.) and TBSCl (7.3 g, 48.4 mmol, 5.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 20 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (B, 7.5 g, 9.6 mmol, 99%).

[0549] Step 2: To a solution of olefin B (7.6 g, 9.7 mmol, 1.0 equiv.) in degassed THF:H.sub.2O (210 mL:21 mL, 0.01M) under nitrogen at 0° C. was added osmium tetroxide (24.4 mL, 1.9 mmol, 0.2 equiv., 2.5% solution in tent-butanol) followed by N-methylmorpholine N-oxide (2.3 g, 19.5 mmol, 2.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 13 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium sulfite, diluted with ethyl acetate, and the organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (C, 6.8 g, 8.3 mmol, 86%).

[0550] Step 3: To a solution of diol C (7.9 g, 9.7 mmol, 1.0 equiv.) in benzene (350 mL, 0.03M) under nitrogen at room temperature was added lead tetraacetate (8.6 g, 19.4 mmol, 2.0 equiv.). The reaction was stirred for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. The reaction was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (D, 2.5 g, 5.26 mmol, 54%).

[0551] Step 4: To a solution of aldehyde D (1.4 g, 2.9 mmol, 1.0 equiv.) in THF (9.5 mL, 0.5M) was added ethoxyethene (11.1 mL, 40.0 equiv.) and pyridinium p-toluenesulfonate (0.07 g, 0.3 mmol, 0.1 equiv.) at room temperature. The reaction was stirred for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The ethyl acetate was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (E, 1.2 g, 2.2 mmol, 75%).

[0552] Step 5: To a solution of corresponding sulfone (1.5 equiv.) in THF (0.02M) under nitrogen at −78° C. was added KHMDS (1.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde E (1.0 equiv.) in THF was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride, diluted with ethyl acetate, and warmed to room temperature. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (F).

[0553] Step 6: To a solution of acetate F (1.0 equiv.) in methanol (0.1M) at room temperature was added potassium carbonate (1.1 equiv.). The reaction was run for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with water, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil (G) was advanced into the next step without additional purification.

[0554] Step 7: To a solution of alcohol (G) (1.0 equiv.) in dichloromethane (0.1M) at room temperature was added N,N-dimethylaminopyridine (0.5 equiv.) followed by 4-nitrophenyl chloroformate (2.0 equiv.). The reaction was stirred at room temperature for three hours. Next, the corresponding amine (3.0 equiv.) was added at room temperature. After stirring for one hour, the reaction was quenched with water and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution, and the organic layer was concentrated. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (H).

[0555] Step 8: To a solution of silyl ether (H, 1.0 equiv.) in methanol (0.1M) at room temperature was added p-methoxytoluenesulfonic acid (3.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (1-59).

Exemplified Protocol for the Synthesis of compound 46

[0556] Steps 1-4 as above.

[0557] Step 5: To a solution of (S)-2-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine (233.0 mg, 0.7 mmol, 1.4 equiv.) in THF (2.5 mL, 0.2M) under nitrogen at −78° C. was added KHMDS (1.5 mL, 0.75 mmol, 1.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde E (280.0 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. over 1 hour. The reaction was quenched with ammonium chloride, diluted with ethyl acetate, and warmed to room temperature. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired Julia product (F, 180 mg, 0.3 mmol, 54%).

[0558] Step 6: To a solution of acetate F (250.0 mg, 0.4 mmol, 1.0 equiv.) in methanol (3 mL, 0.1M) at room temperature was added potassium carbonate (58.0 mg, 0.4 mmol, 1.1 equiv.). The reaction was run for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with water, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting foamy solid (G, 235 mg, 0.4 mmol, 100%) was advanced into the next step without additional purification.

[0559] Step 7: To a solution of alcohol G (22.0 mg, 0.04 mmol, 1.0 equiv.) in dichloromethane (0.5 mL, 0.1M) at room temperature was added N,N-dimethylaminopyridine (2.1 mg, 0.02 mmol, 0.5 equiv.) followed by 4-nitrophenyl chloroformate (14.4 mg, 0.08 mmol, 2.0 equiv.). The reaction was stirred at room temperature for three hours. Next, 1-(tetrahydro-2H-pyran-4-yl)piperazine (20.4 mg, 0.12 mmol, 3.0 equiv.) was added at room temperature. After stirring for one hour, the reaction was quenched with water and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution, and the organic layer was concentrated. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (H, 26.0 mg, 0.03 mmol, 80%).

[0560] Step 8: To a solution of silyl ether (H, 26.0 mg, 0.03 mmol, 1.0 equiv.) in methanol (0.3 mL, 0.1M) at room temperature was added p-methoxytoluenesulfonic acid (17.0 mg, 0.09 mmol, 3.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (compound 46, 16.3 mg, 0.025 mmol, 85%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ:8.48 (ddd, J=4.9, 1.9, 1.0 Hz, 1H), 7.54 (td, J=7.7, 1.9 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 6.15-6.34 (m, 1H), 6.04 (d, J=10.8 Hz, 1H), 5.93 (dd, J=15.1, 7.5 Hz, 1H), 5.48-5.67 (m, 2H), 5.08 (d, J=10.5 Hz, 1H), 4.94 (d, J=9.5 Hz, 1H), 3.95 (dd, J=11.3, 3.8 Hz, 2H), 3.53-3.76 (m, 2H), 3.37-3.49 (m, 5H), 3.22-3.37 (m, 2H), 2.35-2.57 (m, 7H), 1.88 (s, 1H), 1.44-1.70 (m, 11H), 1.14-1.39 (m, 8H), 0.72-0.89 (m, 3H), MS (ES+)=626.6[M+H].

TABLE-US-00004 TABLE 1 Structures and analytical data for Compounds 1-60 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00118] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.78 Hz, 3 H) 1.07 (d, J = 6.65 Hz, 3 H) 1.23 (s, 3 H) 1.30- 1.43 (m, 4 H) 1.55-1.79 (m, 7H) 1.84-2.01 (m, 4 H) 2.28-2.34 (m, 5 H) 2.42 (t, J = 4.96 Hz, 4 H) 2.51- 2.66 (m, 3 H) 3.41 (td, J = 6.87, 1.94 Hz, 2 H) 3.48 (t, J = 6.78 Hz, 2 H) 3.51-3.86 (m, 4 H) 4.96 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.55-5.68 (m, 2 H) 5.74 (dd, J = 15.18 9.66 Hz, 1 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.29 (dt, J = 14.81, 10.54 Hz, 1 H) 604.3 1 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9- pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1- carboxylate [00119] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.73-0.91 (m, 5 H) 0.92-1.04 (m, 5 H) 1.07-1.33 (m, 5 H) 1.37- 1.59 (m, 3 H) 1.60-1.71 (m, 2 H) 1.80 (s, 1 H) 1.86-2.07 (m, 2 H) 2.24-2.52 (m, 3 H) 2.89-3.09 (m, 1 H) 3.34-3.50 (m, 1 H) 3.52-3.62 (m, 1H) 3.64-3.75 (m, 1 H) 3.76- 4.03 (m, 2 H) 4.83 (s, 1 H) 4.87- 5.04 (m, 1 H) 5.24-5.53 (m, 2 H) 5.53-5.69 (m, 1 H) 5.99 (d, J = 11.04 Hz, 1 H) 6.24 (dd, J = 15.18, 10.92 Hz, 1 H) 534.3 2 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6S)-7-[[(2R,3R)-3-hydroxypentan-2- yl]carbamoyloxy]-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate [00120] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.87-0.97 (m, 3 H) 0.97-1.15 (m, 5 H) 1.21 (s, 1 H) 1.29-1.40 (m, 1 H) 1.46-1.70 (m, 5 H) 1.72-1.77 (m, 1 H) 1.82 (s, 1 H) 2.08 (s, 1 H) 2.18 (s, 1 H) 2.35-2.63 (m, 3 H) 3.05 (t, J = 7.03 Hz, 2 H) 3.14-3.27 (m, 3 H)3.50 (dd, J = 3.26, 1.51 Hz, 1 H) 3.62-3.79 (m, 3 H) 3.79-4.08 (m, 3 H) 4.96 (br. s., 1 H) 5.07 (d, J = 9.79 Hz, 1 H) 5.38-5.52 (m, 1 H) 5.54-5.72 (m, 2 H) 5.97 (dd, J = 17.07, 10.79 Hz, 1 H) 6.21-6.49 (m, 1 H) 8.57 (s, 1 H) 3 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-7- (propylcarbamoyloxy)hepta-2,4-dien-2-yl]-12-oxo- 1-oxacyclododec-4-en-6-yl] acetate [00121] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.53 Hz, 6 H) 1.01- 1.15 (m, 3 H) 1.21 (s, 3 H) 1.29- 1.47 (m, 2 H) 1.50-1.71 (m, 4 H) 1.77 (d, J = 1.00 Hz, 3 H) 2.04-2.09 (m, 3 H) 2.18 (s, 1 H) 2.39 (s, 1 H) 2.48-2.68 (m, 4 H) 2.89 (s, 3 H) 3.15 (s, 1 H) 3.19-3.29 (m, 2 H) 3.31-3.50 (s, 1 H) 3.69 (s, 1 H) 3.74- 3.88 (m, 1 H) 3.89-4.15 (m, 2 H) 5.07 (d, J = 9.79 Hz, 2 H) 5.51-5.64 (m, 1 H) 5.64-5.76 (m, 2 H) 6.09- 6.19 (m, 1 H) 6.37 (ddd, J = 15.12, 10.85, 0.88 Hz, 1 H) 7.25 (dd, J = 8.28, 1.00 Hz, 1 H) 7.73 (d, J = 8.03 Hz, 1 H) [00122] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.34- 1.46 (m, 2 H) 1.54-1.67 (m, 2 H) 1.77 (d, J = 0.88 Hz, 3 H) 1.82-1.95 (m, 4 H) 2.08 (s, 3 H) 2.49-2.70 (m, 4 H) 3.34-3.39 (m, 4 H) 3.75-3.87 (m, 1 H) 3.98 (dd, J = 6.78, 1.38 Hz, 2 H) 5.07 (d, J = 9.91 Hz, 2 H) 5.59 (dd, J = 15.18 9.79 Hz, 1 H) 5.65- 5.76 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.37 (ddd, J = 15.15, 10.82, 1.00 Hz, 1 H) 522.4 5 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] pyrrolidine-1-carboxylate [00123] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.60-1.79 (m, 15 H) 2.05- 2.35 (m, 5 H) 2.43 (d, J = 3.26 Hz, 6 H) 2.78 (s, 3 H) 2.86-3.00 (m, 3 H) 3.44-3.62 (m, 4 H) 3.64-3.75 (m, 2 H) 3.76-4.05 (m, 6 H) 4.37-4.56 (m, 3 H) 4.95 (d, J = 10.79 Hz, 1 H) 5.41-5.79 (m, 3H) 6.00 (d, J = 10.79 Hz, 1 H) 6.13-6.39 (m, 1 H) 6 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-7- [methyl(propyl)carbamoyl]oxyhepta-2,4-dien-2-yl]- 12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptyl- 4-oxidopiperazin-4-ium-1-carboxylate [00124] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.31- 1.47 (m, 2 H) 1.62 (dd, J = 15.25, 8.34 Hz, 2 H) 1.75-1.78 (m, 3 H) 2.08 (s, 3 H) 2.51-2.66 (m, 4 H) 2.91 (s, 6 H) 3.81 (br. s., 1 H) 3.97 (dd, J = 6.65, 1.76 Hz, 2 H) 45.07 (d, J = 9.91 Hz, 2 H) 5.51-5.75 (m, 3 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.37 (ddd, J = 15.18, 10.79, 1.00 Hz, 1 H) 518.4 7 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7- (dimethylcarbamoyloxy)-6-methylhepta-2,4-dien-2- yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00125] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.06- 1.15 (m, 9 H) 1.21 (s, 3 H) 1.28- 1.45 (m, 2 H) 1.54-1.70 (m, 2 H) 1.74-1.78 (m, 3 H) 2.08 (s, 3 H) 2.51-2.68 (m, 4 H) 3.76-3.87 (m, 546.4 1 H) 3.93-4.03 (m, 2 H) 5.06 (d, J = 9.79 Hz, 2 H) 5.55-5.75 (m, 3 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.37 (ddd, J = 15.12, 10.85, 0.88 Hz, 1 H) 8 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7- (diethylcarbamoyloxy)-6-methylhepta-2,4-dien-2- yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00126] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.89 (d, J = 6.65 Hz, 3 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.13 (d, J = 6.78 Hz, 6 H) 1.21 (s, 3 H) 1.29-1.45 (m, 2 H) 1.54-1.71 (m, 2 H) 1.75-1.78 (m, 3 H) 2.08 (s, 3 H) 2.51-2.67 (m, 4 H) 2.76 (s, 3 H) 3.77-3.83 (m, 1 H) 3.98 (d, J = 7.03 Hz, 2 H) 4.33 (br. s., 1 H) 5.06 (d, J = 9.91 Hz, 2 H) 5.55- 5.63 (m, 1 H) 5.65-5.75 (m, 2 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.37 (ddd, J = 15.12, 10.85, 0.88 Hz, 1 H) 546.5 9 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-7- [methyl(propan-2-yl)carbamoyl]oxyhepta-2,4-dien- 2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate [00127] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.87-0.98 (m, 6 H) 1.09 (d, J = 6.90 Hz, 3 H) 1.16-1.22 (m, 3 H) 1.32 (br. s., 2 H) 1.38 (d, J = 9.91 Hz, 2 H) 1.49-1.68 (m, 4 H) 1.75-1.78 (m, 3 H) 2.08 (s, 3 H) 2.52-2.66 (m, 4 H) 2.89 (s, 3 H) 3.28-3.37 (m, 18 H) 3.80 (d, J = 6.15 Hz, 1 H) 3.98 (d, J = 7.03 Hz, 2 H) 4.87 (s, 72 H) 5.05- 5.09 (m, 2 H) 5.55-5.62 (m, 1 H) 5.66-5.75 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.33-6.40 (m, 1 H) 560.5 10 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7- [butyl(methyl)carbamoyl]oxy-6-methylhepta-2,4- dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00128] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.77-0.98 (m, 9 H) 1.01- 1.18 (m, 7 H) 1.20-1.34 (m, 10 H) 1.34-1.53 (m, 5 H) 1.58-1.66 (m, 2 H) 1.76 (s, 3 H) 2.06-2.09 (m, 3 H) 2.50-2.68 (m, 5 H) 2.73 (s, 3 H) 3.94-4.07 (m, 3 H) 5.06 (d, J = 9.79 Hz, 2 H) 5.53-5.64 (m, 1 H) 5.65- 5.75 (m, 2 H) 6.12 (d, J = 10.04 Hz, 1 H) 6.37 (dd, J = 15.18, 10.79 Hz, 1 H) 560.5 11 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butan-2- yl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien- 2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00129] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.23- 1.30 (m, 2 H) 1.31 (s, 4 H) 1.34- 1.49 (m, 3 H) 1.62 (dd, J = 15.62, 8.22 Hz, 2 H) 1.75-1.79 (m, 2 H) 2.03- 2.09 (m, 3 H) 2.51-2.65 (m, 3 H) 3.15 (s, 1 H) 3.81 (d, J = 3.76 Hz, 1 H) 3.87-3.98 (m, 1 H) 4.59 (s, 4 H) 4.97 (s, 1 H) 5.07 (d, J = 9.79 Hz, 2 H) 5.57 (dd, J = 15.18, 9.79 Hz, 1 H) 5.67-5.77 (m, 2 H) 6.11 (d, J = 10.79 Hz, 1 H) 6.37 (ddd, J = 15.15, 10.82, 1.00 Hz, 1 H) 490.3 12 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7- carbamoyloxy-6-methylhepta-2,4-dien-2-yl]-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-6-yl] acetate [00130] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.78 (d, J = 6.65 Hz, 3 H) 0.80- 0.91 (m, 1 H) 0.95 (d, J = 6.78 Hz, 3 H) 1.09 (s, 3 H) 1.17-1.30 (m, 2 H) 1.40-1.59 (m, 2 H) 1.63-1.73 (m, 4 H) 1.78-1.87 (m, 3 H) 1.96 (s, 3 H) 2.38-2.55 (m, 4 H) 3.19-3.27 (m, 10 H) 3.28-3.41 (m, 1 H) 3.64- 3.75 (m, 1 H) 3.79-3.90 (m, 2 H) 4.46 (s, 1 H) 4.74 (s, 25 H) 4.94 (d, J = 9.66 Hz, 2 H) 5.46 (dd, J = 15.18, 9.79 Hz, 1 H) 5.54-5.64 (m, 2 H) 6.01 (d, J = 10.92 Hz, 1 H) 6.19-6.31 (m, 1 H) 566.5 13 [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] (2R)-2-(methoxymethyl)pyrrolidine-1- carboxylate [00131] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.90 Hz, 3 H) 1.21 (s, 2 H) 1.48- 1.71 (m, 2 H) 1.77 (s, 3 H) 2.08 (s, 3 H) 2.48-2.70 (m, 4 H) 2.95 (s, 3 H) 3.38-3.58 (m, 4 H) 3.69-4.06 (m, 3 H) 5.01-5.16 (m, 2 H) 5.59 (dd, J = 15.43, 9.79 Hz, 1 H) 5.69 (s, 2 H) 6.12 (d, J = 10.29 Hz, 1 H) 6.38 (dd, J = 15.43, 11.04 Hz, 1 H) 562.3 14 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6S)-7-[2- methoxyethyl(methyl)carbamoyl]oxy-6- methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00132] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.02 Hz, 3 H) 1.07 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.34- 1.47 (m, 2 H) 1.48-1.49 (m, 1 H) 1.51-1.73 (m, 2 H) 1.78 (d, J = 1.00 Hz, 3 H) 2.08 (s, 3 H) 2.19-2.34 (m, 2 H) 2.46-2.66 (m, 3 H) 3.37 (s, 3 H) 3.74-4.07 (m, 6 H) 5.07 (d, J = 9.79 Hz, 2 H) 5.49-5.80 (m, 3 H) 6.12 (d, J = 10.67 Hz, 1 H) 6.36 (ddd, J = 15.06, 10.67, 1.25 Hz, 1 H) 15 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] azetidine-1-carboxylate [00133] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.18 (d, J = 6.27 Hz, 3 H) 1.21 (s, 3 H) 1.28-1.48 (m, 3 H) 1.53-1.69 (m, 3 H) 1.76 (d, J = 1.00 Hz, 3 H) 1.79-2.06 (m, 3 H) 2.08 (s, 3 H) 2.55 (br. s., 4 H) 3.36- 3.45 (m, 1 H) 3.73-4.11 (m, 4 H) 5.06 (m, J = 9.54 Hz, 2 H) 5.58 (dd, J = 15.31, 9.79 Hz, 1 H) 5.65-5.77 (m, 2 H) 6.13 (d, J = 9.79 Hz, 1 H) 6.37 (dd, J = 15.81, 10.54 Hz, 1 H) 536.4 16 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] (2S)-2-methylpyrrolidine-1-carboxylate [00134] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.77 (d, J = 6.65 Hz, 3 H) 0.97 (d, J = 6.90 Hz, 3 H) 1.01-1.14 (m, 6 H) 1.19-1.32 (m, 2 H) 1.39-1.57 (m, 3 H) 1.64 (s, 3 H) 1.96 (s, 3 H) 2.36-2.61 (m, 4 H) 3.24-3.34 (m, 2 H) 3.60-3.74 (m, 1 H) 3.74-3.94 (m, 3 H) 4.86-5.00 (m, 2 H) 5.46 (dd, J = 15.18, 9.79 Hz, 1 H) 5.56 (m, 2 H) 5.98 (d, J = 9.91 Hz, 1 H) 6.25 (dd, J = 16.06, 10.54 Hz, 1 H) 536.3 17 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] (2S)-2-methylpyrrolidine-1-carboxylate [00135] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.00-0.00 (m, 1 H) 0.90 (d, J = 6.78 Hz, 3 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.29-1.70 (m, 12 H) 1.77 (d, J = 1.00 Hz, 3 H) 2.08 (s, 3 H) 2.46-2.71 (m, 4 H) 3.37-3.47 (m, 4 H) 3.73-3.86 (m, 1 H) 3.92- 4.03 (m, 2 H) 5.05 (m, 2 H) 5.59 (dd, J = 15.18, 9.79 Hz, 1 H) 5.64-5.77 (m, 2 H) 6.12 (dd, J = 10.79, 1.00 Hz, 1 H) 6.37 (ddd, J = 15.12, 10.85, 0.88 Hz, 1 H) 18 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] piperidine-1-carboxylate [00136] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.40 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.32- 1.47 (m, 2 H) 1.53-1.69 (m, 2 H) 1.77 (s, 3 H) 1.80-1.89 (m, 1 H) 1.90-2.01 (m, 3 H) 2.08 (s, 3 H) 2.55 (br. s., 4 H) 3.35-3.47 (m, 2 H) 3.47-3.67 (m, 2 H) 3.74-3.90 (m, 2 H) 3.90-4.07 (m, 2 H) 5.02-5.16 (m, 2 H) 5.59 (dd, J = 15.18, 9.79 Hz, 1 H) 5.70 (d, J = 9.66 Hz, 2 H) 6.14 (d, J = 10.67 Hz, 1 H) 6.38 (dd, J = 15.06, 11.04 Hz, 1 H) 19 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] (2R)-2-(hydroxymethyl)pyrrolidine-1- carboxylate [00137] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.10 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.33- 1.46 (m, 2 H) 1.53-1.70 (m, 2 H) 1.77 (s, 3 H) 1.85-2.06 (m, 3 H) 2.08 (s, 3 H) 2.47-2.70 (m, 4 H) 3.47 (d, J = 4.39 Hz, 3 H) 3.76-3.86 (m, 1 H) 3.92-4.05 (m, 2 H) 4.31- 4.46 (m, 1 H) 5.01-5.10 (m, 2 H) 5.57 (dd, J = 15.43 9.79 Hz, 1 H) 5.66-5.82 (m, 2 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.38 (ddd, J = 15.18, 10.85, 0.69 Hz, 1 H) 20 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] (3R)-3-hydroxypyrrolidine-1-carboxylate [00138] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.30- 1.45 (m, 2 H) 1.56-1.69 (m, 2 H) 1.74-1.82 (m, 3 H) 2.08 (s, 3 H) 2.47-2.71 (m, 4 H) 3.39-3.55 (m, 4 H) 3.55-3.71 (m, 4 H) 3.73-3.85 (m, 1 H) 3.95-4.06 (m, 2 H) 4.98- 5.16 (m, 2 H) 5.58 (dd, J = 14.93, 9.54 Hz, 1 H) 5.65-5.76 (m, 2 H) 6.13 (d, J = 11.04 Hz, 1 H) 6.38 (ddd, J = 15.18, 10.92, 0.88 Hz, 1 H) 560.1 21 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] morpholine-4-carboxylate [00139] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.08 (d, J = 6.90 Hz, 3 H) 1.21 (s, 3 H) 1.29- 1.45 (m, 3 H) 1.54-1.68 (m, 2 H) 1.77 (d, J = 1.00 Hz, 3 H) 2.08 (s, 3 H) 2.32 (s, 3 H) 2.37-2.47 (m, 4 H) 2.48-2.71 (m, 4 H) 3.44-3.57 (m, 4 H) 3.73-3.88 (m, 1 H) 3.91-4.06 (m, 2 H) 5.02-5.15 (m, 2 H) 5.59 (dd, J = 15.31, 10.04 Hz, 1 H) 5.64- 5.77 (m, 2 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.37 (ddd, J = 15.15, 10.89, 0.94 Hz, 1 H) 551.2 22 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-2-yl]-2-methylhepta-3,5- dienyl] 4-methylpiperazine-1-carboxylate [00140] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.21 (s, 3 H) 1.31 (s, 4 H) 1.49-1.70 (m, 3 H) 1.73- 1.82 (m, 3 H) 2.08 (s, 3 H) 2.55 (s, 4 H) 3.03 (t, J = 6.34 Hz, 2 H) 3.69 (t, J = 6.27 Hz, 2 H) 3.75-3.86 (m, 1 H) 4.02 (d, J = 6.78 Hz, 2 H) 4.45 (s, 2 H) 4.61-4.61 (m, 1 H) 5.08 (s, 2 H) 5.58 (dd, J = 15.18, 9.79 Hz, 1 H) 5.64-5.79 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.37 (ddd, J = 15.15, 10.82, 1.00 Hz, 1 H) 562.6 23 3-thiazolidinecarboxylic acid [(2R,3E,5E)-6- [(2R,3S,4E,6R,7R,10R)-6-acetyloxy-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-2-yl]-2-methylhepta-3,5-dienyl] ester [00141] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.73-0.92 (m, 4 H) 0.94-1.05 (m, 3 H) 1.08- 1.34 (m, 8 H) 1.38-1.58 (m, 3 H) 1.61 (br. s., 1 H) 1.66 (s, 3 H) 1.71- 1.82 (m, 4 H) 1.87 (d, J = 15.06 Hz, 1 H) 1.97 (s, 1 H) 2.24 (s, 3 H) 2.32 (br. s., 4 H) 2.36-2.58 (m, 4 H) 3.09- 3.38 (m, 4 H)3.39-3.48 (m, 7 H) 3.55-3.73 (m, 2 H) 3.79 (s, 1 H) 3.89 (qd, J = 10.46, 6.78 Hz, 2 H) 4.05 (q, J = 7.03 Hz, 1 H) 4.95 (d, J = 9.29 Hz, 1 H) 5.09 (d, J = 10.54 Hz, 1 H) 5.23 (s, 1 H) 5.49-5.71 (m, 3 H) 6.02 (d, J = 10.54 Hz, 1 H) 6.20 (dd, J = 15.06, 10.79 Hz, 1 H) [00142] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 6.20 (dd, J = 15.1, 10.8 Hz, 1H), 6.02 (d, J = 10.8 Hz, 1H), 5.37-5.76 (m, 3H), 5.08 (d, J = 10.5 Hz, 1H), 4.95 (d, J = 9.5 Hz, 1H), 4.40 (br. s., 1H), 3.81-4.00 (m, 2H), 3.64-3.73 (m, 1H), 3.10-3.56 (m, 9H), 2.38-2.62 (m, 4H), 2.24 (s, 3H), 1.81-1.99 (m, 3H), 1.57-1.77 (m, 5H), 1.39-1.52 (m, 1H), 1.17 (s, 3H), 1.09-1.37 (m, 5H), 1.00 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H) 622.7 25 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00143] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 6.21 (dd, J = 15.1, 10.8 Hz, 1H), 6.02 (d, J = 10.8 Hz, 1H), 5.50-5.70 (m, 3H), 5.23 (s, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.95 (d, J = 9.3 Hz, 1H), 3.80- 4.02 (m, 3H), 3.48-3.74 (m, 4H), 3.44 (br. s., 6H), 3.24-3.38 (m, 1H), 2.36-2.59 (m, 5H), 2.32 (br. s., 4H), 2.25 (s, 4H), 1.87-2.08 (m, 2H), 1.58-1.82 (m, 7H), 1.41-1.57 (m, 2H), 1.19-1.36 (m, 3H), 1.17 (s, 3H), 1.08 (br. s., 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H) 636.5 26 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine- 1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00144] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.15-7.24 (m, 4H), 6.23 (dd, J = 14.7, 10.4 Hz, 1H), 6.03 (d, J = 11.0 Hz, 1H), 5.49- 5.69 (m, 2H), 5.08 (d, J = 10.5 Hz, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.65 (d, J = 16.3 Hz, 3H), 3.89-4.08 (m, 2H), 3.67 (br. s., 1H), 3.35-3.49 (m, 4H), 2.36-2.63 (m, 3H), 2.30 (br. s., 3H), 2.23 (s, 3H), 1.97 (s, 1H), 1.87 (s, 1H), 1.55-1.73 (m, 4H), 1.40-1.55 (m, 2H), 1.09-1.32 (m, 5H), 0.97- 1.09 (m, 3H), 0.81 (d, J = 6.5 Hz, 3H) 654.5 27 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10- dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1- carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]- 2-methylhepta-3,5-dienyl] 1,3-dihydroisoindole-2- carboxylate [00145] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.63 (d, J = 8.0 Hz, 1H), 7.25-7.53 (m, 2H), 6.12-6.36 (m, 1H), 6.03 (s, 1H), 6.00 (s, 1H), 5.41-5.67 (m, 2H), 5.04-5.16 (m, 1H), 4.75-5.03 (m, 1H), 4.35- 4.54 (m, 1H), 3.89 (d, J = 6.5 Hz, 1H), 3.60-3.77 (m, 1H), 3.54 (d, J = 11.0 Hz, 1H), 3.44 (br. s., 1H), 3.38 (br. s., 1H), 3.05-3.32 (m, 1H), 2.69-2.92 (m, 1H), 2.36-2.62 (m, 2H), 2.22- 2.36 (m, 2H), 2.07-2.21 (m, 1H), 1.91-2.06 (m, 1H), 1.87 (d, J = 10.5 Hz, 1H), 1.55-1.76 (m, 3H), 1.13- 1.41 (m, 4H), 0.94-1.13 (m, 3H), 0.66-0.93 (m, 3H) 652.8 28 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10- dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1- carbonyl)oxy-12-oxo-1-oxacyclododec-4-en-2-yl]- 2-methylhepta-3,5-dienyl] indole-1-carboxylate [00146] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.99-1.12 (m, 3 H) 1.02-1.10 (m, 6 H) 1.16 (d, J = 5.65 Hz, 1 H) 1.24-1.25 (m, 3 H) 1.28-1.42 (m, 2 H) 1.49-1.66 (m, 5 H) 1.74 (d, J = 4.14 Hz, 3 H) 1.92 (m, 1 H) 2.34 (br. s., 3 H) 2.38- 2.48 (m, 4 H) 2.49-2.64 (m, 4 H) 3.23-3.38 (m, 1 H) 3.42-3.62 (m, 6 H) 3.62-3.79 (m, 2 H) 3.98 (d, J = 6.40 Hz, 2 H) 5.02 (d, J = 9.41 Hz, 1 H) 5.15 (d, J = 10.67 Hz, 1 H) 5.57- 5.73 (m, 3 H) 6.06-6.12 (m, 1 H) 6.28 (dd, J = 16.31, 11.04 Hz, 1 H) 650.5 29 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6S)-7-[2-(1-hydroxyethyl)pyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00147] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.76-1.00 (d, , J = 6.53 Hz 3 H) 1.01-1.12 (d, J = 6.78 Hz, 3 H) 1.23 (s, 3 H) 1.26 (s, 6 H) 1.28-1.43 (m, 4 H) 1.47-1.62 (m, 1 H) 1.72 (s, 3 H) 1.75-1.94 (m, 3 H) 2.51 (s, 3 H) 2.51-2.62 (m, 4 H) 2.74 (br. s., 4 H) 3.41 (m, 1 H) 3.49 (m, 1H) 3.66 (br. s., 4 H) 3.72 (m, 1 H) 3.70-3.82 (m, 2 H) 3.85- 4.05 (m, 2 H) 5.02 (d, J = 9.29 Hz, 1 H) 5.15 (d, J = 10.79 Hz, 1 H) 5.58- 5.73 (m, 3 H) 6.08 (d, J = 10.16 Hz, 1 H) 6.25 (m, 1 H) 634.3 30 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2- dimethylpyrrolidine-1-carbonyl)oxy-6-methylhepta- 2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo- 1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1- carboxylate [00148] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.13 (d, J = 6.27 Hz, 3 H) 1.16 (d, J = 6.40 Hz, 3 H) 1.24 (s, 3 H) 1.36-1.46 (m, 2 H) 1.50-1.71 (m, 4 H) 1.76 (s, 3 H) 2.07-2.23 (m, 2 H) 2.51-2.70 (m, 7 H) 2.92 (br. s., 4 H) 3.50-3.90 (m, 5 H) 3.91-4.03 (m, 4 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.61 (dd, J = 15.18, 9.66 Hz, 1 H) 5.65-5.79 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.37 (dd, J = 14.93, 10.79 Hz, 1 H) 634.5 31 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)- 2,5-dimethylpyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00149] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.79 (br. s., 1H), 7.45 (s, 1H), 7.19 (s, 3H), 7.08 (d, J = 7.5 Hz, 2H), 6.77-7.00 (m, 1H), 6.13-6.37 (m, 1H), 6.04 (m, 2H), 5.49-5.70 (m, 3H), 5.23 (s, 1H), 5.02-5.16 (m, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.09-4.37 (m, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.83-3.99 (m, 2H), 3.65 (d, J = 19.3 Hz, 1H), 3.34-3.50 (m, 4H), 3.05 (t, J = 8.5 Hz, 2H), 2.64 (br. s., 1H), 2.37-2.60 (m, 3H), 2.30 (br. s., 3H), 2.23 (s, 3H), 1.98 (s, 1H), 1.87 (s, 1H), 1.81 (s, 1H), 1.57- 1.70 (m, 4H), 1.40-1.57 (m, 3H), 1.11-1.31 (m, 5H), 1.05 (d, J = 6.5 Hz, 3H), 0.70-0.92 (m, 3H) 654.5 [00150] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.05- 1.14 (m, 3 H) 1.24 (s, 3 H) 1.34- 1.46 (m, 2 H) 1.53-1.71 (m, 2 H) 1.76 (s, 3 H) 1.95-2.30 (m, 2 H) 2.55 (br. s., 5 H) 2.57-2.69 (m, 2 H) 2.74 (br. s., 4 H) 3.40-3.52 (m, 2 H) 3.53-3.86 (m, 7 H) 3.91-4.10 (m, 2 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.25 (dt, J = 52.95, 3.33 Hz, 1 H) 5.60 (dd, J = 15.18, 9.79 Hz, 1 H) 5.65-5.79 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.31-6.43 (m, 1 H) 625.6 33 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3- fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta- 2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo- 1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1- carboxylate [00151] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.35- 1.45 (m, 2 H) 1.54-1.71 (m, 2 H) 1.77 (s, 3 H) 1.81-2.10 (m, 4 H) 2.46 (s, 3 H) 2.54 (d, J = 3.64 Hz, 2 H) 2.62 (br. s., 6 H) 2.72 (br. s., 1 H) 3.35-3.47 (m, 3 H) 3.52-3.74 (m, 4 H) 3.78-3.85 (m, 1 H) 4.00 (d, J = 5.14 Hz, 3 H) 4.27-4.54 (m, 2 H) 4.96 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.71 (s, 3 H) 6.12 (d, J = 10.16 Hz, 1 H) 6.37 (dd, J = 15.31, 10.92 Hz, 1 H) 639.5 34 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2- (fluoromethyl)pyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00152] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.65 Hz, 6 H) 1.08 (d, J = 6.65 Hz, 1 H) 1.14 (br. s., 1 H) 1.23 (s, 3 H) 1.27-1.42 (m, 3 H) 1.45-1.64 (m, 1 H) 1.72 (s, 3 H) 1.73-1.93 (m, 2 H) 1.75-1.93 (m, 15 H) 2.26-2.35 (m, 2 H) 2.35 (s, 3 H) 2.45 (br. s., 4 H) 2.48-2.74 (m, 5 H) 3.39 (m, 1 H) 3.45 (m, 1 H) 3.54 (t, J = 4.89 Hz, 4 H) 3.70-3.78 (m, 1 H) 4.01 (m, 1 H) 4.11 (m, 1 H) 4.36 (d, J = 5.52 Hz, 2 H) 5.02 (d, J = 9.41 Hz, 1 H) 5.15 (d, J = 10.67 Hz, 1 H) 5.57-5.75 (m, 3 H) 6.08 (d, J = 10.67 Hz, 1 H) 6.19- 6.41 (m, 1 H) 648.4 [00153] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.20 (s, 3 H) 1.25- 1.39 (m, 4 H) 1.45 (d, J = 7.03 Hz, 3 H) 1.72 (d, J = 1.00 Hz, 3 H) 2.07 (br. s., 1 H) 2.09 (s, 3 H) 2.45-2.63 (m, 3 H) 3.51 (d, J = 9.41 Hz, 1 H) 3.66- 3.81 (m, 2 H) 5.08 (d, J = 9.16 Hz, 1 H) 5.15 (d, J = 10.54 Hz, 1 H) 5.60- 5.66 (m, 2 H) 5.99 (dd, J = 15.06, 7.40 Hz, 1 H) 6.11 (d, J = 11.92 Hz, 1 H) 6.27-6.35 (m, 1 H) 7.11 (ddd, J = 7.40, 4.89, 1.13 Hz, 1 H) 7.16 (d, J = 7.91 Hz, 1 H) 7.61 (t, J = 7.36 Hz, 1 H) 8.54 (d, J = 5.02 Hz, 1 H) 472.2 36 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate [00154] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86 (d, J = 6.78 Hz, 3 H) 1.20 (s, 3 H) 1.28- 1.53 (m, 4 H) 1.44 (d, J = 7.03 Hz, 3 H) 1.73 (d, J = 1.00 Hz, 3 H) 2.04- 2.12 (m, 4 H) 2.46-2.61 (m, 3 H) 3.52 (d, J = 10.92 Hz, 1 H) 3.66-3.85 (m, 2 H) 5.07 (d, J = 9.03 Hz, 1 H) 5.15 (d, J = 10.67 Hz, 1 H) 5.55-5.71 (m, 2 H) 6.00 (dd, J = 15.12, 7.47 Hz, 1 H) 6.10 (d, J = 10.79 Hz, 1 H) 6.32 (ddd, J = 15.18, 10.79, 1.13 Hz, 1 H) 7.11 (t, J = 6.13 Hz, 1 H) 7.14-7.18 (m, 1 H) 7.26 (s, 2 H) 7.61 (t, J = 7.63 Hz, 1 H) 8.54 (d, J = 5.00 Hz, 1 H) 472.2 37 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate [00155] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86-0.92 (m, 3 H) 1.21 (s, 3 H) 1.22-1.39 (m, 4 H) 1.33 (d, J = 7.15 Hz, 3 H) 1.42 (m, 3 H) 1.73 (s, 3 H) 2.07-2.11 (m, 4 H) 2.44-2.69 (m, 4 H) 3.03 (br. s., 1 H) 3.48-3.55 (m, 1 H) 3.64-3.83 (m, 3 H) 3.92-3.99 (m, 1 H) 5.08 (d, J = 8.91 Hz, 1 H) 5.15 (d, J = 10.67 Hz, 1 H) 5.63 (t, J = 8.78 Hz, 2 H) 5.94 (dd, J = 15.18, 7.65 Hz, 1 H) 6.10 (d, J = 10.55 Hz, 1 H) 6.24-6.33 (m, 1 H) 6.99-7.04 (m, 2 H) 7.57 (t, J = 7.66 Hz, 1 H) 530.3 38 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)- 6-[6-[(2R)-1-hydroxypropan-2-yl]pyridin-2- yl]hepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] acetate [00156] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.10-8.34 (m, 1H), 6.93 (s, 1H), 6.38-6.63 (m, 1H), 6.17-6.32 (m, 1H), 5.52-5.73 (m, 1H), 5.30-5.52 (m, 1H), 5.01- 5.16 (m, 1H), 4.95 (d, J = 9.3 Hz, 1H), 3.97-4.09 (m, 1H), 3.93 (br. s., 1H), 3.52 (br. s., 1H), 3.42 (br. s., 1H), 3.35 (br. s., 1H), 2.74 (t, J = 7.3 Hz, 1H), 2.54 (t, J = 7.4 Hz, 1H), 2.46 (br. s., 1H), 1.92-2.19 (m, 3H), 1.82-1.90 (m, 1H), 1.61-1.81 (m, 2H), 1.50 (br. s., 5H), 1.34-1.45 (m, 2H), 1.01-1.10 (m, 2H), 0.94 (dd, J = 6.7, 4.6 Hz, 1H), 0.64-0.90 (m, 3H) 600.6 39 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2- (dimethylamino)pyrimidin-4-yl]hepta-2,4-dien-2- yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1- carboxylate [00157] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.28- 1.41 (m, 1 H) 1.45 (d, J = 6.90 Hz, 3 H) 1.51-1.71 (m, 3 H) 1.73 (s, 3 H) 1.91 (s, 1 H), 2.42 (s, 3 H), 2.43- 2.64 (m, 6 H) 3.47 (m, 4 H) 3.58- 3.83 (m, 2 H) 5.01 (d, J = 9.54 Hz, 1 H) 5.14 (d, J = 10.67 Hz, 1 H) 5.51- 5.75 (m, 2 H) 5.99 (dd, J = 15.06, 7.53 Hz, 1 H) 6.11 (d, J = 10.79 Hz, 1 H) 6.27-6.34 (m, 1 H) 7.11 (ddd, J = 7.43, 4.86, 1.13 Hz, 1 H) 7.16 (d, J = 7.78 Hz, 1 H) 7.60 (td, J = 7.69, 1.82 Hz, 1 H) 8.54 (d, J = 5.03 Hz, 1 H) 556.3 [00158] .sup.1H NMR (CD.sub.2Cl.sub.2) δ: 8.90-9.14 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.32- 7.54 (m, 1H), 6.29-6.53 (m, 1H), 6.12 (d, J = 10.8 Hz, 1H), 5.85-6.07 (m, 1H), 5.63-5.84 (m, 1H), 5.05- 5.23 (m, 1H), 4.98 (d, J = 9.5 Hz, 1H), 3.70 (br. s., 1H), 3.48 (br. s., 2H), 3.30 (br. s., 1H), 2.44-2.65 (m, 2H), 2.35 (d, J = 8.8 Hz, 2H), 2.00- 2.20 (m, 1H), 1.82-2.00 (m, 1H), 1.70-1.80 (m, 1H), 1.64 (d, J = 11.0 Hz, 1H), 1.44-1.58 (m, 6H), 1.24- 1.43 (m, 2H), 1.20 (s, 1H), 1.12 (d, J = 5.5 Hz, 1H), 0.66-0.91 (m, 3H) 41 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhepta- 2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00159] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.72-0.88 (m, 4 H) 1.09 (d, J = 6.27 Hz, 2 H) 1.13-1.33 (m, 8 H) 1.36-1.46 (m, 4 H) 1.49 (br. s., 6 H) 1.66 (s, 3 H) 1.82 (br. s., 1 H) 2.00 (d, J = 19.32 Hz, 2 H) 2.30 (br. s., 3 H) 2.37-2.64 (m, 3 H) 3.07 (d, J = 7.28 Hz, 2 H) 3.29- 3.56 (m, 4 H) 3.67 (br. s., 1 H) 3.73- 3.95 (m, 2 H) 4.95 (d, J = 9.29 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.47-5.67 (m, 2 H) 5.93-6.16 (m, 2 H) 6.17-6.41 (m, 1 H) 6.93 (s, 1 H) 6.99-7.13 (m, 1 H) 7.45 (s, 1 H) 8.53-8.74 (m, 2 H) 557.46 42 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhepta- 2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00160] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.57 (d, J = 5.0 Hz, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 6.1 Hz, 1H), 6.34 (dd, J = 14.6, 10.3 Hz, 1H), 6.14 (d, J = 10.8 Hz, 1H), 6.02 (dd, J = 15.1, 7.5 Hz, 1H), 5.57-5.78 (m, 2H), 5.32 (s, 1H), 5.17 (d, J = 10.8 Hz, 1H), 5.04 (d, J = 9.5 Hz, 1H), 3.60-3.84 (m, 2H), 3.51 (br. s., 4H), 2.76 (br. s., 1H), 2.44-2.67 (m, 6H), 1.98 (s, 1H), 1.66-1.81 (m, 4H), 1.51-1.66 (m, 3H), 1.22-1.49 (m, 8H), 1.08 (d, J = 6.3 Hz, 5H), 0.79-1.00 (m, 3H) 584.5 43 [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-propan-2-ylpiperazine-1-carboxylate [00161] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 4.0 Hz, 1H), 7.54 (td, J = 7.7, 1.9 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H),7.05 (t, J = 6.2 Hz, 1H), 6.25 (dd, J = 14.6, 11.0 Hz, 1H), 6.04 (d, J = 11.0 Hz, 1H), 5.93 (dd, J = 15.2, 7.4 Hz, 1H), 5.46-5.70 (m, 2H), 5.08 (d, J = 10.5 Hz, 1H), 4.94 (d, J = 9.5 Hz, 1H), 3.54-3.76 (m, 2H), 3.28-3.53 (m, 4H), 2.37-2.59 (m, 5H), 1.89 (br. s., 1H), 1.57-1.71 (m, 4H), 1.42-1.57 (m, 5H), 1.33-1.39 (m, 3H), 1.14- 1.30 (m, 5H), 1.01 (br. s., 6H), 0.77- 0.93 (m, 3H) 596.6 44 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-tert-butylpiperazine-1-carboxylate [00162] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 4.9 Hz, 1H), 7.54 (td, J = 7.7, 2.0 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 7.05 (t, J = 6.2 Hz, 1H), 6.25 (ddd, J = 15.1, 10.9, 1.1 Hz, 1H), 6.04 (d, J = 10.8 Hz, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.48-5.67 (m, 2H), 5.08 (d, J = 10.5 Hz, 1H), 4.94 (d, J = 9.3 Hz, 1H), 3.58-3.73 (m, 2H), 3.36-3.52 (m, 5H), 2.33-2.57 (m, 8H), 1.89 (s, 1H), 1.73-1.83 (m, 2H), 1.57-1.69 (m, 7H), 1.42-1.57 (m, 4H), 1.15- 1.40 (m, 10H), 0.74-0.88 (m, 3H) 610.6 45 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cyclopentylpiperazine-1-carboxylate [00163] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.54 (td, J = 7.7, 1.9 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 6.1 Hz, 1H), 6.15-6.34 (m, 1H), 6.04 (d, J = 10.8 Hz, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.48-5.67 (m, 2H), 5.08 (d, J = 10.5 Hz, 1H), 4.94 (d, J = 9.5 Hz, 1H), 3.95 (dd, J = 11.3, 3.8 Hz, 2H), 3.53-3.76 (m, 2H), 3.37-3.49 (m, 5H), 3.22-3.37 (m, 2H), 2.35-2.57 (m, 7H), 1.88 (s, 1H), 1.44-1.70 (m, 11H), 1.14-1.39 (m, 8H), 0.72-0.89 (m, 3H) 626.6 46 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(oxan-4-yl)piperazine-1-carboxylate [00164] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 5.1 Hz, 1H), 7.54 (td, J = 7.7, 1.9 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 6.0 Hz, 1H), 6.25 (ddd, J = 15.2, 10.8, 1.1 Hz, 1H), 6.04 (d, J = 10.5 Hz, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.44-5.65 (m, 2H), 5.06 (d, J = 10.5 Hz, 1H), 4.83 (d, J = 9.3 Hz, 1H), 3.91-4.13 (m, 4H), 3.51-3.76 (m, 3H), 3.42 (br. s., 4H), 2.35-2.59 (m, 3H), 2.30 (s, 1H), 2.22 (br. s., 1H), 1.98 (s, 2H), 1.52-1.77 (m, 10H), 1.32-1.51 (m 9H), 1.10-1.32 (m, 9H), 0.72-0.90 (m, 3H) 650.6 47 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 6-cycloheptyl-2,6-diazaspiro[3.3]heptane-2- carboxylate [00165] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.56 (d, J = 4.9 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 6.1 Hz, 1H), 6.34 (dd, J = 15.3, 10.8 Hz, 1H), 6.13 (d, J = 11.0 Hz, 1H), 6.02 (dd, J = 15.1, 7.5 Hz, 1H), 5.57-5.74 (m, 2H), 5.16 (d, J = 10.8 Hz, 1H), 5.03 (d, J = 9.5 Hz, 1H), 3.92 (br. s., 1H), 3.69-3.83 (m, 3H), 3.53 (d, J = 11.0 Hz, 1H), 2.98 (br. s., 2H), 2.79 (br. s., 2H), 2.48-2.72 (m, 5H), 2.28 (br. s., 1H), 2.01 (br. s., 1H), 1.69-1.79 (m, 7H), 1.66 (br. s., 1H), 1.44-1.63 (m, 10H), 1.23-1.42 (m, 7H), 1.07 (br. s., 3H), 0.85-0.94 (m, 3H) 652.7 [00166] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.56 (d, J = 4.9 Hz, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 6.1 Hz, 1H), 6.33 (ddd, J = 15.1, 10.9, 1.1 Hz, 1H), 6.13 (d, J = 10.8 Hz, 1H), 6.02 (dd, J = 15.1, 7.5 Hz, 1H), 5.57-5.74 (m, 2H), 5.16 (d, J = 10.5 Hz, 1H), 5.03 (d, J = 9.3 Hz, 1H), 3.68-3.79 (m, 2H), 3.46-3.56 (m, 5H), 2.69-2.77 (m, 1H), 2.49- 2.65 (m, 3H), 2.30 (br. s., 4H), 1.97- 2.09 (m, 3H), 1.88 (quin, J = 9.1 Hz, 2H), 1.66-1.80 (m, 7H), 1.55 (t, J = 11.9 Hz, 1H), 1.22-1.47 (m, 8H), 0.87-0.93 (m, 3H) 596.6 [00167] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 6.1 Hz, 1H), 6.14-6.35 (m, 1H), 6.04 (d, J = 9.8 Hz, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.46-5.68 (m, 2H), 5.08 (d, J = 10.8 Hz, 1H), 4.94 (d, J = 9.5 Hz, 1H), 3.93 (br. s., 1H), 3.51-3.77 (m, 3H), 3.42 (s, 1H), 2.83 (d, J = 11.3 Hz, 2H), 2.73 (s, 3H), 2.37-2.60 (m, 3H), 2.20 (s, 3H), 2.04 (br. s., 1H), 1.89-2.00 (m, 3H), 1.81 (br. s., 1H), 1.46-1.73 (m, 10H), 1.14-1.39 (m, 8H), 0.75-0.86 (m, 3H) 584.6 50 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] N-methyl-N-(1-methylpiperidin-4-yl)carbamate [00168] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 4.9 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.05 (t, J = 6.2 Hz, 1H), 6.25 (ddd, J = 15.1, 10.8, 1.0 Hz, 1H), 6.05 (d, J = 10.8 Hz, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.49-5.67 (m, 2H), 5.23 (s, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.96 (d, J = 9.3 Hz, 1H), 3.54-3.71 (m, 6H), 3.34-3.48 (m, 5H), 2.39-2.58 (m, 3H), 1.97 (s, 1H), 1.85 (s, 1H), 1.59- 1.70 (m, 5H), 1.47 (t, J = 11.9 Hz, 1H), 1.15-1.39 (m, 8H), 0.77-0.86 (m, 3H) 543.5 51 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] morpholine-4-carboxylate [00169] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 4.8 Hz, 1H), 7.54 (td, J = 7.7, 1.8 Hz, 1H), 7.02-7.12 (m, 2H), 6.18- 6.31 (m, 1H), 6.06 (s, 1H), 6.03 (s, 1H), 5.93 (dd, J = 15.1, 7.5 Hz, 1H), 5.47-5.67 (m, 2H), 5.08 (d, J = 10.8 Hz, 1H), 4.91 (dd, J = 16.3, 9.5 Hz, 1H), 4.31 (br. s., 1H), 4.22 (br. s., 1H), 3.44-3.70 (m, 4H), 3.42 (br. s., 1H), 3.35 (d, J = 6.0 Hz, 1H), 3.15 (d, J = 9.8 Hz, 1H), 2.91 (d, J = 9.0 Hz, 1H), 2.69-2.80 (m, 1H), 2.61-2.69 (m, 1H), 2.32-2.57 (m, 7H), 2.00 (s, 1H), 1.93 (br. s., 1H), 1.82 (d, J = 9.8 Hz, 1H), 1.57-1.73 (m, 7H), 1.46 (t, J = 13.3 Hz, 1H), 1.14-1.39 (m, 8H), 0.73-0.87 (m, 3H) 568.5 52 [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] (1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate [00170] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.48 (d, J = 5.1 Hz, 1H), 7.69 (d, J = 5.8 Hz, 1H), 7.36-7.61 (m, 1H), 7.00-7.15 (m, 2H), 6.25 (dd, J = 15.1, 10.8 Hz, 1H), 6.04 (d, J = 10.8 Hz, 1H), 5.93 (dd, J = 15.2, 7.4 Hz, 1H), 5.48-5.69 (m, 2H), 5.08 (d, J = 10.5 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 3.53-3.79 (m, 4H), 3.31-3.53 (m, 2H), 2.36- 2.61 (m, 3H), 2.28 (br. s., 1H), 1.90 (br. s., 3H), 1.66 (s, 6H), 1.60 (br. s., 2H), 1.54 (br. s., 2H), 1.30-1.51 (m, 10H), 1.25 (d, J = 10.5 Hz, 1H), 1.14- 1.22 (m, 3H), 0.80 (d, J = 6.8 Hz, 3H) 664.9 53 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 8-cycloheptyl-3,8-diazabicyclo[3.2.1]octane-3- carboxylate [00171] .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.90 (d, J = 6.78 Hz, 3 H) 1.24-1.49 (m, 9 H) 1.51-1.64 (m, 2 H) 1.64-1.85 (m, 5 H) 2.01 (br. s.,4 H) 2.43-2.58 (m, 5 H) 2.60-2.77 (m, 4 H) 3.48-3.62 (m, 4 H) 3.62-3.82 (m, 3 H) 4.96- 5.10 (m, 1 H) 5.17 (d, J = 10.79 Hz, 1 H) 5.58-5.76 (m, 2 H) 6.01 (d, J = 7.53 Hz, 1 H) 6.04 (d, J = 7.53 Hz, 1 H) 6.12 (s, 1 H) 6.15 (s, 1 H) 6.24- 6.43 (m, 1 H) 7.10-7.22 (m, 2 H) 7.63 (td, J = 7.72, 1.88 Hz, 1 H) 8.57 (d, J = 4.85 Hz, 1 H) 570.5 54 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-methyl-1,4-diazepane-1-carboxylate [00172] .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.80- 1.00 (m, 3 H) 1.13-1.39 (m, 11 H) 1.42-1.48 (m, 3 H) 1.52-1.66 (m, 6 H) 1.66-1.88 (m,7 H) 1.99 (s, 1 H) 2.30 (br. s., 1 H) 2.46-2.66 (m, 7 H) 3.40-3.60 (m, 5 H) 3.64-3.85 (m, 2 H) 5.03 (d, J = 9.29 Hz, 1 H) 5.17 (d, J = 10.79 Hz, 1 H) 5.57-5.75 (m, 2 H) 6.00 (d, J = 7.53 Hz, 1 H) 6.04 (d, J = 7.53 Hz, 1 H) 6.12 (s, 1 H) 6.15 (s, 1 H) 6.27-6.41 (m, 1 H) 7.10-7.22 (m, 2 H) 7.63 (td, J = 7.72, 1.88 Hz, 1 H) 8.57 (d, J = 4.84 Hz, 1 H) 624.7 55 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cyclohexylpiperazine-1-carboxylate [00173] .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.88 (d, J = 6.78 Hz, 4 H) 1.20-1.46 (m, 7 H) 1.49-1.62 (m, 2 H) 1.66-1.77 (m, 5 H) 1.81 (br. s., 1 H) 1.88 (br. s., 1 H) 2.44-2.66 (m, 3 H) 2.77-2.90 (m, 4 H) 3.02 (s, 1 H) 3.39-3.50 (m, 4 H) 3.61-3.79 (m, 2 H) 5.02 (d, J = 9.54 Hz, 1 H) 5.15 (d, J = 10.54 Hz, 1 H) 5.54-5.74 (m, 2 H) 6.00 (dd, J = 15.06, 7.53 Hz, 1 H) 6.11 (d, J = 10.54 Hz, 1 H) 6.32 (ddd, J = 15.06, 10.79, 1.00 Hz, 1 H) 7.12 (t, J = 6.21 Hz, 1 H) 7.16 (d, J = 8.14 Hz, 1 H) 7.61 (t, J = 7.78 Hz, 1 H) 8.55 (d, J = 4.95 Hz, 1 H) 542.5 [00174] .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.82- 0.97 (m, 3 H) 1.25-1.37 (m, 4 H) 1.39-1.65 (m, 14 H) 1.75 (s, 7 H) 1.90 (br. s., 1 H) 2.06 (m, 1 H) 2.38 (s, 1 H) 2.49-2.77 (m, 4 H) 2.88 (br. s., 3 H) 3.40-3.62 (m, 3 H) 3.62- 3.89 (m, 4 H) 5.03 (t, J = 9.41 Hz, 1 H) 5.17 (d, J = 10.54 Hz, 1H) 5.57- 5.76 (m, 2 H) 6.02 (dd, J = 15.31, 7.53 Hz, 1 H) 6.13 (d, J = 10.79 Hz, 1 H) 6.34 (ddd, J = 15.12, 10.73, 1.00 Hz, 1 H) 7.14 (t, J = 6.17 Hz, 1H) 7.18 (d, J = 7.36 Hz, 1 H) 7.28 (s, 2 H) 7.63 (t, J = 7.75 Hz, 1 H) 8.57 (d, J = 4.98 Hz, 1 H) 652.5 [00175] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.81- 0.86 (m, 1 H) 0.88-0.93 (m, 3 H) 1.03 (d, J = 6.78 Hz, 3 H) 1.07-1.17 (m, 1 H) 1.21-1.26 (m, 6 H) 1.28- 1.34 (m, 2 H) 1.40 (t, J = 7.34 Hz, 4 H) 1.48-1.68 (m, 3 H) 1.74 (s, 3 H) 2.29-2.65 (m, 12 H) 3.10 (d, J = 7.28 Hz, 3 H) 3.42-3.57 (m, 7 H) 3.68- 3.78 (m, 1 H) 4.98-5.07 (m, 1 H) 5.12-5.19 (m, 1 H) 5.30 (s, 1 H) 5.54-5.75 (m, 3 H) 6.11 (s, 1 H) 6.28 (s, 1 H) 509.50 58 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2- yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6- yl] 4-methylpiperazine-1-carboxylate [00176] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.86 (s, 1 H) 0.93 (d, J = 6.78 Hz, 2 H) 1.23- 1.49 (m, 9 H) 1.54 (d, J = 11.80 Hz, 1 H) 1.61 (br s, 6 H) 1.65-1.77 (m, 4 H) 1.80 (br s, 2 H) 2.00 (br s, 1 H) 2.49-2.66 (m, 4 H) 2.69 (br s, 3 H) 2.80 (br s, 2 H) 3.32 (s, 1 H) 3.52 (d, J = 6.27 Hz, 1 H) 3.62-3.83 (m, 2 H) 4.15 (br s, 2 H) 5.02 (d, J = 9.29 Hz, 1 H) 5.17 (d, J = 10.79 Hz, 1 H) 5.53- 5.77 (m, 2 H) 6.01 (dd, J = 15.06, 7.53 Hz, 1 H) 6.13 (d, J = 10.79 Hz, 1 H) 6.33 (ddd, J = 15.12, 10.73, 1.25 Hz, 1 H) 7.14 (t, J = 6.11 Hz, 1 H) 7.18 (d, J = 7.56 Hz, 1 H) 7.28 (s, 3 H) 7.63 (td, J = 7.72, 1.88 Hz, 1 H) 8.57 (d, J = 4.94 Hz, 1 H) 638.34 [00177] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.90 (d, J = 6.78 Hz, 3 H) 1.25 (s, 3 H) 1.33- 1.40 (m, 2 H) 1.41-1.49 (m, 5 H) 1.55-1.62 (m, 4 H) 1.66-1.83 (m, 10 H) 1.99 (s, 1 H) 2.13-2.23 (m, 2 H) 2.43-2.70 (m, 9 H) 2.82-2.95 (m, 2 H) 3.53 (d, J = 10.92 Hz, 1 H) 3.67-3.81 (m, 2 H) 4.02-4.10 (m, 1 H) 4.97-5.07 (m, 1 H) 5.10-5.21 (m, 1 H) 5.57-5.67 (m, 1 H) 5.67- 5.76 (m, 1 H) 5.94-6.07 (m, 1 H) 6.08-6.21 (m, 1 H) 6.26-6.40 (m, 1 H) 7.10-7.22 (m, 2 H) 7.57-7.70 (m, 1 H) 8.53-8.61 (m, 1 H) 686.78 60 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-(8,8-difluoro-3-azabicyclo[3.2.1]octan-3- yl)piperidine-1-carboxylate
Compounds 61-104 (Table 2) were prepared by the method of Scheme 2.

##STR00178##

General Protocol for the Synthesis of Compounds 61-104:

[0561] Step 1: A solution of E7107 (I, 3.7 g, 5.1 mmol, 1.0 equiv.) under nitrogen in DMF (100 mL, 0.05M) at 0° C. was treated with imidazole (2.5 g, 36.1 mmol, 7.0 equiv.) and TBSCl (3.9 g, 25.7 mmol, 5.0 equiv.) was added. The reaction was allowed to warm to room temperature and stirred for 20 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was diluted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (J, 4.7 g, 5.0 mmol, 96%).

[0562] Step 2: To a solution of olefin J (4.7 g, 5.0 mmol, 1.0 equiv.) in THF:H.sub.2O (10:1, 133 mL:13 mL, 0.03M) under nitrogen at 0° C. was added osmium tetroxide (12.4 mL, 1.0 mmol, 0.2 equiv., 2.5% solution) followed by N-methylmorpholine N-oxide (1.16 g, 9.9 mmol, 2.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 13 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium sulfite, diluted with ethyl acetate, and the organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (K, 4.8 g, 4.9 mmol, 99%).

[0563] Step 3: To a solution of diol K (4.4 g, 4.5 mmol, 1.0 equiv.) in benzene (100 mL, 0.05M) under nitrogen at room temperature was added lead tetraacetate (4.0 g, 9.0 mmol, 2.0 equiv.). The reaction was stirred for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium sulfite and diluted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The desired product (L, 1.5 g, 2.3 mmol, 52%) was advanced crude.

[0564] Step 4: To a solution of the corresponding sulfone (2.5 equiv.) in THF (0.02M) under nitrogen at −78° C. was added KHMDS (2.5 equiv.) dropwise and the reaction was stirred for 10 minutes. Then aldehyde L (1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for five hours and then allowed to warm to room temperature overnight. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (M).

[0565] Step 5: A solution of silyl ether M (1.0 equiv.) in Me0H (0.02M) under nitrogen at room temperature was treated with pTsOH (2.0 equiv.). The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then diluted with ethyl acetate and washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by preparative TLC (dichloromethane/methanol as eluant) to afford the desired product (61-104). [0566] Exemplified Protocol for the Synthesis of Compound 63

[0567] Steps 1-3 as above.

[0568] Step 4: To a solution of (S)-2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl pyrrolidine-1-carboxylate (45.0 mg, 0.12 mmol, 2.5 equiv.) in THF (2.0 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.23 mL, 0.12 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 10 minutes. Then aldehyde L (30.0 mg, 0.05 mmol, 1.0 equiv.) in THF (0.2 mL) was added dropwise. The reaction was stirred at −78° C. for five hours and then allowed to warm to room temperature overnight. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (M, 35 mg, 0.04 mmol, 76%).

[0569] Step 5: A solution of silyl ether M (35.0 mg, 0.04 mmol, 1.0 equiv.) in MeOH (2.0 mL, 0.02M) under nitrogen at room temperature was treated with pTsOH (15.0 mg, 0.08 mmol, 2.0 equiv.). The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then diluted with ethyl acetate and washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by preparative TLC (dichloromethane/methanol as eluant) to afford the desired product (compound 63, 22.2 mg, 32 mmol, 80%). .sup.1H NMR (400 MHz, METHANOL-d4) δ:0.90 (d, J=6.65 Hz, 3 H) 1.09 (d, J=6.78 Hz, 3H) 1.24 (s, 3H) 1.32-1.45 (m, 2H) 1.47-1.85 (m, 15H) 1.85-1.94 (m, 4H) 1.95-2.10 (m, 2H) 2.50-2.68 (m, 4H) 2.96-3.08 (m, 4H) 3.09-3.21 (m, 1H) 3.34-3.39 (m, 4H) 3.52-3.88 (m, 5H) 3.92-4.06 (m, 2H) 4.97 (d, J=9.66 Hz, 1H) 5.07 (d, J=10.67 Hz, 1 H) 5.61 (dd, J=15.18, 9.79 Hz, 1H) 5.72 (d, J=9.79 Hz, 2H) 6.12 (dd, J=10.79, 1.00 Hz, 1H) 6.37 (ddd, J=15.12, 10.85, 0.88 Hz, 1H). MS (ES+)=688.5[M+H].sup.+.

TABLE-US-00005 TABLE 2 Compounds 61-104 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00179] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.19 (s, 2H), 6.05-6.26 (m, 1H), 5.94-6.05 (m, 1H), 5.45-5.69 (m, 3H), 5.08 (d, J = 10.5 Hz, 1H), 4.95 (d, J = 9.5 Hz, 1H), 3.67 (br. s., 2H), 3.28-3.54 (m, 8H), 2.36-2.62 (m, 7H), 2.09-2.32 (m, 3H), 1.86 (dt, J = 13.1, 6.6 Hz, 3H), 1.73-1.81 (m, 3H), 1.55-1.71 (m, 9H), 1.24-1.51 (m, 11H), 1.15-1.22 (m, 4H), 0.97 (d, J = 6.8 Hz, 3H), 0.74-0.91 (m, 3H) 686.5 61 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9- pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00180] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.69-0.86 (m, 8 H) 0.93- 1.01 (m, 2 H) 1.09-1.24 (m, 15 H) 1.29 (d, J = 4.52 Hz, 2 H) 1.37-1.53 (m, 5 H) 1.65 (s, 2 H) 1.74 (d, J = 10.79 Hz, 1 H) 1.91 (s, 1 H) 2.11 (t, J = 7.78 Hz, 1 H) 2.33-2.59 (m, 4 H) 2.61-2.73 (m, 1 H) 2.78 (s, 1 H) 2.91-3.07 (m, 1 H) 3.11 (t, J = 7.28 Hz, 1 H) 3.32-3.41 (m, 1 H) 3.44 (br. s., 1 H) 3.60-3.76 (m, 1H) 3.86 (br. s., 1 H) 3.92-4.12 (m, 1 H) 4.47 (s, 1 H) 4.95 (d, J = 10.79 Hz, 1 H) 5.39 (s, 1 H) 5.40-5.42 (m, 1 H) 5.43-5.70 (m, 2H) 6.00 (d, J = 9.79 Hz, 1 H) 6.18-6.35 (m, 1 H) 62 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6S)-6-methyl-7- [methyl(propyl)carbamoyl]oxyhepta-2,4-dien-2-yl]- 12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00181] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.32- 1.45 (m, 2 H) 1.47-1.85 (m, 15 H) 1.85-1.94 (m, 4 H) 1.95-2.10 (m, 2 H) 2.50-2.68 (m, 4 H) 2.96-3.08 (m, 4 H) 3.09-3.21 (m, 1 H) 3.34-3.39 (m, 4 H) 3.52-3.88 (m, 5 H) 3.92- 4.06 (m, 2 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.61 (dd, J = 15.18 9.79 Hz, 1 H) 5.72 (d, J = 9.79 Hz, 2 H) 6.12 (dd, J = 10.79, 1.00 Hz, 1 H) 6.37 (ddd, J = 15.12, 10.85, 0.88 Hz, 1 H) 688.5 63 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1- carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00182] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.65 Hz, 3 H) 1.10 (d, J = 6.90 Hz, 3 H) 1.24 (s, 3 H) 1.34- 1.47 (m, 2 H) 1.49-2.11 (m, 20 H) 2.12-2.14 (m, 1 H) 2.50-2.68 (m, 4 H) 3.17 (br. s., 4 H) 3.39-3.53 (m, 4 H) 3.61-4.06 (m, 7 H) 4.31-4.45 (m, 1 H) 4.98 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.56-5.81 (m, 3 H) 6.12 (d, J = 10.29 Hz, 1 H) 6.37 (dd, J = 15.18, 10.79 Hz, 1 H) 704.5 64 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00183] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.90 Hz, 3 H) 1.10 (d, J = 6.78 Hz, 3 H) 1.20-1.26 (m, 3 H) 1.29-1.43 (m, 4 H) 1.45-1.88 (m, 17 H) 1.91-2.01 (m, 5 H) 2.52-2.65 (m, 4 H) 2.77-2.99 (m, 5 H) 3.36- 3.46 (m, 2 H) 3.46-4.06 (m, 10 H) 4.96 (d, J = 9.54 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.60 (dd, J = 14.93, 9.91 Hz, 1 H) 5.65-5.78 (m, 2 H) 6.12 (d, J = 11.42 Hz, 1 H) 6.37 (dd, J = 14.87, 10.60 Hz, 1 H) 718.5 65 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine- 1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00184] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.90 Hz, 3 H) 1.24 (s, 3 H) 1.43- 1.95 (m, 28 H) 2.03-2.10 (m, 2 H) 2.56-2.71 (m, 4 H) 3.19 (br. s., 5 H) 3.36-3.40 (m, 4 H) 3.50 (d, J = 1.76 Hz, 1 H) 3.63-3.92 (m, 4 H) 3.93- 4.03 (m, 2 H) 4.78 (d, J = 3.39 Hz, 1 H) 4.97 (d, J = 4.77 Hz, 1 H) 4.99 (d, J = 5.77 Hz, 1 H) 5.58-5.82 (m, 3 H) 6.13 (d, J = 10.79 Hz, 1 H) 6.37 (ddd, J = 15.15, 10.89, 0.82 Hz, 1 H) 785.6 66 [(2S,3S,4E,6S,7S,10R)-7-hydroxy-3,7-dimethyl-2- [(2E,4E,6R)-6-methyl-7-(pyrrolidine-1- carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-10- (pyrrolidine-1-carbonyloxy)-1-oxacyclododec-4-en- 6-yl] 4-cycloheptylpiperazine-1-carboxylate [00185] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.13-1.21 (m, 3 H) 1.24 (s, 3 H) 1.36-1.73 (m, 13 H) 1.75-1.90 (m, 6 H) 1.92-2.11 (m, 4 H) 2.55 (br. s., 4 H) 3.13 (br. s., 4 H) 3.21-3.29 (m, 1 H) 3.36-3.42 (m, 2 H) 3.59-4.06 (m, 8 H) 4.98 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.54 Hz, 1 H) 5.56-5.80 (m, 3 H) 6.12 (d, J = 11.17 Hz, 1 H) 6.37 (dd, J = 14.74, 10.73 Hz, 1 H) 702.5 67 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2- methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00186] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.92 (d, J = 6.78 Hz, 3 H) 1.02-1.14 (m, 6 H) 1.24- 1.27 (m, 3 H) 1.29-1.30 (m, 1 H) 1.33- 1.61 (m, 14 H) 1.64-2.09 (m, 21 H) 2.19-2.33 (m, 1 H) 2.45-2.73 (m, 9 H) 2.80-2.99 (m, 1 H) 3.19-3.41 (m, 1 H) 3.54 (br. s., 7 H) 3.80 (s, 1 H) 3.92- 4.04 (m, 2 H) 5.04 (d, J = 9.41 Hz, 1 H) 5.18 (d, J = 10.67 Hz, 1 H) 5.69 (s, 3 H) 6.11 (d, J = 10.67 Hz, 1 H) 6.29 (dd, J = 14.93, 10.92 Hz, 1 H) 702.4 68 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3- methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00187] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.92 (d, J = 6.65 Hz, 3 H) 1.00-1.14 (m, 6 H) 1.25 (s, 3 H) 1.28-1.65 (m, 13 H) 1.67-1.86 (m, 6 H) 1.91-2.13 (m, 3 H) 2.16- 2.32 (m, 1 H) 2.37-2.90 (m, 25 H) 2.94-3.07 (m, 5 H) 3.14-3.41 (m, 3 H) 3.41-3.67 (m, 2 H) 3.80 (br. s., 5 H) 3.89-4.08 (m, 2 H) 5.03 (d, J = 9.16 Hz, 1 H) 5.18 (d, J = 10.67 Hz, 1 H) 5.70 (d, J = 9.29 Hz, 3 H) 6.06-6.15 (m, 1 H) 6.24-6.35 (m, 1 H) 702.3 69 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3- methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00188] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.92 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.27 Hz, 3 H) 1.25 (s, 3 H) 1.28-1.42 (m, 2 H) 1.44-1.65 (m 9 H) 1.66-1.81 (m, 6 H) 1.84- 2.05 (m, 5 H) 2.10-2.71 (m, 19 H) 2.80 (t, J = 4.77 Hz, 4 H) 2.90-3.02 (m, 1 H) 3.51 (s, 2 H) 3.68 (t, J = 4.64 Hz, 4 H) 3.74-3.84 (m, 1 H) 3.74-3.84 (m, 1 H) 3.92-4.13 (m, 2 H) 4.21-4.45 (m, 1 H) 5.03 (d, J = 9.41 Hz, 1 H) 5.16 (d, J = 10.67 Hz, 1 H) 5.42-5.56 (m, 1 H) 5.57-5.82 (m, 3 H) 6.10 (d, J = 11.04 Hz, 1 H) 6.29 (dd, J = 15.06, 11.04 Hz, 1 H) 731.5 70 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2- carbamoylpyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00189] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.96 (br. s., 24 H) 2.54 (d, J = 3.64 Hz, 4 H) 3.10 (br. s., 5 H) 3.36-3.42 (m, 2 H) 3.44-3.53 (m, 1 H) 3.57-3.87 (m, 4 H) 3.89-4.09 (m, 3 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.79 Hz, 1 H) 5.71 (s, 3 H) 6.11 (d, J = 11.04 Hz, 1 H) 6.37 (dd, J = 14.93, 11.42 Hz, 1 H) 732.4 71 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2- [(2E,4E,6S)-7-[(2R)-2-(methoxymethyl)pyrrolidine- 1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00190] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.15 (dd, J = 11.80, 6.40 Hz, 3 H) 1.23 (s, 6 H) 1.58 (d, J = 10.42 Hz, 15 H) 1.76 (s, 5 H) 1.83- 2.21 (m, 4 H) 2.47-2.81 (m, 9 H) 3.98 (d, J = 6.78 Hz, 9 H) 4.96 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.58 (dd, J = 15.18, 9.91 Hz, 1 H) 5.64-5.78 (m, 2 H) 6.12 (d, J = 10.67 Hz, 1 H) 6.37 (dd, J = 15.06, 10.79 Hz, 1 H) 716.4 72 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)- 2,5-dimethylpyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00191] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.35- 1.44 (m, 2 H) 1.76 (s, 16 H) 1.96- 2.29 (m, 4 H) 2.51-2.71 (m, 4 H) 3.02- 3.14 (m, 4 H) 3.13-3.26 (m, 2 H) 3.40-4.13 (m, 11 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.06 (d, J = 10.79 Hz, 1 H) 5.25 (d, J = 52.70 Hz, 1 H) 5.60 (dd, J = 15.18, 9.66 Hz, 1 H) 5.65-5.81 (m, 2 H) 6.12 (d, J = 10.42 Hz, 1 H) 6.37 (dd, J = 14.87, 10.85 Hz, 1 H) 706.4 73 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3- fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta- 2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo- 1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00192] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.65 Hz, 3 H) 1.24 (s, 3 H) 1.35- 1.46 (m, 2 H) 1.76 (s, 15 H) 1.78- 1.88 (m, 2 H) 1.95-2.07 (m, 3 H) 2.51- 2.69 (m, 4 H) 3.09 (br. s., 4 H) 3.16- 3.25 (m, 2 H) 3.39-4.10 (m, 11 H) 4.98 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.25 (dt, J = 53.33, 3.64 Hz, 1 H) 5.61 (dd, J = 15.18, 9.79 Hz, 1 H) 5.72 (m, J = 9.54 Hz, 2 H) 6.12 (d, J = 10.04 Hz, 1 H) 6.31-6.43 (m, 1 H) 706.4 74 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3- fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta- 2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo- 1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00193] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.89-0.92 (m, 3 H) 1.06-1.14 (m, 3 H) 1.24 (s, 3 H) 1.34-1.46 (m, 6 H) 1.76 (s, 24 H) 2.55 (br. s., 4 H) 3.06 (br. s., 5 H) 3.13-3.22 (m, 2 H) 3.38- 3.52 (m, 1 H) 3.54-4.12 (m, 8 H) 4.97 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.79 Hz, 1 H) 5.57-5.81 (m, 3 H) 6.12 (d, J = 10.42 Hz, 1 H) 6.31-6.46 (m, 1 H) 716.5 75 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2- dimethylpyrrolidine-1-carbonyl)oxy-6-methylhepta- 2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo- 1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00194] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.72-0.93 (m, 3 H) 1.01 (d, J = 2.26 Hz, 4 H) 1.12- 1.32 (m, 7 H) 1.39-1.56 (m, 8 H) 1.60- 1.72 (m, 5 H) 1.73-1.83 (m, 3 H) 1.99 (d, J = 6.27 Hz, 2 H) 2.38-2.58 (m, 3 H) 2.82 (s, 1 H) 2.90 (d, J = 5.77 Hz, 3 H) 3.02-3.19 (m, 1 H) 3.30 (dt, J = 12.86, 6.24 Hz, 4 H) 3.64-3.77 (m, 4 H) 3.77-3.84 (m, 2 H) 4.94 (d, J = 9.29 Hz, 2 H) 5.01-5.18 (m, 2 H) 5.41 (d, J = 12.30 Hz, 1 H) 5.47-5.67 (m, 2 H) 5.71 (d, J = 15.31 Hz, 1 H) 6.02 (d, J = 11.29 Hz, 1 H) 6.07-6.25 (m, 1 H) 6.40-6.50 (m, 1 H) 8.24 (br. s., 1 H) 702.4 76 [(2S,3S,4E,6R,7R,10R)-2-[(2E,4E)-6,6-dimethyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]- 7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00195] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.65-0.92 (m, 4 H) 0.94-1.22 (m, 9 H) 1.23-1.33 (m, 3 H) 1.36-1.57 (m, 8 H) 1.59 (br. s., 1 H) 1.61-1.69 (m, 4 H) 1.79 (br. s., 5 H) 1.87-2.04 (m, 3 H) 2.10 (s, 3 H) 2.25 (br. s., 6 H) 2.33-2.52 (m, 5 H) 2.59 (d, J = 10.54 Hz, 2 H) 2.70- 2.86 (m, 3 H) 2.89 (s, 1 H) 2.95 (d, J = 3.51 Hz, 1 H) 2.99-3.07 (m, 1 H) 3.10 (s, 1 H) 3.15 (s, 1 H) 3.22-3.34 (m, 4 H) 3.35-3.52 (m, 1 H) 3.54- 3.68 (m, 3 H) 3.70 (br. s., 1 H) 3.74- 3.98 (m, 2 H) 4.76 (br. s., 1 H) 4.85- 5.02 (m, 2 H) 5.40 (s, 1 H) 5.46-5.75 (m, 3 H) 5.93-6.06 (m, 1 H) 6.07- 6.22 (m, 1 H) 799.48 [00196] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (dd, J = 6.65, 2.76 Hz, 3 H) 1.09 (dd, J = 6.78, 2.26 Hz, 3 H) 1.24 (s, 3 H) 1.36-1.44 (m, 2 H) 1.46-2.10 (m, 22 H) 2.15-2.36 (m, 1 H) 2.51- 2.69 (m, 2 H) 3.15 (d, J = 1.51 Hz, 4 H) 3.23-3.30 (m, 1 H) 3.41-3.60 (m, 2 H) 3.63-4.08 (m, 7 H) 4.21-4.30 (m, 1 H) 4.98 (d, J = 9.54 Hz, 1 H) 5.07 (d, J = 10.54 Hz, 1 H) 5.61 (dd, J = 15.06, 9.66 Hz, 1 H) 5.71 (s, 2 H) 6.13 (s, 1 H) 6.30-6.45 (m, 1 H) 732.5 78 (2R)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4- cycloheptylpiperazine-1-carbonyl)oxy-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-2-yl]-2-methylhepta-3,5- dienoxy]carbonylpyrrolidine-2-carboxylic acid [00197] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.05- 1.17 (m, 3 H) 1.24 (s, 3 H) 1.33-1.45 (m, 2 H) 1.48-1.89 (m, 16 H) 1.96- 2.10 (m, 2 H) 2.51-2.71 (m, 6 H) 3.12 (br. s., 4 H) 3.59-3.88 (m, 9 H) 4.04 (br. s., 2 H) 4.98 (d, J = 9.66 Hz, 1 H) 5.06 (d, J = 10.67 Hz, 1 H) 5.61 (dd, J = 15.18, 9.79 Hz, 1 H) 5.66-5.79 (m, 2 H) 6.12 (d, J = 10.67 Hz, 1 H) 6.39 (dd, J = 15.18, 10.92 Hz, 1 H) 702.6 79 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-(3- oxopyrrolidine-1-carbonyl)oxyhepta-2,4-dien-2-yl]- 12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00198] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 5.90 Hz, 3 H) 1.09 (t, J = 5.65 Hz, 3 H) 1.24 (s, 3H) 1.32- 1.45 (m, 2 H) 1.50-1.89 (m, 16 H) 2.01-2.12 (m, 2 H) 2.20 (q, J = 7.19 Hz, 2 H) 2.53-2.70 (m, 4 H) 3.19 (br. s., 4 H) 3.35-3.44 (m, 2 H) 3.81 (d, J = 5.40 Hz, 7 H) 3.99 (d, J = 6.53 Hz, 2 H) 4.55-4.70 (m, 4 H) 4.98 (d, J = 9.54 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.72 (d, J = 9.66 Hz, 3 H) 6.08-6.18 (m, 1 H) 6.30-6.43 (m, 1 H) 730.5 80 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4- cycloheptylpiperazine-1-carbonyl)oxy-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-2-yl]-2-methylhepta-3,5-dienyl] 2-oxa-7- azaspiro[3.4]octane-7-carboxylate [00199] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.77-0.89 (m, 6 H) 1.00 (d, J = 6.78 Hz, 3 H) 1.12 (d, J = 6.02 Hz, 1 H) 1.15-1.22 (m,4 H) 1.25-1.28 (m, 1 H) 1.29-1.54 (m, 11 H) 1.55-1.81 (m, 14 H) 1.90 (br. s., 1 H) 1.97 (s, 1 H) 2.37-2.58 (m, 8 H) 3.21-3.38 (m, 5 H) 3.38-3.49 (m, 4 H) 3.56-3.75 (m, 1 H) 3.80-3.98 (m, 2 H) 4.05 (d, J = 7.28 Hz, 1 H) 4.95 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.50-5.69 (m, 3 H) 6.01 (d, J = 10.79 Hz, 1 H) 6.10-6.30 (m, 1 H) 688.65 81 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1- carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00200] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.47-0.61 (m, 2 H) 0.63-0.90 (m, 6 H) 1.02 (s, 1 H) 1.15-1.28 (m, 5 H) 1.30-1.51 (m, 9 H) 1.56 (br. s., 1 H) 1.59-1.68 (m, 5 H) 1.70-1.87 (m, 5 H) 2.35-2.60 (m, 8 H) 2.63-2.75 (m, 2 H) 2.81 (d, J = 0.75 Hz, 1 H) 2.89 (s, 1 H) 3.17- 3.39 (m, 4 H) 3.42-3.56 (m, 4 H) 3.57- 3.73 (m, 1 H) 3.80 (d, J = 11.04 Hz, 1 H) 3.90-4.13 (m, 2 H) 4.94 (d, J = 9.29 Hz, 1 H) 4.95 (d, J = 9.29 Hz, 1 H) 5.07 (d, J = 10.54 Hz, 1 H) 5.14 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.44-5.66 (m, 3 H) 6.00 (d, J = 11.04 Hz, 1 H) 6.17 (d, J = 10.79 Hz, 1 H) 6.23 (m, J = 10.79 Hz, 1 H) 6.56 (d, J = 11.54 Hz, 1 H) 700.52 [00201] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.78 Hz, 3 H) 1.10 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.34- 1.45 (m, 2 H) 1.49-1.90 (m, 16 H) 2.00-2.11 (m, 2 H) 2.51-2.70 (m, 4 H) 3.09-3.21 (m, 4 H) 3.23-3.30 (m, 1 H) 3.37 (s, 1 H) 3.54-3.62 (m, 2 H) 3.63-4.04 (m, 7 H) 4.07 (d, J = 3.26 Hz, 2 H) 4.98 (d, J = 9.66 Hz, 1 H) 5.07 (d, J = 10.79 Hz 1 H) 5.57-5.66 (m, 1 H) 5.67-5.79 (m, 2 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.39 (dd, J = 14.74, 10.35 Hz, 1 H) 720.5 83 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S,4R)- 3,4-dihydroxypyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00202] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.78 (d, J = 6.78 Hz, 3 H) 0.97 (d, J = 6.65 Hz, 3 H) 1.06-1.17 (m, 3 H) 1.23-1.32 (m, 2 H) 1.33-1.76 (m, 16 H) 1.82-1.93 (m, 2 H) 1.94-2.10 (m, 4 H) 2.35-2.57 (m, 4 H) 2.80- 3.07 (m, 6 H) 3.24-3.29 (m, 1 H) 3.31- 3.74 (m, 8 H) 3.86 (d, J = 6.53 Hz, 2 H) 4.85 (d, J = 9.66 Hz, 1 H) 4.95 (d, J = 10.79 Hz, 1 H) 5.49 (dd, J = 15.18, 9.79 Hz, 1 H) 5.53-5.70 (m, 2 H) 6.00 (d, J = 10.67 Hz, 1 H) 6.25 (dd, J = 14.87, 11.36 Hz, 1 H) 732.6 84 (3S)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4- cycloheptylpiperazine-1-carbonyl)oxy-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-2-yl]-2-methylhepta-3,5- dienoxy]carbonylpyrrolidine-3-carboxylic acid [00203] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.88 (d, J = 6.78 Hz, 3 H) 1.06 (d, J = 6.90 Hz, 3 H) 1.21 (s, 3 H) 1.31- 1.67 (m, 13 H) 1.69-1.98 (m, 8 H) 2.16 (d, J = 8.53 Hz, 1 H) 2.36 (s, 3 H) 2.39 (s, 3 H) 2.47-2.67 (m, 4 H) 2.75- 3.02 (m, 6 H) 3.11-3.23 (m, 1 H) 3.49-3.74 (m, 6 H) 3.78 (d, J = 3.39 Hz, 1 H) 3.97 (d, J = 6.27 Hz, 2 H) 4.56 (br. s., 2 H) 4.93 (d, J = 9.66 Hz, 1 H) 5.04 (d, J = 10.67 Hz, 1 H) 5.51-5.62 (m, 1 H) 5.63-5.77 (m, 2 H) 6.09 (d, J = 11.29 Hz, 1 H) 6.34 (dd, J = 14.81, 10.79 Hz, 1 H) 731.6 85 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S)-3- (dimethylamino)pyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00204] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.88 (d, J = 6.78 Hz, 3 H) 1.06 (d, J = 6.90 Hz, 3 H) 1.21 (s, 3 H) 1.31- 1.67 (m, 13 H) 1.69-1.98 (m, 8 H) 2.16 (d, J = 8.53 Hz, 1 H) 2.36 (s, 3 H) 2.39 (s, 3 H) 2.47-2.67 (m, 4 H) 2.75- 3.02 (m, 6 H) 3.11-3.23 (m, 1 H) 3.49-3.74 (m, 6 H) 3.78 (d, J = 3.39 Hz, 1 H) 3.97 (d, J = 6.27 Hz, 2 H) 4.56 (br. s., 2 H) 4.93 (d, J = 9.66 Hz, 1 H) 5.04 (d, J = 10.67 Hz, 1 H) 5.51-5.62 (m, 1 H) 5.63-5.77 (m, 2 H) 6.09 (d, J = 11.29 Hz, 1 H) 6.34 (dd, J = 14.81, 10.79 Hz, 1 H) 686.6 86 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,5- dihydropyrrole-1-carbonyloxy)-6-methylhepta-2,4- dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00205] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.24 (s, 3 H) 1.35- 1.46 (m, 2 H) 1.47-1.73 (m, 11 H) 1.74-2.09 (m, 11 H) 2.50-2.69 (m, 4 H) 2.96-3.07 (m, 4 H) 3.07-3.18 (m, 1 H) 3.37 (s, 2 H) 3.53-3.88 (m, 5 H) 3.92-4.06 (m, 3 H) 4.29-4.51 (m, 2 H) 4.95-5.01 (m, 1 H) 5.04-5.10 (m, 1 H) 5.55-5.81 (m, 3 H) 6.12 (d, J = 10.42 Hz, 1 H) 6.37 (dd, J = 15.00, 10.98 Hz, 1 H) 720.6 87 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2- (fluoromethyl)pyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00206] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.78 (d, J = 6.65 Hz, 3 H) 0.97 (d, J = 6.78 Hz, 3 H) 1.12 (s, 3 H) 1.24- 1.31 (m, 2 H) 1.34 (s, 9 H) 1.38-1.63 (m, 10H) 1.65 (d, J = 0.88 Hz, 3 H) 1.67- 1.78 (m, 3 H) 1.89-2.06 (m, 3 H) 2.40-2.56 (m, 4 H) 3.00-3.12 (m, 5 H) 3.24-4.01 (m, 11 H) 4.86 (d, J = 9.66 Hz, 1 H) 4.95 (d, J = 10.67 Hz, 1 H) 5.50 (m, J = 9.66 Hz, 1 H) 5.54-5.67 (m, 2 H) 6.00 (d, J = 10.67 Hz, 1 H) 6.25 (dd, J = 15.06, 10.79 Hz, 1 H) 803.7 88 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-[(2- methylpropan-2-yl)oxycarbonylamino]pyrrolidine- 1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00207] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.03-0.02 (m, 1 H) 0.61-0.69 (m, 1 H) 0.83 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.16 (s, 3 H) 1.28- 1.37 (m, 2 H) 1.39-1.63 (m, 13 H) 1.64-1.78 (m, 5 H) 1.83-1.95 (m, 2 H) 2.44-2.58 (m, 4 H) 2.76-2.86 (m, 6 H) 2.93 (s, 3 H) 3.28-3.34 (m, 2 H) 3.43-3.77 (m, 7 H) 3.80-3.95 (m, 2 H) 4.87-4.91 (m, 2 H) 4.97-5.02 (m, 1 H) 5.48-5.72 (m, 3 H) 6.01-6.08 (m, 1 H) 6.22-6.33 (m, 1 H) 700.5 89 [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4- cycloheptylpiperazine-1-carbonyl)oxy-7,10- dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-2-yl]-2-methylhepta-3,5-dienyl] 3- azabicyclo[3.1.0]hexane-3-carboxylate [00208] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.70-0.93 (m, 4 H) 1.00 (d, J = 6.78 Hz, 1 H) 1.12- 1.21 (m, 5 H) 1.24-1.50 (m, 14H) 1.55- 1.76 (m, 11 H) 1.90 (br. s., 2 H) 2.14 (s, 1 H) 2.36-2.57 (m, 7 H) 3.22-3.43 (m, 5 H) 3.43-3.59 (m, 1 H) 3.68 (br. s., 1 H) 4.94 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.44-5.72 (m, 2 H) 5.82 (dd, J = 15.43, 6.90 Hz, 1 H) 6.03 (d, J = 10.54 Hz, 1 H) 6.09-6.25 (m, 1 H) 7.16-7.21 (m, 3 H) 7.44 (d, J = 7.28 Hz, 1 H) 8.41 (br. s., 2 H) 638.28 90 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhepta- 2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00209] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.78 Hz, 3 H) 1.22 (s, 3 H) 1.27- 1.56 (m, 10 H) 1.45 (d, J = 6.90 Hz, 3 H) 1.65-1.71 (m, 3 H) 1.72 (s, 3 H) 1.79 (m, 2 H) 1.96 (s, 1 H) 2.43-2.64 (m, 8 H) 3.47 (m, 6 H) 3.58-3.83 (m, 2 H) 5.01 (d, J = 9.54 Hz, 1 H) 5.14 (d, J = 10.67 Hz, 1 H) 5.51-5.75 (m, 2 H) 5.99 (dd, J = 15.06, 7.53 Hz, 1 H) 6.11 (d, J = 10.79 Hz, 1 H) 6.25-6.34 (m, 1 H) 7.11 (ddd, J = 7.43, 4.86, 1.13 Hz, 1 H) 7.16 (d, J = 7.78 Hz, 1 H) 7.60 (td, J = 7.69, 1.82 Hz, 1 H) 8.54 (d, J = 5.03 Hz, 1 H) 638.5 91 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00210] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.23 (s, 3 H) 1.26- 1.55 (m, 10 H) 1.63-1.72 (m, 3 H) 1.73 (s, 3 H) 1.79 (m, 2 H) 1.96 (br. s., 1 H) 2.51 (m, 9 H) 3.49 (s, 4 H) 3.65 (d, J = 6.90 Hz, 2 H) 3.74 (m, 2 H) 5.08 (d, J = 10.92 Hz, 1 H) 5.15 (d, J = 10.67 Hz, 1 H) 5.51-5.64 (m, 1 H) 5.65- 5.76 (m, 1 H) 5.98 (dt, J = 14.74, 7.18 Hz, 1 H) 6.12 (d, J = 10.67 Hz, 1 H) 6.37 (dd, J = 14.93, 10.79 Hz, 1 H) 7.13 (dd, J = 7.47, 5.08 Hz, 1 H) 7.16 (d, J = 7.78 Hz, 1 H) 7.56-7.66 (m, 1 H) 8.53 (d, J = 4.14 Hz, 1 H) 624.3 92 [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa- 2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00211] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.01-8.23 (m, 1H), 6.14-6.29 (m, 2H), 6.03 (d, J = 11.5 Hz, 1H), 5.77-5.98 (m, 1H), 5.44-5.68 (m, 2H), 5.23 (s, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.94 (d, J = 9.3 Hz, 1H), 3.67 (br. s., 2H), 3.31-3.58 (m, 8H), 3.23 (d, J = 3.8 Hz, 1H), 2.37-2.64 (m, 6H), 2.14 (s, 1H), 1.72-1.98 (m, 6H), 1.53-1.71 (m, 8H), 1.37-1.53 (m, 8H), 1.12-1.37 (m, 10H), 0.90-1.07 (m, 1H), 0.70-0.90 (m, 4H) 708.9 93 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1- ylpyrimidin-4-yl)hepta-2,4-dien-2-yl]-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00212] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.64-0.89 (m, 4 H) 1.07-1.32 (m, 7 H) 1.32- 1.53 (m, 10 H) 1.59-1.70 (m, 5 H) 1.81 (s, 1 H) 1.89 (br. s., 2 H) 2.33- 2.56 (m, 6 H) 2.71 (br. s., 4 H) 2.76- 3.03 (m, 2 H) 3.42 (s, 1 H) 3.60 (br. s., 3 H) 3.63-3.90 (m, 2 H) 4.93 (d, J = 9.54 Hz, 1H) 5.08 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.49-5.75 (m, 2 H) 5.90 (dd, J = 15.18, 7.65 Hz, 1 H) 6.04 (d, J = 9.79 Hz, 1 H) 6.14-6.31 (m, 1 H) 8.22 (br. s., 1 H) 8.28-8.38 (m, 1 H) 8.38-8.49 (m, 2 H) 639.69 94 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-pyrazin-2-ylhepta- 2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00213] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.03-8.25 (m, 1H), 6.13-6.29 (m, 2H), 6.03 (d, J = 11.5 Hz, 1H), 5.89 (ddd, J = 15.2, 7.9, 4.8 Hz, 1H), 5.48-5.68 (m, 2H), 5.15 (s, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.77- 5.02 (m, 1H), 3.68 (br. s., 1H), 3.27- 3.53 (m, 4H), 3.08-3.13 (m, 4H), 2.34- 2.58 (m, 6H), 1.89 (br. s., 1H), 1.81 (s, 1H), 1.63-1.75 (m, 4H), 1.60 (br. s., 2H), 1.40-1.54 (m, 11H), 1.37 (br. s., 2H), 1.13-1.34 (m, 8H), 0.70-0.94 (m, 4H) 682.9 95 [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2- (dimethylamino)pyrimidin-4-yl]hepta-2,4-dien-2- yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate [00214] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.70-0.92 (m, 4 H) 1.00 (d, J = 6.53 Hz, 1 H) 1.14- 1.21 (m, 4 H) 1.24-1.27 (m, 1 H) 1.29- 1.55 (m, 14 H) 1.55-1.68 (m, 7 H) 1.72 (br. s., 2 H) 1.89 (br. s., 1 H) 2.14 (s, 1 H) 2.21-2.30 (m, 3 H) 2.34-2.60 (m, 7 H) 3.06 (s, 1 H) 3.16 (s, 1 H) 3.42 (br. s., 5 H) 3.59 (t, J = 7.15 Hz, 1 H) 3.67 (br. s., 1 H) 4.94 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.54 Hz, 1 H) 5.23 (s, 1 H) 5.48-5.74 (m, 2 H) 5.92 (ddd, J = 15.06, 7.53, 4.77 Hz, 1 H) 6.04 (d, J = 10.54 Hz, 1 H) 6.13-6.30 (m, 1 H) 6.78-6.99 (m, 2 H) 8.32 (dd, J = 5.02, 2.26 Hz, 1 H) [00215] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.73-0.88 (m, 4 H) 1.06 (br. s., 1 H) 1.07 (br. s., 1 H) 1.12 (s, 1 H) 1.15-1.27 (m, 7 H) 1.29 (br. s., 1 H) 1.31-1.49 (m, 11 H) 1.54- 1.76 (m, 12H) 1.89 (br. s., 2 H) 2.19- 2.31 (m, 3 H) 2.34-2.57 (m, 7 H) 2.69 (s, 1 H) 3.06 (s, 1 H) 3.11- 3.27(m, 1 H) 3.27-3.51 (m, 5 H) 3.66 (br. s., 1 H) 3.80 (t, J = 6.90 Hz, 1 H) 4.94 (d, J = 9.54 Hz, 1 H) 5.07 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.48- 5.71 (m, 2 H) 5.79-6.05 (m, 2 H) 6.07- 6.25 (m, 1 H) 6.88-7.05 (m, 1 H) 7.29-7.41 (m, 1 H) 8.24-8.48 (m, 1 H) [00216] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.68-0.92 (m, 4 H) 1.00 (d, J = 6.78 Hz, 1 H) 1.06 (br. s., 1 H) 1.08 (br. s., 1 H) 1.12 (br. s., 1 H) 1.14-1.21 (m, 5 H) 1.24-1.50 (m, 15 H) 1.55-1.69 (m, 7 H) 1.73 (br. s., 2 H) 1.78-1.92 (m, 1 H) 1.98 (s, 1 H) 2.14 (s, 1 H) 2.36-2.58 (m, 7 H) 3.06 (s, 1 H) 3.23 (d, J = 4.02 Hz, 1 H) 3.32- 3.50 (m, 5 H) 3.67 (br. s., 1 H) 3.72- 3.89 (m, 1 H) 4.05 (q, J = 7.03 Hz, 1 H) 4.94 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.54 Hz, 1 H) 5.44-5.68 (m, 2 H) 5.94-6.16 (m, 2 H) 6.31 (dd, J = 14.43, 10.92 Hz, 1 H) 6.93 (s, 1 H) 7.01-7.12 (m, 1 H) 7.45 (s, 1 H) 8.57-8.67 (m, 2 H) 639.53 [00217] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.77 (dd, J = 12.42, 6.65 Hz, 2 H) 1.06-1.17 (m, 2 H) 1.17-1.28 (m, 7 H) 1.39-1.61 (m 9 H) 1.63-1.71 (m, 3 H) 1.80-1.97 (m, 2 H) 2.06 (s, 1 H) 2.27 (s, 1 H) 2.36-2.60 (m, 2 H) 2.96 (br. s., 3 H) 3.11 (q, J = 7.28 Hz, 4 H) 3.50-3.77 (m, 4 H) 3.86 (t, J = 7.15 Hz, 1 H) 4.85 (d, J = 9.79 Hz, 3 H) 4.94 (d, J = 10.54 Hz, 2 H) 5.39 (s, 1 H) 5.48 (ddd, J = 15.31, 9.79, 2.01 Hz, 1 H) 5.61 (ddd, J = 15.25, 9.60, 1.25 Hz, 1 H) 5.90 (dd, J = 15.06, 7.78 Hz, 1 H) 6.03 (d, J = 10.79 Hz, 1 H) 6.20-6.46 (m, 1 H) 7.12-7.21 (m, 1 H) 7.48-7.69 (m, 2 H) 8.97 (br. s., 1 H) 639.59 [00218] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.67-0.94 (m, 5 H) 0.94-1.10 (m, 9 H) 1.14-1.27 (m, 10 H) 1.30-1.50 (m, 15 H)1.53 (br. s., 1 H) 1.58 (br. s., 1 H) 1.61-1.69 (m, 6 H) 1.73 (s, 1 H) 1.79 (d, J = 1.00 Hz, 2 H) 1.86 (d, J = 3.26 Hz, 3 H) 1.97 (s, 1 H) 2.10-2.15 (m, 4H) 2.20-2.32 (m, 2 H) 2.32-2.44 (m, 2 H) 2.51 (br. s., 3 H) 2.71 (br. s., 5 H) 2.87 (br. s., 2 H) 2.98 (q, J = 7.28 Hz, 4 H) 3.05-3.22 (m 2 H) 3.27(d, J = 9.29 Hz, 1 H) 3.36- 3.53 (m, 3 H) 3.53-3.72 (m, 6 H) 3.81 (br. s., 2 H) 4.05 (q, J = 7.03 Hz, 2 H) 4.83-5.02 (m, 3 H) 5.23 (s, 1 H) 5.28-5.50 (m, 3 H) 5.50-5.76 (m, 3 H) 6.29 (s, 1 H) 6.33 (s, 1 H) 6.39 (d, J = 11.04 Hz, 1 H) 6.45-6.61 (m, 1 H) 6.63-6.86 (m, 2 H) 6.93 (s, 1 H) 7.32 (dd, J = 5.40, 1.38 Hz, 1 H) 7.45 (s, 2 H) 8.56 (d, J = 5.52 Hz, 1 H) 8.64 (d, J = 5.27 Hz, 2 H) 9.05 (d, J = 1.00 Hz, 2 H) 9.11-9.30 (m, 2 H) 639.47 [00219] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.72-0.87 (m, 3 H) 1.14-1.21 (m, 3 H) 1.25 (br. s., 1 H) 1.27 (s, 1 H) 1.29-1.53 (m, 12 H) 1.56-1.63 (m, 2 H) 1.65-1.74 (m, 4 H) 1.82-2.00 (m, 1 H) 2.10 (s, 1 H) 2.35-2.56 (m, 7 H) 3.32-3.48 (m, 5 H) 3.56-3.73 (m, 1 H) 3.80 (t, J = 7.15 Hz, 1 H) 4.94 (d, J = 9.29 Hz, 1 H) 5.08 (d, J = 10.54 Hz, 1 H) 5.47- 5.66 (m, 2 H) 5.94-6.13 (m, 2 H) 6.17- 6.35 (m, 1 H) 6.93-7.13 (m, 1 H) 8.59-8.65 (m, 2 H) 639.53 101 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00220] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.76-0.88 (m, 3 H) 0.91 (br. s., 1 H) 1.14-1.21 (m, 4 H) 1.24-1.50 (m, 12 H) 1.54-1.75 (m, 7H) 1.84-2.00 (m, 2 H) 2.10 (s, 1 H) 2.33-2.56 (m, 7 H) 3.15 (s, 1 H) 3.33-3.48 (m, 7 H) 3.55-3.72 (m, 1 H) 3.79 (t, J = 7.15 Hz, 1 H) 4.04 (s, 1H) 4.94 (d, J = 9.29 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1H) 5.47-5.67 (m, 2 H) 5.92-6.13 (m, 2 H) 6.21-6.38 (m, 1 H) 7.06 (t, J = 4.89 Hz, 1 H) 7.45 (s, 1 H) 8.61 (d, J = 4.77 Hz, 2 H) 639.53 102 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2- ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00221] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.70-0.91 (m, 5 H) 1.00 (d, J = 6.53 Hz, 1 H) 1.15- 1.22 (m, 6 H) 1.25 (dd, J = 7.78, 2.51 Hz, 1 H) 1.29-1.49 (m, 14 H) 1.56- 1.75 (m, 9 H) 1.81 (s, 1 H) 1.89 (br. s., 1 H) 1.98 (s, 1 H) 2.06-2.28 (m, 1 H) 2.35-2.55 (m, 11 H) 3.23 (d, J = 3.76 Hz, 1 H) 3.39 (br. s., 5 H) 3.54-3.80 (m, 2 H) 4.05 (q, J = 7.03 Hz, 1 H) 4.94 (d, J = 9.29 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H) 5.45-5.68 (m, 3 H) 5.96-6.15 (m, 2 H) 6.29 (dd, J = 15.18, 10.67 Hz, 1 H) 6.91 (dd, J = 5.14, 2.13 Hz, 1 H) 8.41-8.52 (m, 1 H) [00222] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.68-0.91 (m, 4 H) 1.13-1.22 (m, 4 H) 1.25-1.53 (m, 17 H) 1.53-1.76 (m, 9 H) 1.81- 2.00 (m,4 H) 2.35-2.57 (m, 7 H) 3.05- 3.30 (m, 1 H) 3.30-3.49 (m, 8 H) 3.67 (br. s., 1 H) 4.94 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.23 (s, 1 H)5.45-5.68 (m, 2 H) 5.92-6.13 (m, 3 H) 6.15-6.42 (m, 2 H) 7.22-7.22 (m, 1 H) 7.22-7.32 (m, 1 H) 707.65 104 [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7- dimethyl-12-oxo-2-[(2E,4E)-6-(6-pyrrolidin-1- ylpyridin-2-yl)hepta-2,4-dien-2-yl]-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine- 1-carboxylate
Compounds 105-115 were prepared by the method of Scheme 3.

##STR00223## ##STR00224##

General Protocol for the Synthesis of Compounds 105-115:

[0570] Step 1: A solution of 6-deoxypladienolide D (N, 100.0 mg, 0.2 mmol, 1.0 equiv.) under nitrogen in DMF (8 mL, 0.2M) at 0° C. was treated with imidazole (89.2 mg, 1.3 mmol, 7.0 equiv.) and TBSCl (140.3 mg, 0.9 mmol, 5.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 20 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (O, 143.0 mg, 0.19 mmol, 100%).

[0571] Step 2: To a solution of olefin O (30.0 mg, 0.04 mmol, 1.0 equiv.) in degassed THF:H.sub.2O (10:1, 1.0 mL:0.1 mL, 0.01M) under nitrogen at 0° C. was added osmium tetroxide (0.1 mL, 0.008 mmol, 0.2 equiv., 2.5% solution in tent-butanol) followed by N-methylmorpholine N-oxide (9.2 mg, 0.08 mmol, 2.0 equiv.). The reaction was allowed to warm to room temperature and stirred for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium sulfite, diluted with ethyl acetate, and the organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (P, 29.2 mg, 0.04 mmol, 93%).

[0572] Step 3: To a solution of triol P (498.2 mg, 0.6 mmol, 1.0 equiv.) in benzene (25 mL, 0.03M) under nitrogen at room temperature was added lead tetraacetate (553.4 mg, 1.2 mmol, 2.0 equiv.). The reaction was stirred for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. The reaction was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (Q, 232 mg, 0.5 mmol, 80%).

[0573] Step 4: To a solution of the corresponding sulfone (2.5 equiv.) in THF (0.02M) under nitrogen at −78° C. was added KHMDS (2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde Q (1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. over 1 hr. The reaction was quenched with aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (R).

[0574] Step 5: To a solution of acetate R (1.0 equiv.) in methanol (0.1M) at room temperature was added potassium carbonate (2.5 equiv.). The reaction was run for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with water, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil (S) was advanced crude into the next step.

[0575] Step 6: To a solution of alcohol (S) (1.0 equiv.) in dichloroethane (0.1M) at room temperature was added N,N-dimethylaminopyridine (0.3 equiv.) followed by 4-nitrophenyl chloroformate (4.0 equiv.). The reaction was stirred at room temperature for 24 hours. Next, the corresponding amine (10.0 equiv.) was added at room temperature. After stirring for one hour, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (T).

[0576] Step 7: To a solution of silyl ether T in methanol (0.1M) at room temperature was added p-methoxytoluenesulfonic acid (2.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (105-115). (Table 3)

Exemplified Protocol for the Synthesis of Compound 114

[0577] Steps 1-3 as above.

[0578] Step 4: To a solution containing (S)-2-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine (44.0 mg, 0.1 mmol, 2.5 equiv.) and THF (2.0 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.27 mL, 0.1 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde Q (25 mg, 0.05 mmol, 1.0 equiv.) in THF (0.1 mL) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. over 1 hr. The reaction was quenched with aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (R, 21.0 mg, 0.04 mmol, 69%).

[0579] Step 5: To a solution of acetate R (15.2 mg, 0.03 mmol, 1.0 equiv.) in methanol (2 mL, 0.1M) at room temperature was added potassium carbonate (9.1 mg, 0.07 mmol, 2.5 equiv.). The reaction was run for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with water, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil (S, 14 mg, 0.03 mmol, 100%) was advanced crude into the next step.

[0580] Step 6: To a solution of alcohol (S, 4.2 mg, 0.008 mmol, 1.0 equiv.) in dichloromethane (1 mL, 0.1M) at room temperature was added N,N-dimethylaminopyridine (0.3 mg, 0.002 mmol, 0.3 equiv.) followed by 4-nitrophenyl chloroformate (6.4 mg, 0.03 mmol, 4.0 equiv.). The reaction was stirred at room temperature for 24 hours. Next, N-methyl piperazine (0.009 mL, 0.08 mmol, 10.0 equiv.) was added at room temperature. After stirring for one hour, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (T, 4.9 mg, 0.007 mmol, 94%).

[0581] Step 7: To a solution of silyl ether T (4.9 mg, 0.007 mmol, 1.0 equiv.) in methanol (0.7 mL, 0.1M) at room temperature was added p-methoxytoluenesulfonic acid (3.6 mg, 0.02 mmol, 2.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (compound 114, 3.6 mg, 0.007 mmol, 89%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J=6.78 Hz, 3H) 0.99 (d, J=6.90 Hz, 3H) 1.13-1.33 (m, 2H) 1.44 (d, J=6.90 Hz, 3H) 1.47-1.51 (m, 1H) 1.73 (d, J=0.75 Hz, 3H) 1.74-1.81 (m, 1 H) 1.84-1.97 (m, 1H) 2.30 (s, 3H) 2.36 (br. s., 4H) 2.39-2.61 (m, 3H) 3.41 (m, 1H) 3.49 (br. s., 4H) 3.67-3.74 (m, 2H) 4.86 (t, J=10.04 Hz, 1H) 5.13 (d, J=10.67 Hz, 1H) 5.35 (dd, J=14.93, 9.66 Hz, 1H) 5.54 (dd, J=15.06, 9.91 Hz, 1H) 6.00 (dd, J=15.12, 7.47 Hz, 1H) 6.12 (d, J=10.92 Hz, 1H) 6.32 (ddd, J=15.09, 10.82, 1.07 Hz, 1H) 7.11 (ddd, J=7.53, 4.89, 1.13 Hz, 1H) 7.16 (d, J=7.91 Hz, 1H) 7.61 (td, J=7.65, 1.88 Hz, 1H) 8.55 (d, J=4.96 Hz, 1H), MS (ES+): 540.3 [M+H].sup.+. [0582] Compound 116 was prepared by the method of Scheme 4.

##STR00225##

[0583] Step 1: To a solution of intermediate Q (35 mg, 0.062 mmol, 1 equiv) and SPE-11 (23.20 mg, 0.068 mmol, 1.1 equiv) in tetrahydrofuran (3 mL) at rt under nitrogen atmosphere, triphenylarsine (18.98 mg, 0.062 mmol, 1 equiv), silver(I) oxide (71.8 mg, 0.31 mmol, 5 equiv), and Tris(dibenzylideneacetone)dipalladium (0) (11.35 mg, 0.012 mmol, 0.2 equiv) were added successively and stirred for 16 hr under dark at the same temperature. The solid was filtered off through Celite and the pad washed with EtOAc. Excess solvent was removed under reduced pressure and the obtained residue was purified with silica gel chromatography (0-50% EtOAc/hexanes) to give the desired product (SPE-12, 17.6 mg, 0.027 mmol, 43.6%.

[0584] Step 2: To a solution of SPE-12 (17.6 mg, 0.027 mmol, 1 equiv) in THF (2 mL) was added TBAF (0.216 mL, 0.216 mmol, 8 equiv) at 0° C., then the reaction mixture was gradually warmed up to room temperature and stirred for 2 hr. The reaction mixture was dilrectly applied to silica gel and purified by silica gel chromatography (0-30% EtOAc/hexanes) to give the desired product (Compound 116, 5.2 mg, 9.69 μmol, 35.8%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: ppm 0.86-1.02 (m, 15H) 1.37 (d, J=3.51 Hz, 8H) 1.47-1.55 (m, 2H) 1.62-1.71 (m, 3H) 1.79 (s, 3H) 1.85-1.96 (m, 2H) 2.02 (s, 3H) 2.42-2.48 (m, 1H) 2.55-2.63 (m, 2H) 2.65-2.76 (m, 1H) 2.83-2.94 (m, 1H) 3.50-3.62 (m, 1H) 3.80 (s, 2H) 4.89-4.97 (m, 1H) 5.01-5.09 (m, 1H) 5.39-5.56 (m, 2H) 5.82-5.96 (m, 1H) 6.11-6.20 (m, 1H) 6.49-6.62 (m, 1H). MS(ES+): 535.56[M-H].sup.−.

TABLE-US-00006 TABLE 3 Compounds 105-116 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00226] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.06 (d, J = 6.78 Hz, 3 H) 1.16-1.32 (m, 2 H) 1.33-1.55 (m, 10 H) 1.61-1.70 (m, 2 H) 1.73 (s, 3 H) 1.76- 1.92 (m, 7H) 2.41-2.63 (m, 9H) 3.32 (br. s., 2 H) 3.35-3.53 (m, 7 H) 3.71 (s, 1 H, OH) 3.90-4.01 (m, 2 H) 4.86 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.54 Hz, 1 H) 5.36 (dd, J = 15.00, 9.60 Hz, 1 H) 5.55 (dd, J = 15.00, 9.85 Hz, 1 H) 5.69 (dd, J = 15.12, 7.47 Hz, 1 H) 6.09 (d, J = 10.79 Hz, 1 H) 6.27 (dd, J = 15.12, 10.85 Hz, 1 H) 672.5 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-cycloheptylpiperazine-1-carboxylate [00227] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.65 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.06 (d. J = 6.78 Hz, 3 H) 1.16-1.33 (m, 2 H) 1.33- 1.56 (m, 10 H) 1.62-1.70 (m, 2 H) 1.73 (s, 3 H) 1.78 (br. s., 2 H) 1.85-2.08 (m, 3 H) 2.37- 2.63 (m, 9 H) 3.31-3.62 (m, 10 H) 3.71 (s, 1 H, OH) 3.90-4.04 (m, 2 H) 4.42- 4.50 (m, 1 H) 4.85 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.31- 5.39 (m, 1 H) 5.55 (dd, J = 14.93, 9.91 Hz, 1 H) 5.69 (dd, J = 15.06, 7.53 Hz, 1 H) 6.09 (d, J = 11.29 Hz, 1 H) 6.20-6.31 (m, 1 H 688.4 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4- en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00228] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.06 (d, J = 6.78 Hz, 3 H) 1.15-1.35 (m, 2 H) 1.36-1.55 (m, 1 H) 1.73 (s, 3 H) 1.77-1.96 (m, 5 H) 2.30 (s, 3 H) 2.36 (br. s., 4 H) 2.41-2.66 (m, 5 H) 3.24-3.44 (m, 4 H) 3.48 (br. s., 4 H) 3.63 (t, J = 6.90 Hz, 1 H) 3.70 (d, J = 7.15 Hz, 1 H) 3.96 (qd, J = 10.37, 6.78 Hz, 2 H) 4.86 (t, J = 9.98 Hz, 1 H) 5.14 (d, J = 10.67 Hz, 1 H) 5.36 (dd, J = 15.06, 9.66 Hz, 1 H) 5.55 (dd, J = 14.93, 9.91 Hz, 1 H) 5.69 (dd, J = 15.12, 7.47 Hz, 1 H) 6.09 (d, J = 10.79 Hz, 1 H) 6.26 (dd, J = 15.25, 10.10 Hz, 1 H) 590.3 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-methylpiperazine-1-carboxylate [00229] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.65 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.07 (d, J = 6.90 Hz, 3 H) 1.19-1.25 (m, 1 H) 1.37-1.54 (m, 1 H) 1.73 (s, 3 H) 1.76-1.83 (m, 1 H) 1.87- 2.05 (m, 3 H) 2.30 (s, 3 H) 2.35 (br. s., 4 H) 2.44-2.63 (m, 5 H) 3.30-3.60 (m, 9 H) 3.72 (m, 2 H) 3.91-4.03 (m, 2 H) 4.46-4.50 (m, 1 H) 4.86 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.54 Hz, 1 H) 5.32-5.40 (dd, J = 14.93, 10.04 Hz, 1 H) 5.55 (dd, J = 14.93, 9.91 Hz, 1 H) 5.69 (dd, J = 15.31, 7.65 Hz, 1 H) 6.09 (d, J = 10.79 Hz, 1 H) 6.27 (dd, J = 14.81, 11.04 Hz, 1 H) 606.3 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-methylpiperazine-1-carboxylate [00230] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.07 (d, J = 6.78 Hz, 3 H) 1.15-1.34 (m, 2 H) 1.36-1.53 (m, 1 H) 1.57 (d, J = 6.40 Hz, 1 H) 1.74 (s, 3 H) 1.77-1.93 (m, 3 H) 1.95-2.07 (m, 1 H) 2.42 (s, 3 H) 2.45-2.68 (m, 7 H) 3.17- 3.43 (m, 2 H) 3.45-3.73 (m, 9 H) 3.84- 4.04 (m, 3 H) 4.86 (t, J = 9.98 Hz, 1 H) 5.14 (d, J = 10.67 Hz, 1 H) 5.36 (dd, J = 15.00, 9.60 Hz, 1 H) 5.56 (dd, J = 15.00, 9.98 Hz, 1 H) 5.68 (dd, J = 15.06, 7.28 Hz, 1 H) 6.09 (d, J = 11.04 Hz, 1 H) 6.27 (dd, J = 15.12, 10.85 Hz, 1 H) 620.7 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2- (hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate [00231] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.90 Hz, 3 H) 1.06 (d, J = 6.78 Hz, 3 H) 1.16-1.31 (m, 2 H) 1.38-1.57 (m, 9 H) 1.60-1.70 (m, 3 H) 1.73 (s, 3 H) 1.74- 1.95 (m, 5 H) 1.98 (t, J = 5.02 Hz, 2 H) 2.42-2.64 (m, 9 H) 3.32-3.48 (m, 6 H) 3.71 (s, 1 H) 3.99 (br. s., 3 H) 4.17-4.68 (m, 2 H) 4.86 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.36 (dd, J = 15.06, 9.66 Hz, 1 H) 5.55 (dd, J = 15.00, 9.85 Hz, 1 H) 5.60-5.73 (m, 1 H) 6.09 (d, J = 10.79 Hz, 1 H) 6.27 (dd, J = 14.81, 10.79 Hz, 1 H) 704.6 [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00232] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.06 (d, J = 6.78 Hz, 3 H) 1.15-1.29 (m, 2 H) 1.47 (br. s., 1 H) 1.73 (s, 3 H) 1.78-1.96 (m, 4 H) 1.99 (t, J = 4.89 Hz, 2 H) 2.49 (s, 3 H) 2.49-2.65 (m, 4 H) 2.68 (br. s., 4 H) 3.39 (m, 2 H) 3.63 (br. s., 4 H) 3.66-3.75 (m, 1 H) 3.87-4.08 (m, 3 H) 4.21-4.69 (m, 3 H) 4.86 (t, J = 10.16 Hz, 1 H) 5.14 (d, J = 10.67 Hz, 1 H) 5.35 (dd, J = 15.06, 9.66 Hz, 1 H) 5.56 (dd, J = 14.93, 10.04 Hz, 1 H) 5.67 (m, 1 H) 6.09 (d, J = 10.67 Hz, 1 H) 6.27 (dd, J = 14.81, 10.54 Hz, 1 H) 622.5 [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate [00233] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86 (d, J = 6.78 Hz, 3 H) 0.96 (d, J = 6.78 Hz, 3 H) 1.15-1.37 (m, 3 H) 1.45 (d, J = 6.90 Hz, 3 H) 1.74 (s, 3 H) 1.76-1.84 (m, 1H) 1.87-1.96 (m, 1 H) 2.02 (s, 3 H) 2.52 (m, 3 H) 3.41 (d, J = 11.04 Hz, 1 H) 3.69 (m, 2 H) 4.96 (t, J = 10.10 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.33 (dd, J = 14.93, 9.66 Hz 1 H) 5.54 (dd, J = 14.93, 9.91 Hz , 1 H) 5.99 (dd, J = 14.49, 7.47 Hz, 1 H) 6.11 (d, J = 10.29 Hz, 1 H) 6.34 (m, 1 H) 7.18 (m, 2 H) 7.56-7.66 (m, 1 H) 8.56 (d, J = 4.27 Hz, 1 H) 455.2 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2- [(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] acetate [00234] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.13-1.33 (m, 3 H) 1.41- 1.54 (m, 9 H) 1.44 (d, J = 7.03 Hz, 3 H) 1.68 (m, 2 H) 1.73 (s, 3 H) 1.78 (m, 2 H) 1.83-1.94 (m, 1 H) 2.38-2.61 (m, 8 H) 3.29-3.55 (m, 5 H) 3.64-3.74 (m, 2 H) 4.85 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.36 (d, J = 9.66 Hz, 1 H) 5.54 (dd, J = 15.00, 9.98 Hz, 1 H) 6.00 (dd, J = 15.06, 7.53 Hz, 1 H) 6.12 (d, J = 11.04 Hz, 1 H) 6.32 (ddd, J = 15.09, 10.82, 1.07 Hz, 1 H) 7.11 (t, J = 6.17 Hz, 1 H) 7.16 (d, J = 7.78 Hz, 1 H) 7.61 (td, J = 7.69, 1.82 Hz, 1 H) 8.55 (d, J = 4.94 Hz, 1 H) 622.4 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2- [(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00235] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.90 Hz, 3 H) 1.13-1.33 (m, 2 H) 1.44 (d, J = 6.90 Hz, 3 H) 1.47-1.51 (m, 1 H) 1.73 (d, J = 0.75 Hz, 3 H) 1.74-1.81 (m, 1 H) 1.84-1.97 (m, 1 H) 2.30 (s, 3 H) 2.36 (br. s., 4 H) 2.39-2.61 (m, 3 H) 3.41 (m, 1 H) 3.49 (br. s., 4 H) 3.67-3.74 (m, 2 H) 4.86 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.35 (dd, J = 14.93, 9.66 Hz, 1 H) 5.54 (dd, J = 15.06, 9.91 Hz, 1 H) 6.00 (dd, J = 15.12, 7.47 Hz, 1 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.32 (ddd, J = 15.09, 10.82, 1.07 Hz, 1 H) 7.11 (ddd, J = 7.53, 4.89, 1.13 Hz, 1 H) 7.16 (d, J = 7.91 Hz, 1 H) 7.61 (td, J = 7.65, 1.88 Hz, 1 H) 8.55 (d, J = 4.96 Hz, 1 H) 540.3 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2- [(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4- en-6-yl] 4-methylpiperazine-1-carboxylate [00236] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87 (d, J = 6.78 Hz, 3 H) 0.99 (d, J = 6.90 Hz, 3 H) 1.14-1.35 (m, 2 H) 1.44 (d, J = 7.03 Hz, 3 H) 1.47-1.51 (m, 1 H) 1.73 (d, J = 1.00 Hz, 3 H) 1.76-1.80 (m, 1 H) 1.87-1.96 (m, 1 H) 2.42-2.61 (m, 3 H) 2.88 (s, 6 H) 3.39 (d, J = 10.92 Hz, 1 H) 3.65-3.77 (m, 2 H) 4.83 (t, J = 10.04 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.35 (dd, J = 15.00, 9.60 Hz, 1 H) 5.54 (dd, J = 14.93, 9.91 Hz, 1 H) 5.99 (dd, J = 15.06, 7.53 Hz, 1 H) 6.11 (d, J = 10.92 Hz, 1 H) 6.33 (dd, J = 14.81, 10.92 Hz, 1 H) 7.09-7.15 (m, 1 H) 7.15-7.21 (m, 1 H) 7.57-7.67 (m, 1 H) 8.55 (d, J = 4.93 Hz, 1 H) 485.2 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2- [(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] N,N-dimethylcarbamate [00237] .sup.1H NMR (400 MHz, METHANOL-d4) δ: ppm 0.86-1.02 (m, 15 H) 1.37 (d, J = 3.51 Hz, 8 H) 1.47-1.55 (m, 2 H) 1.62-1.71 (m, 3 H) 1.79 (s, 3 H) 1.85- 1.96 (m, 2 H) 2.02 (s, 3 H) 2.42-2.48 (m, 1 H) 2.55-2.63 (m, 2 H) 2.65-2.76 (m, 1 H) 2.83-2.94 (m, 1 H) 3.50-3.62 (m, 1 H) 3.80 (s, 2 H) 4.89-4.97 (m, 1 H) 5.01-5.09 (m, 1 H) 5.39-5.56 (m, 2 H) 5.82-5.96 (m, 1 H) 6.11-6.20 (m, 1 H) 6.49-6.62 (m, 1 H) 535.56 [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3- [(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate
Compounds 117-134 were prepared by the method of Scheme 5.

##STR00238## ##STR00239## ##STR00240##

General Protocol for the Synthesis of Compounds 117-134:

[0585] Step 1: To a solution of NaH (8.3 g, 207 mmol, 1.2 equiv.) in diethyl ether (400 mL, 0.1M) at 0° C. was added diethyl-2-methylmalonate (U, 30 g, 172 mmol, 1.0 equiv.) dropwise. The reaction was gradually warmed to reflux and stirred at reflux for three hours. The reaction was then cooled to room temperature and iodoform (67.8 g, 172 mmol, 1.0 equiv.) was added dropwise. The reaction was once again heated at reflux for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was cooled to 0° C., quenched with 10% aqueous hydrochloric acid, diluted with ether, and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was then dissolved in ethanol/water/methanol (400 mL, 3:1:1) and KOH (48.3 g, 861 mmol, 5.0 equiv.) was added at room temperature. The solution was then heated to and maintained at 75° C. for 24 hours. The reaction was cooled to room temperature and concentrated in vacuo. The resulting oil was diluted with ethyl acetate and water, extracted into ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (V, 26 g, 123 mmol, 71%).

[0586] Step 2: To a solution of acid V (25.0 g, 118 mmol, 1.0 equiv.) in THF (400 mL, 0.3M) at 0° C. was added lithium aluminum hydride (4.9 g, 130 mmol, 1.1 equiv.). The reaction was gradually warmed to room temperature and stirred for four hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was cooled to 0° C. and quenched with water. The resulting suspension was charged with Rochelle's salt solution (20% by volume) and stirred at room temperature for three hours. The mixture was filtered while washing with ethyl acetate and the volume of the filtrate was reduced in vacuo. Ethyl acetate was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (W, 15 g, 76 mmol, 64%).

[0587] Step 3: To a solution of alcohol W (60 mg, 0.3 mmol, 1.0 equiv.) in diethyl ether (2 mL, 0.1M) at room temperature was added manganese dioxide (395 mg, 4.5 mmol, 15.0 equiv.). The reaction was stirred for two hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was filtered through Celite® and the filtrate was concentrated in vacuo. The crude product (X, 59 mg, 0.30 mmol, 99%) was advanced without purification.

[0588] Step 4: To a solution of (1R,2S)-2-(N-benzyl-2,4,6-trimethylphenylsulfonamido)-1-phenylpropyl propionate (1.9 g, 4.4 mmol, 1.0 equiv.), prepared according to literature precedent (Masamune et al. J. Am. Chem. Soc. 1997, 119, 2586-2587) in dichloromethane (40 mL, 0.1M) at −78° C. was added triethylamine (1.7 ml, 12.3 mmol, 3.0 equiv.) followed by dropwise addition of dicyclohexyl(((trifluoromethyl)sulfonyl)oxy)borane (2.67 g, 8.0 mmol, 2.0 equiv.). The reaction was stirred at −78° C. for two hours. Next, a solution of (E)-3-iodo-2-methylacrylaldehyde (X, 1.2 g, 6.2 mmol, 1.5 equiv.) in dichloromethane (3 mL) was added dropwise over thirty minutes. The reaction was stirred at −78° C. for two hours and then allowed to warm to 0° C. The reaction was quenched with the addition of aqueous hydrogen peroxide (16 mL, 20.5 mmol) and the reaction was allowed to gradually warm to room temperature. The solvent volume was reduced in vacuo and the solution was diluted with dichloromethane and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (Y, 1.9 g, 2.8 mmol, 69%).

[0589] Step 5: To a solution of alcohol Y (2.8 g, 4.1 mmol, 1.0 equiv.) in dichloromethane (50 mL, 0.1M) at −78° C. was added 2,6-lutidine (1.0 mL, 8.3 mmol, 2.0 equiv.) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.9 mL, 1.2 equiv.). The reaction was gradually warmed to room temperature and quenched with aqueous ammonium chloride. Ethyl acetate was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (Z, 2.8 g, 3.5 mmol, 85%).

[0590] Step 6: To a solution of ester Z (2.8 g, 3.5 mmol, 1.0 equiv.) in dichloromethane (40 mL, 0.1M) at 0° C. was added DIBAL (8.9 mL, 8.9 mmol, 2.5 equiv.). The reaction was stirred for one hour and then quenched with Rochelle's salt solution (20% by volume) and stirred at room temperature for three hours. The mixture was filtered through Celite® while washing with ethyl acetate and the volume of the filtrate was reduced in vacuo. Ethyl acetate was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (AA, 1.1 g. 2.8 mmol, 80%).

[0591] Step 7: To a solution of alcohol AA (2.97 g, 8.0 mmol, 1.0 equiv.) in dichloromethane (80 mL, 0.1M) at 0° C. was added Dess-Martin periodinane (4.4 g, 10.4 mmol, 1.3 equiv.). The reaction was stirred for two hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was concentrated in vacuo and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (BB, 2.6 g, 7.1 mmol, 88%).

[0592] Step 8: To a solution of methyltriphenylphosphonium bromide (11.8 g, 33.0 mmol, 3.0 equiv.) in THF (110 mL, 0.1M) at 0° C. was added n-butyl lithium (13.2 mL, 33.0 mmol, 3.0 equiv.). The reaction was stirred for 30 minutes and then cooled to −78° C. Aldehyde BB (4.1, 11.0 mmol, 1.0 equiv.) in THF (0.5 M) was added dropwise and the reaction was stirred for one hour. The reaction was quenched with ammonium chloride and warmed to room temperature. Ethyl acetate was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (CC, 3.8 g, 10.4 mmol, 94%).

[0593] Step 9: To a solution of olefin CC (0.1 g, 0.4 mmol, 1.0 equiv.) in THF (4 mL, 0.1M) at 0° C. was added TBAF (0.45 mL, 0.4 mmol, 1.1 equiv.). The reaction was stirred for 30 minutes or until the reaction was determined to be complete by LCMS or TLC. Diethyl ether was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (DD, 0.1 g, 0.4 mmol, 99%) was advanced without purification.

[0594] Step 10: To a solution of alcohol DD (0.15 g, 0.4 mmol, 1.0 equiv.) in dichloromethane (4 mL, 0.1M) at 0° C. was added EDC (0.10 g, 0.5 mmol, 1.3 equiv.) followed by nonenoic acid (0.08 g, 0.4 mmol, 1.1 equiv.) and DMAP (catalytic). The reaction was gradually warmed to room temperature and stirred overnight. Ethyl acetate was added and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (EE, 0.13 g, 0.33 mmol, 81%).

[0595] Step 11: To a solution of ester EE (0.5 g, 1.3 mmol, 1.0 equiv.) in degassed toluene (65 mL, 0.05M) at room temperature was added benzoquinone (0.007 g, 0.06 mmol, 0.05 equiv.) followed by Hoyveda-Grubbs catalyst (0.08 g, 0.13, 0.1 equiv.). The reaction was gradually warmed to 60° C. and stirred overnight. Once determined to be complete by TLC or LCMS, the reaction was concentrated. The crude material (FF) was used in the following step without further purification

[0596] Step 12: To a solution of macrocycle FF (1.0 equiv.) in dioxane (65 mL, 0.05M) was added selenium dioxide (0.4 g, 3.8 mmol, 3.0 equiv.) at room temperature. The reaction was heated to 80° C. for 3 hours. Ethyl acetate was added, and the organic layer was washed with water and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (GG, 0.3 g, 0.8 mmol, 64%).

[0597] Step 13: To a solution of alcohol GG (1.0 equiv.) in MTBE (0.1M) at room temperature was added triethylamine (5.0 equiv.), para-nitrophenylchloroformate (3.0 equiv.), DMAP (catalytic) and the reaction was stirred overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched with water. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (HH) was advanced without purification.

[0598] Step 14: To a solution of carbonate HH (1.0 equiv.) in MTBE (0.1M) at room temperature was added the corresponding amine (2.0 equiv.). Once determined to be complete by TLC or LCMS, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (II).

[0599] Step 15: To a solution of vinyl iodide II (1.0 equiv.) in THF (0.1M) at room temperature was added vinyl pinacol boronate (2.5 equiv.), silver oxide (5.0 equiv.), triphenylarsine (1.2 equiv.), and Pd.sub.2(dba).sub.3 (0.15 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was filtered through Celite®. Dichloromethane was added and the organic layer was washed with water and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (JJ).

[0600] Step 16: To a solution of diene JJ (1.0 equiv.) in THF:H.sub.2O (0.1M) at 0° C. was added N-methylmorpholine N-oxide (1.2 equiv.) and osmium tetroxide in t-BuOH (0.1 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched by addition of aqueous sodium bicarbonate. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material (KK) was advanced without further purification.

[0601] Step 17: To a solution of diol KK (1.0 equiv.) in benzene (0.1M) at room temperature was added lead tetraacetate (1.2 equiv.). The reaction was stirred at room temperature for 40 minutes or until determined to be complete by TLC or LCMS. The reaction was quenched by addition of Na.sub.2S.sub.2O.sub.3 and then sodium bicarbonate. Dichloromethane was added, and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (LL).

[0602] Step 18: To a solution of the corresponding sulfone (2.5 equiv.) in THF (0.1M) at −78° C. was added KHMDS (2.5 equiv.) and the reaction was stirred at −78° C. for one hour. Next, a solution of aldehyde LL in THF (1.0 equiv.) was added dropwise at −78° C. The reaction was allowed to warm gradually to −20° C. and stirred at −20° C. for two hours. The reaction was quenched with aqueous sodium bicarbonate and ethyl acetate was added. The organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (117-134).

Exemplified Protocol for the Synthesis of Compound 128

[0603] Steps 1-12 as above.

[0604] Step 13: To a solution of alcohol GG (0.30 g, 0.8 mmol, 1.0 equiv.) in MTBE (3.0 mL, 0.1M) at room temperature was added triethylamine (0.55 mL, 4.0 mmol, 5.0 equiv.), para-nitrophenyl chloroformate (0.24 g, 1.2 mmol, 2.0 equiv.), and DMAP (0.12 g, 0.9 mmol, 1.2 equiv.) and the reaction was stirred overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched with water. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (HH) was advanced without purification.

[0605] Step 14: To a solution of carbonate HH (1.0 equiv.) in MTBE (0.1M) at room temperature was added N-methylpiperazine (0.13 mL, 1.2 mmol, 1.5 equiv.). Once determined to be complete by TLC or LCMS, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (II, 0.30 g, 0.5 mmol, 67.5%).

[0606] Step 15: To a solution of vinyl iodide II (0.15 g, 0.30 mmol, 1.0 equiv.) in THF (3.0 mL, 0.1M) at room temperature was added vinyl pinacol boronate (0.13 mL, 0.30 mmol, 2.5 equiv.), silver oxide (0.35 g, 1.50 mmol, 5.0 equiv.), triphenylarsine (0.11 g, 0.36 mmol, 1.2 equiv.), and Pd.sub.2(dba).sub.3 (0.04 g, 0.04 mmol, 0.15 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was filtered through Celite®. Dichloromethane was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (JJ, 0.12 g, 0.3 mmol, 96%).

[0607] Step 16: To a solution of diene JJ (0.12 g, 0.3 mmol, 1.0 equiv.) in THF:H.sub.2O (4 mL:0.4mL, 0.1M) at 0° C. was added N-methylmorpholine N-oxide (0.04 g, 0.35 mmol, 1.2 equiv.) and osmium tetroxide in t-BuOH (0.37 mL, 0.03 mmol, 0.1 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched by addition of aqueous sodium bicarbonate. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material (JJ, 0.13 g, 0.3 mmol, 100%) was advanced without further purification.

[0608] Step 17: To a solution of diol KK (0.10 g, 0.23 mmol, 1.0 equiv.) in acetone (3.0 mL, 0.1M) at room temperature was added diacetoxyiodobenzene (0.12 g, 0.27 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 40 minutes or until determined to be complete by TLC or LCMS. The reaction was quenched by addition of Na.sub.2S.sub.2O.sub.3 and then sodium bicarbonate. Dichloromethane was added, and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (LL, 0.05 g, 0.11 mmol, 49%).

[0609] Step 18: To a solution of (S)-2-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine (0.08 g, 0.25 mmol, 2.5 equiv.) in THF (0.6 mL, 0.1M) at −78° C. was added KHMDS (0.50 mL, 0.25 mmol, 2.5 equiv.) and the reaction was stirred at −78° C. for one hour. Next, a solution of aldehyde LL (0.04 g, 0.1 mmol, 1.0 equiv.) in THF (0.1 mL.) was added dropwise at −78° C. The reaction was allowed to warm gradually to −20° C. and stirred at −20° C. for two hours. The reaction was quenched with aqueous sodium bicarbonate and ethyl acetate was added. The organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 128, 0.03 g, 0.06 mmol, 60%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87 (d, J=6.76 Hz, 3H) 1.25 (br. s, 4H) 1.43 (d, J=6.8 Hz, 3H) 1.60 (br. s., 4H) 1.76-1.85 (m, 3H) 2.22 (m, 1H) 2.31 (br. s, 4H), 2.37 (br. s, 4H) 2.45-2.53 (m, 1H) 3.48 (br. s., 4H) 3.70 (m, 1H) 4.99-5.12 (m, 2H) 5.36 (m, 1H) 5.43-5.51 (m, 1H) 5.98 (dd, J=15.06, 7.53 Hz, 1H) 6.13 (d, J=11.17 Hz, 1 H) 6.32 (ddd, J=15.06, 10.92, 1.13 Hz, 1H) 7.11 (t, J=6.14 Hz, 1H) 7.16 (d, J=8.08 Hz, 1H) 7.61 (td, J=7.69, 1.82 Hz, 1H) 8.54 (d, J=4.96 Hz, 1H). MS (ES+)=510.1 [M+H].sup.+.

TABLE-US-00007 TABLE 4 Compounds 117-134 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00241] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.84 (d, J = 6.78 Hz, 3 H) 1.00 (d, J = 6.78 Hz, 3 H) 1.20 (d, J = 2.76 Hz, 3 H) 1.37-1.60 (m, 12 H) 1.62-1.72 (m, 6 H) 1.72-1.84 (m, 7 H) 1.89-2.33 (m, 19 H) 2.38-2.61 (m, 3 H) 2.74 (br. s., 4 H) 2.90-3.02 (m, 1 H) 3.30 (m, J = 6.02, 6.02 Hz, 4 H) 3.56-3.67 (m, 3 H) 3.90 (qd, J = 10.35, 6.71 Hz, 2 H) 4.91-5.08 (m, 2 H) 5.25-5.36 (m, 1 H) 5.38-5.47 (m, 1 H) 5.62 (dd, J = 15.12, 7.47 Hz, 1 H) 6.04 (dd, J = 10.79, 1.00 Hz, 1 H) 6.21 (ddd, J = 15.31, 10.79, 1.00 Hz, 1 H) 642.4 [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1- carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00242] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.8 Hz, 3 H) 1.06 (d, J = J = 6.8 Hz, 3 H) 1.06 (d, J = 6.8 Hz, 3 H) 1.18-1.36 (m, 4 H) 1.41-1.67 (m, 4 H) 1.73 (m, 3 H) 1.84 (m, 6 H) 2.12-2.27 (m, 1 H) 2.32 (br. s, 4 H) 2.38 (br. s, 4H) 2.43-2.63 (m, 2 H) 3.26-3.44 (m, 4 H) 3.49 (br. s., 4 H) 3.91-4.01 (m, 2 H) 4.12 (d, J = 7.15 Hz, 1 H) 5.02 (d, J = 10.6 Hz, 1H) 5.06-5.13 (m, 1 H) 5.37 (dd, J = 14.93, 9.41 Hz, 1 H) 5.48 (dd, J = 15.06, 9.66 Hz, 1 H) 5.67 (dd, J = 15.12, 7.47 Hz, 1 H) 6.10 (d, J = 10.79 Hz, 1 H) 6.23-6.31 (m, 1 H) 560.4 [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1- carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate [00243] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J = 6.76 Hz, 3 H) 1.06 (d, J = 6.8 Hz, 3 H) 1.25 (m, 4 H) 1.45-1.63 (m, 4 H) 1.73 (s, 3 H) 1.79-1.89 (m, 6 H) 2.18-2.25 (m, 1 H) 2.29-2.37 (m, 1 H) 2.45-2.63 (m, 2 H) 2.87 (s, 6 H) 3.36 (br. s., 4 H) 3.91-4.00 (m, 2 H) 5.00 -5.11 (m, 2 H) 5.34-5.51 (m, 2 H) 5.67 (dd, J = 15.12, 7.34 Hz, 1 H) 6.10 (d, J = 10.92 Hz, 1 H) 6.23-6.31 (m, 1 H) 505.5, 527.4  [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12- oxo-1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] pyrrolidine- 1-carboxylate [00244] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.08 (d, J = 6.8 Hz, 3 H) 1.14 (s, 1 H) 1.20-1.33 (m, 4 H) 1.46-1.63 (m, 4 H) 1.73 (s, 3 H) 1.77-1.90 (m, 2 H) 1.90-2.04 (m, 2 H) 2.24-2.26 (m, 1 H) 2.29-2.38 (m, 1 H) 2.46-2.64 (m, 2 H) 2.87 (s, 6 H) 3.52 (br. s., 4 H) 3.92-4.02 (m, 2 H) 4.43- 4.50 (m, 1 H) 4.98-5.11 (m, 2 H) 5.35- 5.51 (m, 2 H) 5.67 (dd, J = 15.18, 7.65 Hz, 1 H) 6.10 (d, J = 11.04 Hz, 1 H) 6.23-6.31 (m, 1 H) 543.3 [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo- 1-oxacyclododec-4-en-2-yl]-2-methylhepta-3,5-dienyl] (3R)-3- hydroxypyrrolidine-1-carboxylate [00245] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.76 Hz, 2 H) 1.06 (d, J = 6.8 Hz, 2 H) 1.19-1.33 (m, 4 H) 1.41 (br. s., 1 H) 1.47-1.56 (m, 4 H) 1.61 (br. s., 2 H) 1.73 (s, 3 H) 1.79-1.87 (m, 2 H) 1.87-2.04 (m, 2 H) 2.22-2.24 (m, 1 H) 2.33 (br. s, 4H), 2.39 (br. s, 4 H) 2.47- 2.53 (m, 1 H) 2.56-2.63 (m, 1 H) 3.41- 3.57 (m, 8 H) 3.91-4.02 (m, 2 H) 4.45- 4.49 (m, 1 H) 4.98-5.13 (m, 2 H) 5.37 (dd, J = 15.06, 9.41 Hz, 1 H) 5.48 (dd, J = 15.00, 9.60 Hz, 1 H) 5.67 (dd, J = 15.12, 7.22 Hz, 1 H) 6.10 (d, J = 11.29 Hz, 1 H) 6.23-6.31 (m, 1 H) 576.4 [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy- 6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6- yl] 4-methylpiperazine-1-carboxylate [00246] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J = 6.72 Hz, 2 H) 1.06 (d, J = 6.76 Hz, 2 H) 1.14 (br. s., 2 H) 1.19 (br. s, 2 H) 1.26 (br. s., 4 H) 1.47 (br. s, 1 H) 1.54 (s, 3 H) 1.57 (br. s, 4 H) 1.72 (s, 3 H) 1.76-1.91 (m, 4 H) 1.93-2.03 (m, 1 H) 2.2-2.4 (m, 1 H) 2.31 (br. s, 4 H) 2.38 (br. s., 4 H) 2.41-2.63 (m, 2 H) 3.40 (br. s., 2 H) 3.49 (br. s., 4 H) 3.86- 4.04 (m, 3 H) 5.02 (d, J = 10.68 Hz, 1H) 5.06-5.13 (m, 1 H) 5.34-5.42 (m, 1 H) 5.44-5.52 (m, 1 H) 5.66 (dd, J = 15.00, 7.97 Hz, 1 H) 6.10 (d, J = 11.04 Hz, 1 H) 6.27 (dd, J = 14.81, 11.04 Hz, 1 H) 574.6 [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2- methylpyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate [00247] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.88 (d, J = 6.76 Hz, 3 H) 1.06 (d, J = 6.8 Hz, 3 H) 1.25 (m, 4 H) 1.43-1.67 (m, 4 H) 1.73 (s, 3 H) 1.77-1.89 (m, 3 H) 1.96-2.03 (m, 1 H) 2.22-2.25 (m, 1 H) 2.31 (br. s, 4H) 2.37 (br. s, 4 H) 2.47- 2.53 (m, 1H) 2.58-2.64 (m, 1H) 3.32- 3.42 (m, 1 H) 3.44-3.69 (m, 5 H) 2.58- 3.66 (m, 2H) 3.92-4.03 (m, 3 H) 5.02 (d, J = 10.68 Hz, 1H), 5.06-5.13 (m, 1 H) 5.30-5.51 (m, 2 H) 5.66 (dd, J = 15.18, 7.53 Hz, 1 H) 6.10 (d, J = 10.92 Hz, 1 H) 6.27 (dd, J = 15.12, 10.85 Hz, 1 H) 590.5 [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate [00248] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.76 Hz, 3 H) 1.06 (d, J = 6.8 Hz, 3 H) 1.26 (br. s, 4 H) 1.38-1.63 (m, 13 H) 1.64-1.77 (m, 6 H) 1.80 (m, 2 H) 1.88-2.05 (m, 2 H) 2.17-2.26 (m, 1 H) 2.28-2.40 (m, 1 H) 2.42-2.63 (m, 6 H) 3.33-3.56 (m, 8 H) 3.84-4.03 (m, 2 H) 4.48 (br. s, 1 H) 4.97-5.12 (m, 3 H) 5.31-5.51 (m, 2 H) 5.67 (dd, J = 15.06, 7.03 Hz, 1 H) 6.09 (d, J = 10.79 Hz, 1 H) 6.17-6.38 (m, 1 H) 658.5 [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6- methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00249] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 6.12-6.31 (m, 1H), 6.04 (m, 1H), 5.59 (dd, J = 15.1, 7.5 Hz, 1H), 5.36-5.46 (m, 1H), 5.23-5.36 (m, 1H), 4.90-5.08 (m, 2H), 4.31 (d, J = 5.3 Hz, 1H), 3.84-3.99 (m, 3H), 3.81 (br. s., 1H), 3.69-3.78 (m, 1H), 3.50-3.66 (m, 2H), 3.36-3.47 (m, 4H), 3.17-3.35 (m, 1H), 2.91 (q, J = 9.5 Hz, 2H), 2.40-2.60 (m, 5H), 2.08-2.35 (m, 2H), 1.86-2.02 (m, 1H), 1.64-1.82 (m, 6H), 1.38-1.64 (m, 6H), 0.94-1.08 (m, 3H), 0.82 (d, J = 6.8 Hz, 3H) 658.8 [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1- oxacyclododec-4-en-6-yl] 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate [00250] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86 (d, J = 6.78 Hz, 3 H) 1.21-1.31 (m, 4 H) 1.44 (d, J = 7.03 Hz, 3 H) 1.47- 1.60 (m, 2 H) 1.73 (d, J = 1.00 Hz, 3 H) 1.76-1.91 (m, 2 H) 2.00 (s, 3 H) 2.22 (dt, J = 13.87, 4.80 Hz, 1 H) 2.33 (ddd, J = 13.77, 11.95, 4.14 Hz, 1 H) 2.43-2.54 (m, 1 H) 3.70 (quin, J = 6.93 Hz, 1 H) 5.02 (d, J = 10.67 Hz, 1 H) 5.17 (td, J = 10.07, 4.96 Hz, 1 H) 5.35 (dd, J = 14.93, 9.54 Hz, 1 H) 5.48 (dd, J = 14.93, 9.66 Hz, 1 H) 5.98 (dd, J = 15.12, 7.59 Hz, 1 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.32 (ddd, J = 15.09, 10.82, 1.07 Hz, 1 H) 7.11 (ddd, J = 7.53, 4.89, 1.13 Hz, 1 H) 7.16 (d, J = 7.91 Hz, 1 H) 7.61 (td, J = 7.69, 1.82 Hz, 1 H) 8.55 (d, J = 4.88 Hz, 1 H) 426.1 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin- 2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] acetate [00251] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87 (d, J = 6.90 Hz, 4 H) 1.20-1.33 (m, 10 H) 1.44 (d, J = 7.03 Hz, 3 H) 1.46-1.69 (m, 10 H) 1.73 (s, 3 H) 1.79 (m, 4 H) 2.17-2.25 (m, 1 H) 2.27-2.39 (m, 1 H) 2.47 (m, 5 H) 3.07-3.27 (m, 1 H) 3.43 (br. s., 4 H) 3.70 (quin, J = 7.03 Hz, 1 H) 4.99-5.03 (m, 1 H) 5.08 (td, J = 9.82, 4.45 Hz, 1 H) 5.32-5.40 (m, 1 H) 5.42-5.51 (m, 1 H) 5.97 (dd, J = 15.06, 7.40 Hz, 1 H) 6.12 (d, J = 11.42 Hz, 1 H) 6.28-6.36 (m, 1 H) 7.11 (ddd, J = 7.53, 4.89, 1.13 Hz, 1 H) 7.16 (d, J = 7.91 Hz, 1 H) 7.61 (t, J = 7.65 Hz, 1 H) 8.54 (d, J = 4.88 Hz, 1 H) 592.3 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6- pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00252] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87 (d, J = 6.76 Hz, 3 H) 1.25 (br. s, 4H) 1.43 (d, J = 6.8 Hz, 3 H) 1.60 (br. s., 4 H) 1.76-1.85 (m, 3 H) 2.22 (m, 1 H) 2.31 (br. s, 4H), 2.37 (br. s, 4H) 2.45- 2.53 (m, 1H) 3.48 (br. s., 4 H) 3.70 (m, 1 H) 4.99-5.12 (m, 2 H) 5.36 (m, 1 H) 5.43-5.51 (m, 1 H) 5.98 (dd, J = 15.06, 7.53 Hz, 1 H) 6.13 (d, J = 11.17 Hz, 1 H) 6.32 (ddd, J = 15.06, 10.92, 1.13 Hz, 1 H) 7.11 (t, J = 6.14 Hz, 1 H) 7.16 (d, J = 8.08 Hz, 1 H) 7.61 (td, J = 7.69, 1.82 Hz, 1 H) 8.54 (d, J = 4.96 Hz, 1 H) 510.1 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6- pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] 4-methylpiperazine-1-carboxylate [00253] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87 (d, J = 6.76 Hz, 3 H) 1.25 (br. s, 4H) 1.43 (d, J = 6.8 Hz, 3H) 1.46-1.64 (m, 2 H) 1.73 (s, 3H) 1.76-1.86 (m, 2 H) 2.21 (m, 1 H) 2.27-2.37 (m, 1 H) 2.43- 2.54 (m, 1 H) 2.87 (s, 6 H) 3.71 (t, J = 7.03 Hz, 1 H) 4.99-5.10 (m, 2 H) 5.34- 5.50 (m, 2 H) 5.97 (dd, J = 15.06, 7.53 Hz, 1 H) 6.12 (d, J = 10.92 Hz, 1 H) 6.32 (dd, J = 15.18, 10.79 Hz, 1 H) 7.11 (t, J = 6.13 Hz, 1 H) 7.17 (d, J = 7.52 Hz, 1 H) 7.61 (t, J = 7.25 Hz, 1 H) 8.54 (d, J = 4.96 Hz, 1 H) 455.2 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6- pyridin-2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec- 4-en-6-yl] N,N-dimethylcarbamate [00254] 636.9 [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4- yl]hepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-cycloheptylpiperazine-1-carboxylate [00255] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.15-8.34 (m, 1H), 7.39 (s, 1H), 6.23- 6.42 (m, 2H), 6.14 (d, J = 11.3 Hz, 1H), 5.97 (ddd, J = 15.1, 7.8, 3.9 Hz, 1H), 5.30-5.58 (m, 2H), 4.94-5.18 (m, 2H), 3.60 (t, J = 6.3 Hz, 3H), 3.29-3.56 (m, 4H), 2.51 (d, J = 6.8 Hz, 4H), 2.30-2.44 (m, 1H), 2.16-2.29 (m, 1H), 1.91-2.11 (m, 4H), 1.70-1.89 (m, 6H), 1.64 (br. s., 5H), 1.45-1.62 (m, 8H), 1.34-1.44 (m, 4H), 1.18-1.33 (m, 4H), 1.10 (br. s., 1H), 0.78-1.02 (m, 3H) 662.9 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1- ylpyrimidin-4-yl)hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00256] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.03 (dd, J = 5.3, 1.8 Hz, 1H), 7.20 (s, 1H), 6.05-6.23 (m, 2H), 5.96 (d, J = 10.8 Hz, 1H), 5.74-5.87 (m, 1H), 5.13-5.38 (m, 2H), 4.82-5.01 (m, 2H), 4.35 (d, J = 4.3 Hz, 1H), 3.43-3.60 (m, 3H), 3.34 (d, J = 3.3 Hz, 1H), 3.20-3.31 (m, 4H), 2.42 (br. s., 1H), 2.33 (br. s., 4H), 2.01-2.27 (m, 3H), 1.72-1.96 (m, 3H), 1.65 (br. s., 6H), 1.58 (s, 4H), 1.51 (d, J = 7.0 Hz, 2H), 1.18-1.44 (m, 14H), 0.96-1.14 (m, 4H), 0.71-0.85 (m, 11H), 0.46 (q, J = 7.9 Hz, 5H) 793.3 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-[2-[(3S)-3-triethylsilyloxypyrrolidin-1- yl]pyrimidin-4-yl]hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00257] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 8.13 (dd, J = 5.0, 2.3 Hz, 1H), 7.64 (dd, J = 5.8, 3.3 Hz, 1H), 7.34-7.55 (m, 1H), 6.20-6.38 (m, 1H), 6.05 (d, J = 11.3 Hz, 1H), 5.78-5.93 (m, 1H), 5.36-5.65 (m, 2H), 4.87-5.13 (m, 2H), 4.53 (br. s., 1H), 3.91-4.19 (m, 3H), 3.53-3.81 (m, 5H), 3.31-3.48 (m, 3H), 3.18 (d, J = 11.5 Hz, 2H), 2.64-2.85 (m, 1H), 2.47- 2.63 (m, 1H), 2.42 (br. s., 1H), 2.34 (br. s., 1H), 2.20-2.31 (m, 1H), 2.17 (d, J = 6.0 Hz, 1H), 1.84-2.12 (m, 3H), 1.57- 1.81 (m, 8H), 1.55 (s, 2H), 1.51 (s, 4H), 1.39-1.46 (m, 2H), 1.10 (br. s., 1H), 0.94 (dd, J = 6.8, 4.8 Hz, 1H), 0.69-0.90 (m, 7H) 678.9 [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-[(3R)-3-hydroxypyrrolidin-1-yl]pyrimidin-4- yl]hepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4- cycloheptylpiperazine-1-carboxylate [00258] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.79-1.00 (m, 3 H) 1.28 (t, J = 7.15 Hz, 4 H) 1.42-1.67 (m, 6 H) 1.76 (s, 3 H) 1.78 -1.94 (m, 2 H)2.07 (s, 1 H) 2.20- 2.41 (m, 8 H) 2.52 (ddd, J = 10.04, 6.78, 3.26 Hz, 1 H) 3.40-3.57 (m, 4 H) 3.88 (t, J = 7.28 Hz, 1 H) 4.14 (q, J = 7.28 Hz, 1 H)4.97-5.19 (m, 2 H) 5.38 (dd, J = 14.93, 9.41 Hz, 1 H) 5.44-5.57 (m, 1 H) 6.02-6.21 (m, 2 H) 6.27-6.46 (m, 1 H) 7.08-7.21 (m, 1 H) 8.69-8.76 (m, 2 H) 511.32 [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-pyrimidin- 2-ylhepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] 4- methylpiperazine-1-carboxylate
Compounds 135-138 were prepared according to the method of Scheme 6.

##STR00259## ##STR00260## ##STR00261##

General Protocol for the Synthesis of Compounds 135-138:

[0610] Step 1: To a solution of potassium tert-butoxide (1.05 g, 8.9 mmol, 1.05 equiv.) under nitrogen in DMF (20 mL, 0.4M) at room temperature was added 2-methylcyclohexanone MM (1.1 mL, 8.9 mmol, 1.0 equiv.) and the reaction was stirred for 15 hours. The reaction was cooled to 0° C. and allyl chloroformate (1.1 mL, 10.7 mmol, 1.2 equiv) was added dropwise over 5 min. and stirred for 30 min. The reaction was allowed to warm to room temperature and quenched into water. The reaction was extracted with 2:1 dichloromethane/hexanes, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/diethyl ether as eluant) to afford the desired product (ally (2-methylcyclohex-1-en-1-yl) carbonate, NN, 0.7 g, 3.6 mmol, 40%).

[0611] Step 2: To a mixture of (R)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-4,5-dihydrooxazole NN (0.01 g, 0.03 mmol, 0.1 equiv.) and of tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.01 mmol, 0.05 equiv.) was added degassed THF (2.5 mL, 0.01M) under argon. The reaction was allowed to stir at room temperature for 30 min. Allyl (2-methylcyclohex-1-en-1-yl) carbonate (0.1 g, 0.25 mmol, 1.0 equiv.) was added and stirred for 8 hr. Then the reaction was allowed to stand at −20° C. for 16 hr. The reaction was concentrated in vacuo and the resulting crude material was purified by silica gel column chromatography (pentane/diethyl ether as eluent) to afford the desired product ((R)-2-allyl-2-methylcyclohexanone, OO, (0.02 g, 0.12 mmol, 46%).

[0612] Step 3: To a solution of OO (33 mg, 0.22 mmol, 1.0 equiv.) in dichloromethane (4.0 mL, 0.05M) at 0° C. was added sodium bicarbonate (0.13 g, 1.2 mmol, 5.6 equiv.) followed by the addition of peracetic acid (0.17 mL, 0.76 mmol, 30% wt in acetic acid, 3.5 equiv.). The reaction was allowed to warm to room temperature over 4 hours and then stirred at room temperature for an additional 10 hours. The reaction was quenched with sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the desired product (R)-7-allyl-7-methyloxepan-2-one (PP, 0.04 g, 0.22 mmol, 100%) which was advanced crude into the next step.

[0613] Step 4: To a solution of PP (0.04 g, 0.22 mmol, 1.0 equiv.) in anhydrous methanol (6.0 mL, 0.04M) under nitrogen at room temperature was added triethylamine (0.15 mL, 5 equiv.). The reaction was stirred for 8 hours at 90° C. The reaction was cooled to room temperature and potassium carbonate (6.0 mg, 0.04 mmol, 0.2 equiv.) was added. The reaction was stirred for an additional 14 hours at room temperature after which time the reaction was determined to be complete by LCMS or TLC. The reaction was filtered and concentrated to afford the desired product (QQ, 0.04 g, 0.22 mmol, 100%) which was advanced crude into the next step.

[0614] Step 5: To a cooled solution of QQ (0.7 g, 3.6 mmol, 1.0 equiv.) and 2,6-lutidine (0.8 mL, 7.2 mmol, 2 equiv.) in dichloromethane (7 mL, 0.05M) at −78° C. was added dropwise triethylsilyl trifluoromethansulfonate (0.98 mL, 4.3 mmol, 1.2 equiv.). The reaction was stirred at −78° C. for 1 hour after which time the reaction was determined to be complete by LCMS or TLC. The reaction was allowed to warm to room temperature, quenched with sodium bicarbonate, and extracted with dichloromethane. The combined organic fractions were washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (RR, 0.7 g, 2.3 mmol, 63%).

[0615] Step 6: To a cooled solution of RR (0.04 g, 0.13 mmol, 1 equiv.) in THF (2.5 mL, 0.06M) at 0° C. was added hydrogen peroxide (0.06 mL, 30%, 5 equiv.), followed by a solution of lithium hydroxide (0.07 g, 0.64 mmol, 5 equiv.) in water (0.5 mL). The reaction was warmed to room temperature, methanol (8 mL) was added, and the reaction was stirred for 48 hours at room temperature. The reaction was quenched with sodium sulfite followed by saturated citric acid. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (SS, 0.02 g, 0.06 mmol, 47%).

[0616] Step 7: To a solution of acid SS (0.02 g, 0.06 mmol, 1.0 equiv.) in dichloromethane (1.0 mL, 0.06M) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.02 g, 0.09 mmol, 1.5 equiv) and a solution of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol (0.023 g, 0.09 mmol, 1.5 equiv.). The reaction was run for 16 hours and determined to be complete by TLC. The reaction was quenched with water, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (TT, 0.02 g, 0.04 mmol, 63%).

[0617] Step 8: To a degassed solution of olefin TT (0.02 g, 0.04 mmol, 1.0 equiv.) and benzoquinone (0.4 mg, 0.004 mmol, 0.1 equiv) in toluene (10.0 mL, 0.04M) under nitrogen at 20° C. was added the Hoveyda-Grubbs catalyst (0.006 g, 0.01 mmol, 0.2 equiv.). The reaction was stirred at 50° C. for 2 hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes as eluent) to afford the desired product (UU, 0.01 g, 0.02 mmol, 53%).

[0618] Step 9: To a solution of macrocycle UU (0.01 g, 0.02 mmol, 1.0 equiv.) in dioxane (2 mL, 0.1M) under nitrogen was added selenium dioxide (0.007 g, 0.06 mmol, 3.0 equiv.) under nitrogen at room temperature. The reaction was stirred at 85° C. for 20 hours. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes as eluent) to afford the desired product (VV, 0.007 g, 0.013 mmol, 68%).

[0619] Step 10: To a solution of alcohol VV (1.0 equiv.) in MTBE (0.1M) at room temperature was added triethylamine (5.0 equiv.), para-nitrophenylchloroformate (3.0 equiv.), and DMAP (catalytic) and the reaction was stirred overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched with water. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (XX) was advanced without purification.

[0620] Step 11: To a solution of carbonate XX (1.0 equiv.) in MTBE (0.1M) at room temperature was added the corresponding amine (2.0 equiv.). Once determined to be complete by TLC or LCMS, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (YY).

[0621] Step 12: To a solution of vinyl iodide YY (1.0 equiv.) in THF (0.1M) at room temperature was added vinyl pinacol boronate (4.0 equiv.), silver oxide (5.0 equiv.), triphenylarsine (1.2 equiv.), and Pd.sub.2(dba).sub.3 (0.15 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was filtered through Celite®. Dichloromethane was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (ZZ).

[0622] Step 13: To a solution of diene ZZ (1.0 equiv.) in THF:H.sub.2O (0.1M) at 0° C. was added N-methylmorpholine N-oxide (1.2 equiv.) and osmium tetroxide in t-BuOH (0.1 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched by addition of aqueous sodium bicarbonate. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material (AAA) was advanced without further purification.

[0623] Step 14: To a solution of diol AAA (1.0 equiv.) in acetone: H.sub.2O (0.1M) at room temperature was added diacetoxyiodobenzene (1.2 equiv.). The reaction was stirred at room temperature for 40 minutes or until determined to be complete by TLC or LCMS. The reaction was quenched by addition of sodium thiosulfite and then sodium bicarbonate. Dichloromethane was added, and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (BBB).

[0624] Step 15: To a solution of the corresponding sulfone (1.0 equiv.) in THF (0.1M) at −78° C. was added KHMDS (3.0 equiv.) and the reaction was stirred at −78° C. for one hour. Next, a solution of aldehyde BBB in THF (1.0 equiv.) was added dropwise at −78° C. The reaction was allowed to warm gradually to −20° C. and stirred at −20° C. for two hours. The reaction was quenched with aqueous sodium bicarbonate and ethyl acetate was added. The organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (CCC).

[0625] Step 16: To a solution of silyl ether CCC in methanol (0.1M) at room temperature was added p-methoxytoluenesulfonic acid (2.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (135-138), (Table 5).

Exemplified Protocol for the Synthesis of Compound 135

[0626] Steps 1-9 as above.

[0627] Step 10: To a solution of alcohol VV (0.007 g, 0.013 mmol, 1.0 equiv.) in MTBE (1.0 mL, 0.1M) at room temperature was added triethylamine (0.02 mL, 0.09 mmol, 7.0 equiv.), para-nitrophenyl chloroformate (0.009 g, 0.05 mmol, 3.5 equiv.), and DMAP (2.0 mg, 0.016 mmol, 1.2 equiv.). The reaction was stirred overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched with water. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (XX) was advanced without purification.

[0628] Step 11: To a solution of carbonate XX (1.0 equiv.) in MTBE (1.0 mL, 0.1M) at room temperature was added N-methylpiperazine (0.007 mL, 0.07 mmol, 5.0 equiv.). Once determined to be complete by TLC or LCMS, the reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (YY, 0.008 g, 0.012 mmol, 92%).

[0629] Step 12: To a solution of vinyl iodide YY (0.01 g, 0.015 mmol, 1.0 equiv.) in THF (1.0 mL, 0.01M) at room temperature was added vinyl pinacol boronate (0.013 mL, 0.08 mmol, 5.0 equiv.), silver oxide (18.0 mg, 0.08 mmol, 5.0 equiv.), triphenylarsine (5.7 mg, 0.02 mmol, 1.2 equiv.), and Pd.sub.2(dba).sub.3 (3.0 mg, 0.003 mmol, 0.15 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was filtered through Celite®. Dichloromethane was added and the organic layer was washed with water and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (ZZ, 0.009 g, 0.016 mmol, >95%).

[0630] Step 13: To a solution of diene ZZ (0.009 g, 0.016 mmol, 1.0 equiv.) in THF:H.sub.2O (2.0 mL:0.2 mL, 0.1M) at 0° C. was added N-methylmorpholine N-oxide (3.2 mg, 0.03 mmol, 1.5 equiv.) and osmium oxide in t-BuOH (0.05 mL, 0.004 mmol, 0.2 equiv.). The reaction was stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was quenched by addition of aqueous sodium bicarbonate. Ethyl acetate was added and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material (AAA, 0.008 g, 0.014 mmol, 75%) was advanced without further purification.

[0631] Step 14: To a solution of diol AAA (0.07 g, 0.12 mmol, 1.0 equiv.) in acetone:H20 (5 mL:0.5mL, 0.02M) at room temperature was added diacetoxyiodobenzene (0.048 g, 0.15 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 40 minutes or until determined to be complete by TLC or LCMS. The reaction was quenched by addition of sodium thiosulfilte and then sodium bicarbonate. Dichloromethane was added, and the organic layer was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (BBB, 60 mg, 0.11 mmol, 87%).

[0632] Step 15: To a solution of (S)-2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl pyrrolidine-1-carboxylate (0.026 g, 0.07 mmol, 2.5 equiv.) in THF (2.0 mL, 0.01M) at −78° C. was added KHMDS (0.14 mL, 0.07 mmol, 2.5 equiv.) and the reaction was stirred at −78° C. for one hour. Next, a solution of aldehyde BBB (0.015 g, 0.03 mmol, 1.0 equiv.) was added dropwise at −78° C. The reaction was allowed to warm gradually to −20° C. and stirred at −20° C. for two hours. The reaction was quenched with aqueous sodium bicarbonate and ethyl acetate was added. The organic layer was washed with water and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (CCC, 0.016 mg, 0.023 mmol, 76%).

[0633] Step 16: To a solution of silyl ether CCC (0.016 g, 0.023 mmol, 1 equiv.) in methanol (0.2 mL, 0.1M) at room temperature was added p-methoxytoluenesulfonic acid (8.0 mg, 0.04 mmol, 1.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (compound 135, 7 mg, 0.012 mmol, 44%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.89 (d, J=6.78 Hz, 3H) 1.09 (d, J=6.90 Hz, 3H) 1.13-1.31 (m, 5H) 1.35-1.53 (m, 2H) 1.75-1.80 (m, 3H) 1.82-1.94 (m, 5H) 1.94-2.08 (m, 1H) 2.39 (s, 2H) 2.53-2.66 (m, 2H) 2.69 (s, 3H) 2.94 (br. s., 4H) 3.34-3.40 (m, 4H) 3.70 (br. s., 4H) 3.91-4.03 (m, 2H) 4.93-4.99 (m, 1H) 5.07-5.13 (m, 1H) 5.55 (dd, J=15.12, 9.85 Hz, 1H) 5.71 (m, J=9.79 Hz, 2H) 6.13 (d, J=10.67 Hz, 1H) 6.37 (ddd, J=15.12, 10.85, 1.00 Hz, 1H). MS (ES+)=590.5 [M+H].sup.+.

TABLE-US-00008 TABLE 5 Compounds 135-138 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00262] .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.89 (d, J = 6.78 Hz, 3 H) 1.09 (d, J = 6.90 Hz, 3 H) 1.13-1.31 (m, 5 H) 1.35-1.53 (m, 2 H) 1.75- 1.80 (m, 3 H) 1.82-1.94 (m, 5 H) 1.94-2.08 (m, 1 H) 2.39 (s, 2 H) 2.53-2.66 (m, 2 H) 2.69 (s, 3 H) 2.94 (br. s., 4 H) 3.34-3.40 (m, 4 H) 3.70 (br. s., 4 H) 3.91-4.03 (m, 2 H) 4.93- 4.99 (m, 1 H) 5.07-5.13 (m, 1 H) 5.55 (dd, J = 15.12, 9.85 Hz, 1 H) 5.71 (m, J = 9.79 Hz, 2 H) 6.13 (d, J = 10.67 Hz, 1 H) 6.37 (ddd, J = 15.12, 10.85, 1.00 Hz, 1 H) 590.5 [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec- 4-en-6-yl] 4-methylpiperazine-1-carboxylate [00263] .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.89 (d, J = 6.65 Hz, 3 H) 1.10 (d, J = 6.78 Hz, 3 H) 1.13-1.31 (m, 5 H) 1.35-1.53 (m, 2 H) 1.78 (s, 3 H) 1.81-2.08 (m, 6 H) 2.25- 2.46 (m, 2 H) 2.52-2.62 (m, 1 H) 2.64 (s, 3 H) 2.88 (d, J = 2.01 Hz, 4 H) 3.36-3.45 (m, 2 H) 4.00 (d, J = 7.15 Hz, 10 H) 4.95 (d, J = 9.79 Hz, 1 H) 5.10 (d, J = 10.67 Hz, 1 H) 5.55 (dd, J = 15.18, 9.91 Hz, 1 H) 5.70 (m, J = 3.14 Hz, 2 H) 6.11 (d, J = 10.29 Hz, 1 H) 6.38 (dd, J = 15.00, 10.73 Hz, 1 H) 620.5 [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2- (hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1- carboxylate [00264] .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.89 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.90 Hz, 3 H) 1.21 (s, 5 H) 1.31 (s, 8 H) 1.78 (d, J = 0.88 Hz, 3 H) 1.80-2.09 (m, 5 H) 2.32 (s, 3 H) 2.42 (t, J = 5.08 Hz, 6 H) 2.51-2.71 (m, 2 H) 3.41-3.75 (m, 8 H) 3.99 (m, J = 6.71, 4.08 Hz, 2 H) 4.38 (br. s., 1 H) 4.94 (d, J = 9.79 Hz, 1 H) 5.10 (d, J = 10.67 Hz, 1 H) 5.54 (dd, J = 15.18, 9.91 Hz, 1 H) 5.70 (d, J = 9.79 Hz, 2 H) 6.11 (d, J = 10.16 Hz, 1 H) 6.38 (dd, J = 15.06, 10.54 Hz, 1 H) 606.5 [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1- carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec- 4-en-6-yl] 4-methylpiperazine-1-carboxylate [00265] .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.77-0.92 (m, 3 H) 1.07 (t, J = 7.65 Hz, 3 H) 1.13-1.31 (m, 5 H) 1.33-1.52 (m, 2 H) 1.72 (s, 3 H) 1.80-1.91 (m, 1 H) 1.92-2.07 (m, 1 H) 2.22-2.46 (m, 4 H) 2.51 (s, 3 H) 2.55-2.65 (m, 1 H) 2.69 (br. s., 4 H) 3.42-3.91 (m, 9 H) 3.99 (d, J = 6.02 Hz, 2 H) 4.94 (d, J = 9.79 Hz, 1 H) 5.01-5.11 (m, 1 H) 5.45-5.59 (m, 1 H) 5.60-5.79 (m, 3 H) 5.97-6.14 (m, 1 H) 6.35 (dd, J = 14.81, 10.79 Hz, 1 H) 7.50-7.66 (m, 3 H) 7.71 (d, J = 7.53 Hz, 2 H) 750.5 [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-(1-phenyltetrazol- 5-yl)oxypyrrolidine-1-carbonyl]oxyhepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate
Compounds 139-142 were prepared by the method of Scheme 7.

##STR00266## ##STR00267## ##STR00268##

General Protocol for the Synthesis of Compounds 139-142

[0634] Step 1: To a solution of methyl 4-oxopentanoate DDD (10.0 g, 76.8 mmol, 1.0 equiv.) and allyltrimethylsilane (13.4 mL, 84.5 mmol, 1.1 equiv.) under nitrogen in THF (13.4 mL, 6M) at room temperature was added TBAF (1.0 g, 3.8 mmol, 0.05 equiv.) and 4Å molecular sieves (0.2 equiv. wt). The reaction was stirred at reflux for 36 hours. The reaction was filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (5-allyl-5-methyldihydrofuran-2(3H)-one) (EEE, 5.8 g, 21.7 mmol, 28%).

[0635] Step 2: To a cooled solution of N,O-dimethylhydroxylamine hydrochloride (1.7 g, 17.8 mmol, 5.0 equiv.) in THF (20.0 mL, 0.9M) under nitrogen at 0° C. was added trimethylaluminum (7.1 mL, 14.3 mmol, 4.0 equiv.). The reaction was stirred at room temperature for 30 min. A solution of 5-allyl-5-methyldihydrofuran-2(3H)-one, EEE, (0.5 g, 3.6 mmol, 1.0 equiv.) in THF (5.0 mL) was added at 0° C. and the reaction was stirred for 2 hours. The reaction was poured onto a cooled mixture of ethyl acetate and saturated potassium tartrate and stirred for 15 mins. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product (4-hydroxy-N-methoxy-N,4-dimethylhept-6-enamide, FFF) which was advanced crude into the next step.

[0636] Step 3: To a solution of 4-hydroxy-N-methoxy-N,4-dimethylhept-6-enamide FFF (1.0 equiv) in DMF (20.0 mL, 0.9M) at room temperature was added 1H-imidazole (1.2 g, 17.8 mmol, 5.0 equiv.) and chlorotriethylsilane (2.4 mL, 14.3 mmol, 4.0 equiv.). The reaction was stirred at room temperature for 12 hours. The reaction was diluted with brine and extracted with diethyl ether. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired product (N-methoxy-N,4-dimethyl-4-((triethylsilyl)oxy)hept-6-enamide (GGG, 0.56 g, 1.8 mmol, 50%).

[0637] Step 4: To a solution of amide GGG (0.25 g, 0.79 mmol, 1.0 equiv.) in THF (6.0 mL, 0.13M) under nitrogen at −78° C. was added DIBAL-H (1.3 mL, 1.3 mmol, 1.6 equiv.) and stirred for one hour. The reaction was quenched with aqueous hydrochloric acid (1M) and stirred for an additional 15 min. The reaction was extracted with ethyl acetate and the combined organic fractions were concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired product (4-methyl-4-((triethylsilyl)oxy)hept-6-enal, HHH, 0.19 g, 0.74 mmol, 93%).

[0638] Step 5: To a solution of (S)-3-acetyl-4-benzyloxazolidin-2-one HHH (0.15 g, 0.68 mmol, 1 equiv.) in dichloromethane (3.0 mL, 0.2M) under nitrogen at −78° C. was added dibutyl(((trifluoromethyl)sulfonyl)oxy)borane (0.75 mL, 0.75 mmol, 1M toluene, 1.1 equiv.), followed by diisopropylethylamine (0.15 mL, 0.89 mmol, 1.3 equiv.). The reaction was sucessively stirred at −78° C. for 15 min., at 0° C. for 1 hour, and then at −78° C. for 30 min. To the cooled reation mixture was added dropwise 4-methyl-4-((triethylsilyl)oxy)hept-6-enal (0.17 g, 0.68 mmol, 1.0 equiv.) followed by stirring at room temperature for 2 hours. The reaction was quenched with ammonia chloride and extracted with dichloromethane. The combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired diastereomeric products as a separable mixture (III-A and III-B). The stereochemistry of each diastereoisomer was assigned according to their NOE data and cross peak between H4 and H8.

##STR00269##

[0639] .sup.1H NMR (CHLOROFORM-d) δ: 7.09-7.28 (m, 2H), 5.74 (dd, J=17.7, 9.2 Hz, 1H), 4.96 (d, J=11.8 Hz, 1H), 4.54-4.65 (m, 1H), 3.99-4.14 (m, 1H), 3.15-3.27 (m, 1H), 3.05-3.14 (m, 1H), 3.00-3.04 (m, 1H), 2.88-2.98 (m, 1H), 2.63-2.71 (m, 1H), 2.15 (d, J=6.3 Hz, 1H), 1.52-1.59 (m, 1H), 1.20-1.49 (m, 4H), 1.10-1.16 (m, 1H), 0.68-0.91 (m, 7H), 0.47-0.56 (m, 2H).

[0640] .sup.13C NMR (CHLOROFORM-d) δ: 171.2, 153.5, 153.4, 135.4, 135.3, 135.2, 135.1, 135.0, 135.0, 129.4, 129.0, 129.0, 128.9, 127.4, 127.4, 127.3, 117.2, 117.2, 117.1, 117.1, 77.3, 76.4, 75.0, 74.9, 68.5, 66.3, 66.2, 66.2, 66.1, 55.2, 55.2, 55.1, 55.1, 47.3, 46.9, 38.0, 37.9, 37.8, 33.8, 31.2, 31.1, 31.0, 29.8, 27.8, 27.7, 27.6, 27.6, 26.6, 26.5, 26.5, 25.8, 25.5, 25.5, 25.3, 19.2, 19.1, 19.0, 18.9, 14.1, 14.0, 14.0, 13.9, 13.8, 13.8, 7.2, 6.9.

##STR00270##

[0641] .sup.1H NMR (CHLOROFORM-d) δ: 7.27-7.37 (m, 6H), 7.22 (d, J=6.8 Hz, 4H), 5.78-5.87 (m, 1H), 5.03-5.09 (m, 3H), 4.66-4.74 (m, 2H), 4.06-4.25 (m, 6H), 3.28-3.34 (m, 2H), 3.05-3.12 (m, 3H), 2.79-2.83 (m, 1H), 2.57 (s, 2H), 2.20-2.29 (m, 3H), 1.59-1.70 (m, 4H), 1.45-1.54 (m, 2H), 1.31-1.41 (m, 1H), 1.20-1.29 (m, 6H), 0.93-1.00 (m, 15H), 0.57-0.64 (m, 9H).

[0642] .sup.13C NMR (CHLOROFORM-d) δ: 172.8, 172.8, 171.1, 170.3, 153.7, 153.5, 135.3, 135.1, 135.0, 135.0, 129.4, 129.0, 129.0, 128.9, 127.4, 127.4, 117.2, 117.2, 76.8, 75.0, 75.0, 68.6, 68.5, 66.3, 66.1, 60.4, 55.1, 55.1, 55.0, 53.5, 47.3, 47.0, 42.9, 42.8, 38.0, 38.0, 37.8, 37.8, 31.1, 31.1, 30.7, 27.8, 27.6, 26.6, 25.5, 23.8, 21.0, 19.1, 14.2, 14.0, 13.9, 13.7, 7.2, 6.9, 6.8, 6.6.

[0643] Similar protocols were used for III-A and III-B

[0644] Step 6: To a solution of alcohol III-A (1.0 equiv) in DMF (0.09M) at room temperature was added 1H-imidazole (5.0 equiv.) and tert-butylchlorodimethylsilane (2.5 equiv.). The reaction was stirred under nitrogen at room temperature for 3 hours. The reaction was diluted with brine and extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired product (JJJ-A).

[0645] Step 7: To a cooled solution JJJ-A (1.0 equiv.) in THF (0.9M) at 0° C. was added hydrogen peroxide (7.6 equiv.), followed by a solution of lithium hydroxide (8.0 equiv.) in water (0.8M). The reaction was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction was quenched with sodium thiosulfate. The mixture was extracted with ethyl acetate, acidified to pH 3, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired acid (KKK-A). Step 8: To a solution of acid KKK-A (1.0 equiv.) and freshly prepared (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol (1.4 equiv.) (For protocols related to the synthesis of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol, see: Kumar, V. P.; Chandrasekhar, S. Org. Lett. 2013, 15, 3610-3613) in dichloromethane (0.08M) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.3 equiv) and DMAP (catalytic). The reaction was stirred at room temperature for 16 hours and determined to be complete by TLC. The reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the desired ester (LLL-A).

[0646] Step 9: To a degassed solution of olefin LLL-A (1.0 equiv.) and benzoquinone (0.05 equiv) in toluene (0.01M) under nitrogen at 20° C. was added the Hoveyda-Grubbs catalyst 0.1 equiv.). The reaction was stirred at 50° C. for 2 hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes as eluent) to afford the desired product (MMM-A).

[0647] Step 10: To solution of solution of macrocycle MMM-A (1.0 equiv.) in dioxane (0.1M) under nitrogen was added selenium dioxide (4.0 equiv.) under nitrogen at room temperature. The reaction was stirred at 85° C. for 20 hours. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes as eluent) to afford the desired diastereoisomer products: a separable mixture (NNN-A) and (000-A). The stereochemistry of each diastereoisomer was assigned according to their COSY, HMBC, HMQC and NOESY data.

##STR00271##

[0648] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.03-0.03 (m, 4H) 0.49-0.63 (m, 5H) 0.80-0.94 (m, 15H) 1.16-1.23 (m, 3H) 1.25-1.45 (m,3H) 1.39-1.50 (m, 6H) 1.63-1.86 (m, 3H) 2.06 (s, 1H) 2.22-2.48 (m, 2H) 3.73 (dd, J=8.16, 3.89 Hz, 1H) 3.92 (d, J=10.29 Hz, 1H) 3.88-3.96 (m, 1H) 5.06 (d, J=10.79 Hz, 1H) 5.33 (dd, J=15.06, 9.79 Hz, 1H) 5.49 (dd, J=15.06, 9.79 Hz, 1H) 6.40 (d, J=1.00 Hz, 1H) 6.37-6.44 (m,1H) 7.20 (s, 3H).

[0649] .sup.13C NMR (100 MHz, CHLOROFORM-d) δ ppm −4.9, −4.8, 6.8, 7.1, 16.5, 18.1, 19.3, 22.9, 25.8, 29.0, 36.9, 40.4, 40.6, 70.2, 76.7, 78.2, 79.3, 80.8, 83.8, 128.9, 138.4, 143.8, 168.7.

##STR00272##

[0650] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.03-0.02 (m, 6H) 0.47-0.68 (m, 6H) 0.78-0.95 (m, 21H) 1.15-1.35 (m, 6H) 1.37-1.58 (m, 7H) 1.66-1.80 (m, 3H) 2.24-2.48 (m, 3H) 2.56 (d, J=10.79 Hz, 1H) 3.49 (t, J=10.16 Hz, 1H) 3.64-3.80 (m, 1H) 5.05 (d, J=10.54 Hz, 1H) 5.29 (dd, J=15.31, 9.79 Hz, 1H) 5.53 (dd, J=15.31, 9.54 Hz, 1H) 6.38 (d, J=1.00 Hz, 1H) 7.19 (s, 3H).

[0651] .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm −4.8, −4.7, 6.8, 7.1, 16.6, 18.1, 19.2, 24.6, 25.7, 25.8, 30.7, 37.8, 40.6, 41.0, 70.8, 77.2, 77.8, 77.9, 80.5, 83.6, 130.9, 135.6, 143.9, 168.6. NNN-B and OOO-B were isolated using similar procedures starting from III-B

##STR00273##

[0652] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.06-0.04 (m, 6H) −0.02-0.02 (m, 6H) 0.48-0.66 (m, 6H) 0.77-0.94 (m, 20H) 1.16-1.25 (m, 4H) 1.26-1.44 (m, 2H) 1.50 (s, 2H) 1.56-1.72 (m, 2H) 1.74-1.80 (m, 3H) 2.04 (s, 1H) 2.29-2.49 (m, 3H) 2.40-2.50 (m, 1H) 3.80-4.02 (m, 1H) 4.24 (td, J=6.34, 2.64 Hz, 1H) 5.16 (d, J=10.54 Hz, 1H) 5.31-5.41 (m, 2H) 6.39 (d, J=1.00 Hz, 1H) 7.20 (s, 1H).

[0653] .sup.13C NMR (100 MHz, CHLOROFORM-d) δ ppm −5.2, −4.8, 6.7, 7.2, 16.5, 18.0, 19.2, 23.1, 25.8, 26.5, 32.1, 40.6, 40.9, 68.5, 77.2, 78.0, 79. 0, 80.0 , 83.7, 129.5, 137.9, 143.8, 170.1.

##STR00274##

[0654] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.03-0.04 (m, 6H) 0.49-0.70 (m, 6H) 0.78-0.98 (m, 21H) 1.13-1.35 (m, 7H) 1.51 (s, 3H), 1.55-1.67 (m, 1H) 1.69-1.88 (m, 4H) 2.31-2.52 (m, 3H) 2.60 (d, J=11.04 Hz, 1H) 3.45 (t, J=10.29 Hz, 1H) 4.16-4.32 (m, 1H) 5.05-5.25, (m, 2H) 5.57 (dd, J=15.31, 9.79 Hz, 1H) 6.40 (d, J=1.00 Hz, 1H) 7.22 (s, 1H).

[0655] .sup.13C NMR (100 MHz, CHLOROFORM-d) δ ppm −4.90, 6.8, 6.9, 6.9, 7.1, 7.2, 16.4, 17.8, 19.1, 24.3, 25.6, 25.8, 28.1, 29.7, 31.6, 40.4, 41.2, 67.8, 77.2, 77.7, 78.0, 79.9, 83.6, 131.6, 134.6, 143.9, 170.0.

[0656] Step 11: To a solution of NNN-A (1.0 equiv.) in THF (0.1M) at room temperature was added the corresponding 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.0 equiv.), monosilver(I) monosilver(III) monooxide (5.0 equiv.), triphenylarsine (1.2 equiv.), and tetrakis(triphenylphosphine) palladium (0.15 equiv.). The reaction mixture was heated at 60° C. for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was cooled down to room temperature, the mixture was then filtered through Celite®, washed with dichloromethane and concentrated in vacuo. The crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired product (PPP-A)

[0657] Step 12: To a solution of alcohol PPP-A (1.0 equiv.) in dichloromethane (0.1M) at room temperature was added DMAP (0.5 equiv.) followed by 4-nitrophenyl chloroformate (2.0 equiv.). The reaction was stirred at room temperature for three hours. Next, the corresponding amine (3.0 equiv.) was added at room temperature. After stirring for one hour, the reaction was quenched with water and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution, and the organic layer was concentrated. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluant) to afford the desired product (QQQ-A).

[0658] Step 13: To a solution of silyl ether QQQ-A (1 equiv.) in methanol (0.1M) at room temperature was added p-methoxytoluenesulfonic acid (1.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (RRR-A).

[0659] Other diastereoisomers (OOO-A, NNN-B and OOO-B) were subjected to the procedures to afford compounds 139-142.

Exemplified Protocol for the Synthesis of Compound 140

[0660] Steps 1-5 as above.

[0661] Step 6: To a solution of alcohol III-A (0.14 g, 0.3 mmol, 1.0 equiv) in DMF (3.2 mL, 0.09M) at room temperature was added 1H-imidazole (0.10 g, 1.5 mmol, 5.0 equiv.) and tert-butylchlorodimethylsilane (0.11 g, 0.75 mmol, 2.5 equiv.). The reaction was stirred under nitrogen at room temperature for 3 hours. The reaction was diluted with brine and extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired product (JJJ-A, 0.16 g, 0.27 mmol, 92%).

[0662] Step 7: To a cooled solution of JJJ-A (0.16 g, 0.27 mmol, 1.0 equiv.) in THF (0.9M) at 0° C. was added hydrogen peroxide (0.25 mL, 2.3 mmol, 30%, 7.6 equiv.), followed by a solution of lithium hydroxide (0.06 g, 2.4 mmol, 8.0 equiv.) in water (3.0 mL, 0.8M). The reaction was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction was quenched with sodium thiosulfate. The mixture was extracted with ethyl acetate, acidified to pH 3, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired acid (KKK-A, 0.10 g, 0.24 mmol, 80%).

[0663] Step 8: To a solution of acid KKK-A (0.10 g, 0.24 mmol, 1.0 equiv.) and (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol (0.16 g, 0.45 mmol, 1.9 equiv.) in dichloromethane (3.0 mL, 0.08M) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.06 g, 0.31 mmol, 1.3 equiv) and one crystal of DMAP. The reaction was stirred at room temperature for 16 hours and determined to be complete by TLC. The reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the desired ester (LLL-A, 0.17 g, 0.25 mmol, >95%).

[0664] Step 9: To a degassed solution of olefin LLL-A (41.0 mg, 0.06 mmol, 1.0 equiv.) and benzoquinone (0.4 mg, 0.003 mmol, 0.05 equiv) in toluene (6.0 mL, 0.01M) under nitrogen at 20° C. was added the Hoveyda-Grubbs catalyst (4.0 mg, 0.006 mmol, 0.1 equiv.). The reaction was stirred at 50° C. for 2 hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude macrocycle (MMM-A) was carried on to the next step without further purification.

[0665] Step 10: To a solution of macrocycle MMM-A (1.0 equiv.) in dioxane (2 mL, 0.1M) under nitrogen was added selenium dioxide (30.0 mg, 0.25 mmol, 4.0 equiv.) under nitrogen at room temperature. The reaction was stirred at 85° C. for 20 hours. The reaction was diluted with ethyl acetate, and the organic layer was washed with sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes as eluent) to afford the desired separable diastereoisomer products as (NNN-A, 5.5 mg, 0.008 mmol, 13%) and (OOO-A, 6.4 mg, 0.010 mmol, 16%).

[0666] Step 11: To a solution of NNN-A (10.0 mg, 0.015 mmol, 1.0 equiv.) in THF (1.0 mL, 0.01M) at room temperature was added (R,E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl pyrrolidine-1-carboxylate (18.0 mg, 0.06 mmol, 3.8 equiv.), monosilver(I) monosilver(III) monooxide (14.2 mg, 0.06 mmol, 4.0 equiv.), triphenylarsine (5.6 mg, 0.02 mmol, 1.2 equiv.), and tetrakis(triphenylphosphine) palladium (2.1 mg, 0.002 mmol, 0.15 equiv.). The reaction mixture was heated to 60° C. for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was cooled down to room temperature, the mixture was then filtered through Celite®, washed with dichloromethane and concentrated in vacuo. The crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired product (PPP-A, 5.3 mg, 0.006 mmol, 80%).

[0667] Step 12: To a solution of alcohol PPP-A (5.0 mg, 0.007 mmol, 1.0 equiv.) in dichloromethane (0.5 mL, 0.01M) at room temperature was added N,N-dimethylaminopyridine (0.4 mg, 0.003 mmol, 0.5 equiv.) followed by 4-nitrophenyl chloroformate (5.0 mg, 0.02 mmol, 3.5 equiv.). The reaction was stirred at room temperature for three hours. Next, N-methyl piperazine (0.004 mL, 0.03 mmol, 4.5 equiv.) was added at room temperature. After stirring for one hour, the reaction was quenched with water and diluted with dichloromethane. The organic layer was washed with 1N sodium hydroxide solution, and the organic layer was concentrated. The resulting crude carbamate (QQQ-A) was used in the nest step without further purification.

[0668] Step 13: To a solution of carbamate QQQ-A (1.0 equiv.) in methanol (0.1M) at room temperature was added p-methoxytoluenesulfonic acid (2.7 mg, 0.014 mmol, 2.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 140, 2.7 mg, 0.005 mmol, 63%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.00 (s, 1H) 0.06 (s, 1H) 0.65 (s, 1H) 0.74-0.96 (m, 3H) 0.98-1.18 (m, 3H) 1.18-1.45 (m, 5H) 1.61 (d, J=7.28 Hz, 1H) 1.68-1.81 (m, 2H) 1.84 (br. s., 3H) 2.05 (d, J=11.80 Hz, 2H) 2.37 (s, 4H) 2.44 (d, J=14.56 Hz, 2H) 2.50-2.77 (m, 5H) 3.13 (d, J=18.32 Hz, 1H) 3.24 (d, J=6.27 Hz, 1H) 3.26-3.42 (m, 3H) 3.31 (br. s., 1H) 3.37 (br. s., 2H) 3.56 (br. s., 2H) 3.48-3.64 (m, 3H) 3.64 (br. s., 1H) 3.70 (d, J=2.26 Hz, 1H) 3.82-4.03 (m, 2H) 5.16 (dd, J=10.04, 8.03 Hz, 2H) 5.29 (s, 1H) 5.39 (dd, J=14.93, 10.16 Hz, 1H), 5.52-5.75 (m, 2H) 6.09 (d, J=11.29 Hz, 1H) 6.17-6.40 (m, 1H) 6.98 (s, 1H) 7.25 (s, 5H) 7.51 (s, 1H).

TABLE-US-00009 TABLE 6 Compounds 139-142 LCMS data Structure, Compound#, and Chemical Name .sup.1H NMR data (ES+) [00275] .sup.1H NMR (400 MHz, CHLOROFORM- d) δ: 0.00 (s, 1 H) 0.72-0.91 (m, 4 H) 0.92-1.09 (m, 4 H) 1.10-1.30 (m, 4 H) 1.34-1.56 (m, 3 H) 1.56-1.69 (m, 4 H) 1.72-1.81 (m, 4 H) 1.84 (br. s., 1 H) 2.22-2.40 (m, 5 H) 2.40-2.57 (m, 7 H) 3.05 (s, 2 H) 3.09 (s, 1 H) 3.19 (br. s., 1 H) 3.22-3.28 (m, 2 H) 3.31 (br. s., 2 H) 3.49 (br. s., 4 H) 3.64 (s, 1 H) 3.78- 4.01 (m, 2 H) 4.31 (br. s., 1 H) 4.89- 5.11 (m, 2 H) 5.35 (dd, J = 15.31,10.04 Hz, 1 H) 5.51 (dd, J = 14.81, 9.79 Hz, 1 H) 5.62 (dd, J = 15.06, 7.53 Hz, 1 H) 6.03 (d, J = 10.79 Hz, 1 H) 6.20 (dd, J = 14.93, 10.92 Hz, 1 H) 7.19 (s, 2H) [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-methylpiperazine-1-carboxylate [00276] .sup.1H NMR (400 MHz, CHLOROFORM- d) δ: 0.00 (s, 1 H) 0.06 (s, 1 H) 0.65 (s, 1 H) 0.74-0.96 (m, 3 H) 0.98-1.18 (m, 3 H) 1.18-1.45 (m, 5H) 1.61 (d, J = 7.28 Hz, 1 H) 1.68-1.81 (m, 2 H) 1.84 (br. s., 3 H) 2.05 (d, J = 11.80 Hz, 2 H) 2.37 (s, 4 H) 2.44 (d, J = 14.56 Hz, 2 H) 2.50-2.77 (m, 5 H) 3.13 (d, J = 18.32 Hz, 1 H) 3.24 (d, J = 6.27 Hz, 1 H) 3.26-3.42 (m, 3 H) 3.31 (br. s., 1 H) 3.37 (br. s., 2 H) 3.56 (br. s., 2 H) 3.48- 3.64 (m, 3H) 3.64 (br. s., 1 H) 3.70 (d, J = 2.26 Hz, 1 H) 3.82-4.03 (m, 2 H) 5.16 (dd, J = 10.04, 8.03 Hz, 2 H) 5.29 (s, 1 H) 5.39 (dd, J = 14.93, 10.16 Hz, 1 H), 5.52-5.75 (m, 2 H) 6.09 (d, J = 11.29 Hz, 1 H) 6.17-6.40 (m, 1 H) 6.98 (s, 1 H) 7.25 (s, 5 H) 7.51 (s, 1 H) [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-methylpiperazine-1-carboxylate [00277] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.87 (d, J = 6.78 Hz, 3 H) 1.16- 1.25 (m, 5 H) 1.45 (d, J = 7.03 Hz, 5 H) 1.77 (s, 3 H) 1.81-1.91 (m, 1 H) 1.92-2.10 (m, 1 H) 2.26-2.38 (m, 2 H) 2.45 (s, 3 H) 2.55-2.65 (m, 5 H) 3.43- 3.85 (m, 5 H) 4.94 (d, J = 9.79 Hz, 1 H) 5.09 (d, J = 10.67 Hz, 1 H) 5.53 (dd, J = 15.06, 9.91 Hz, 1 H) 5.73 (m, J = 9.66 Hz, 1 H) 6.00 (dd, J = 15.18, 7.53 Hz, 1 H) 6.13 (d, J = 10.67 Hz, 1 H) 6.39 (dd, J = 15.06, 10.79 Hz, 1 H) 7.26-7.30 (m, 1 H) 7.35 (d, J = 7.91 Hz, 1 H) 7.79 (td, J = 7.72, 1.76 Hz, 1 H) 8.46 (d, J = 4.52 Hz, 1 H) 562.3 [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-12-oxo-2- [(2E,4E,6S)-6-pyridin-2-ylhepta-2,4-dien-2-yl]-1- oxacyclododec-4-en-6-yl] 4-methylpiperazine-1-carboxylate [00278] .sup.1H NMR (400 MHz, CHLOROFORM- d) δ: 0.00 (s, 1 H) 0.65-0.90 (m, 3 H) 0.91-1.07 (m, 3 H) 1.09-1.24 (m, 3 H) 1.28-1.45 (m, 2 H) 1.46-1.74 (m, 6 H) 1.78 (br. s., 4 H) 2.03 (br. s., 5 H) 2.35 (s, 4 H) 2.40-2.55 (m, 6 H) 2.82 (s, 1 H) 2.89 (s, 1 H) 3.25 (d, J = 5.27 Hz, 2 H) 3.31 (br. s., 2 H) 3.54 (br. s., 3 H) 3.89 (qd, J = 10.71, 6.78 Hz, 2 H) 4.30 (br. s., 1 H) 4.94 (dd, J = 18.07, 10.04 Hz, 2 H) 5.48 (dd, J = 15.31, 10.04 Hz, 1 H) 5.55-5.83 (m, 2 H) 5.55-5.72 (m, 1 H) 6.02 (d, J = 11.29 Hz, 1 H) 6.20 (dd, J = 14.31, 11.04 Hz, 1 H) 6.93 (s, 1 H) 7.19 (s, 6 H) 7.45 (s, 1 H) [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7- (pyrrolidine-1-carbonyloxy)hepta-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en- 6-yl] 4-methylpiperazine-1-carboxylate

Synthesis of Sulfone Intermediates for Preparation of Urea Compounds

[0669] ##STR00279##

General Protocol for the Synthesis of Sulfone Urea Side Chain

[0670] Step 1: To a solution of R(−)-3-bromo-2-methyl-1-propanol SSS (4.0 g, 26.1 mmol, 1.0 equiv.) in DMF (20.0 mL, 1.3M), was added sodium azide (5.1 g, 78.4 mmol, 3.0 equiv.). The mixture was warmed up to 100° C. and stirred at 100° C. for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. After cooling down to room temperature, the mixture was filtered to remove solid, and washed with diethyl ether. The filtrate was washed with water and brine. After drying over sodium sulfate, filtration and evaporation of the solvent, the crude azido derivative (TTT, 2.4 g, 20.8 mmol, 78%) was used in the next step.

[0671] Step 2: To the mixture of (S)-3-azido-2-methylpropan-1-ol TTT (2.4 g, 20.8 mmol, 1.0 equiv.) and BOC-anhydride (6.8 g, 31.3 mmol, 1.5 equiv.) in THF (100 mL, 0.2M) under nitrogen was added Pd-C (2.2 g, 2.1 mmol, 0.1 equiv.). The reaction was purged and then placed under hydrogen atmosphere, and stirred for 16 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction atmosphere was substituted with nitrogen and the precipitate was removed via filtration through Celite®. The Celite® was washed with MeOH and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired product (UUU, 2.6 g, 13.8 mmol, 66%).

[0672] Step 3: To the solution of Boc-protected amine UUU (2.6 g, 13.8 mmol, 1.0 equiv.), 1-phenyl-1H-tetrazole-5-thiol (2.6 g, 14.5 mmol, 1.05 equiv.) and triphenylphosphine (3.8 g, 14.5 mmol, 1.05 equiv.) in THF (100 mL, 0.1M) at 0° C., DIAD (3.2 ml, 16.5 mmol, 1.2 equiv.) was added dropwise. The reaction mixture maintained at 0° C. and stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was then diluted with ethyl acetate, and washed with water and brine. After drying over sodium sulfate, filtration and evaporation of solvent, the crude material was purified via silica gel (hexane/ethyl acetate) to give the desired product (VVV, 4.3 g, 12.2 mmol, 89%).

[0673] Step 4: To the solution of the tetrazole VVV (0.4 g, 1.1 mmol, 1.0 equiv.) in dichloromethane (7.0 mL, 0.14M) at 0° C., trifluoroacetic acid (3.5 mL, 45.4 mmol, 40.0 equiv.) was added. The reaction mixture was allowed to warm up to 23° C. and stirred for 1 hour, or until the reaction was determined to be complete by LCMS or TLC. The solvent was removed under reduced pressure, and the reaction was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine. After drying over sodium sulfate, filtration and evaporation of the solvent, the crude amine (WWW, 0.3 g, 1.0 mmol, 90%) was used in the next step.

[0674] Step 5: To the solution of the amine WWW (1.0 equiv.) in dichloromethane (0.1M) at 0° C., diisopropylethylamine (4.0 equiv.) and the corresponding carbamic chloride (2.0 equiv.) were added and stirred for 2 hours at the same temperature. Once completion of reaction was confirmed by LCMS or TLC, the solution was diluted with dichloromethane. The organic layer was washed with ammonium chloride, sodium bicarbonate, and brine. After drying with sodium sulfate, filtration and evaporation of the solvent, the crude was purified with silica gel (dichloromethane/methanol) to give the desired urea (XXX).

[0675] Step 6: To a solution of urea XXX (1.0 equiv.) in ethanol (0.1M) at 0° C. was added dropwise a premixed yellow solution of ammonium molybdate tetrahydrate (0.3 equiv.) in 33% hydrogen peroxide (10 equiv.). The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was diluted in ethyl acetate then sodium thiosulfate was added at 0° C. and stirred for 20 minutes. The organic layer was then washed with water, brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired sulfone (YYY).

Exemplified Protocol for the Synthesis of (S)—N—(2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl)pyrrolidine-1-carboxamide.

[0676] Steps 1-4 as above.

[0677] Step 5: To the solution of the amine WWW (0.1 g, 0.4 mmol, 1 equiv.) in dichloromethane (4.4 mL, 0.1M) at 0° C., diisopropylethylamine (0.3 mL, 1.7 mmol, 4 equiv.) and pyrrolidine-1-carbonyl chloride (0.1 mL, 0.8 mmol, 2.0 equiv.) were added and stirred for an additional 2 hours at the same temperature. Once completion of reaction was confirmed by LCMS or TLC, the solution was diluted with dichloromethane. The organic layer was washed with ammonium chloride, sodium bicarbonate, and brine. After drying with sodium sulfate, filtration and evaporation of the solvent, the crude was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired urea (XXX, 0.13 g, 0.4 mmol, 91%).

[0678] Step 6: To a solution of product urea XXX (0.1 g, 0.4 mmol, 1.0 equiv.) in ethanol (3.0 mL, 0.1M) at 0° C. was added dropwise a premixed yellow solution of ammonium molybdate tetrahydrate (0.1 g, 0.12 mmol, 0.3 equiv.) in 33% hydrogen peroxide (0.4 mL, 4.0 mmol, 10 equiv.). The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was diluted in ethyl acetate and sodium thiosulfate was added at 0° C. Stirring was continued for an additional 20 minutes. The organic layer was then washed with water, brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired sulfone, (S)—N—(2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl)pyrrolidine-l-carboxamide (0.1 g, 0.28 mmol, 68%). [0679] Compounds 143 and 144 were prepared using sulfone YYY according to Scheme 9.

##STR00280##

General Protocol for the Synthesis of Urea Compounds 143-144

[0680] Step 1: To a solution of sulfone YYY (2.5 equiv.) in THF (0.02M) under nitrogen at −78° C. was added KHMDS (2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde L (1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (ZZZ).

[0681] Step 2: To a solution of product ZZZ (1.0 equiv.) in methanol (0.1M) was added p-toluenesulfonic acid (3.0 equiv.) at room temperature. The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate. The mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compounds 143-144).

Exemplified Protocol for the Synthesis of Urea Compound 143

[0682] Step 1: To a solution of (S)—N—(2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl)pyrrolidine-1-carboxamide YYY (43.7 mg, 0.12 mmol, 2.5 equiv.) in THF (3.0 mL, 0.02M) under nitrogen at −78° C. was added dropwise KHMDS (0.23 mL, 0.12 mmol, 2.5 equiv.) and the reaction was stirred for 20 minutes. Then aldehyde L (30.0 mg, 0.05 mmol, 1.0 equiv.) in THF was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (ZZZ, 23.3 mg, 0.03 mmol, 63%).

[0683] Step 2: To a solution of product ZZZ (23.3 mg, 0.03 mmol, 1.0 equiv.) in methanol (3.0 mL, 0.1M) was added p-toluenesulfonic acid (16.6 mg, 0.09 mmol, 3.0 equiv.) at room temperature. The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate. The mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 143, 15.6 mg, 0.02 mmol, 78%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J=6.78 Hz, 3H) 0.99-1.08 (d, J=6.65 Hz, 3H) 1.27 (d, J=5.27 Hz, 3H) 1.30-1.61 (m, 17H) 1.90 (s, 3H) 1.60-2.06 (m, 3H) 2.45-2.67 (m, 4H) 2.70-2.84 (m, 5H) 2.84-2.97 (m, 1H) 2.95-3.13 (m, 1H) 3.22-3.36 (m, 4H) 3.61-3.71 (m, 4H) 3.73-3.81 (m, 1H) 5.02 (d, J=9.41 Hz, 1H) 5.16 (d, J=10.67 Hz, 1H) 5.56-5.75 (m, 3H) 6.06-6.12 (d, J=10.92 Hz, 1H) 6.27 (dd, J=15.12, 11.11 Hz, 1H). MS (ES+)=687.6 [M+H].sup.+. [0684] Compound 145 was prepared by the method of Scheme 10.

##STR00281## ##STR00282##

Exemplified Protocol for the Synthesis of Urea Compound 145

[0685] Step 1: To a solution of (S)—N—(2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl)pyrrolidine-1-carboxamide (34.1 mg, 0.09 mmol, 2.5 equiv.) in THF (2.0 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.18 mL, 0.09 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde E (20.0 mg, 0.04 mmol, 1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (AAAA, 15.8 mg, 0.02 mmol, 62%).

[0686] Step 2: To a solution of urea AAAA (25.2 mg, 0.04 mmol, 1.0 equiv.) in methanol (3.0 mL, 0.01M) was added potassium carbonate (14.8 mg, 0.11 mmol, 3.0 equiv.) and stirred at room temperature. After 3 hours, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with ammonium chloride at 0° C. The mixture was then diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired secondary alcohol (BBBB, 26.0 mg, 0.04 mmol, >95%).

[0687] Step 3: To a solution of alcohol BBBB (26.0 mg, 0.04 mmol, 1.0 equiv.) in dichloromethane (2.0 mL, 0.1M) was added diisopropylethylamine (0.05 mL, 0.27 mmol, 7.0 equiv.) and DMAP (1.4 mg, 0.01 mmol, 0.3 equiv.) at 0° C. Then a solution of 4-nitrophenyl carbonochloridate (31.5 mg, 0.16 mmol, 4.0 equiv.) in dichloromethane (0.1M) was added slowly. The reaction was warmed up to room temperature and stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude protected carbonate (CCCC) was used in the next step without further purification.

[0688] Step 4: To a solution of carbonate CCCC (1.0 equiv.) in THF (0.1M) at room temperature was added N-methylpiperazine (0.04 mL,0.4 mmol, 10.0 equiv.) at room temperature. After stirring for one hour, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with water and diluted with ethyl acetate, washed with 1N sodium hydroxide solution, and the organic layer was concentrated. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluant) to afford the desired product (DDDD, 15.1 mg, 0.02 mmol, 49%).

[0689] Step 5: To a solution of carbamate DDDD (15.2 mg, 0.02 mmol, 1.0 equiv.) in methanol (2.0 mL, 0.01M) at room temperature was added p-methoxytoluenesulfonic acid (11.0 mg, 0.06 mmol, 3.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 145, 4.5 mg, 0.008 mmol, 39%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.73 -0.89 (m, 3H) 0.90-1.04 (m, 3H) 1.08-1.33 (m, 6H) 1.40-1.58 (m, 2H) 1.59-1.71 (m, 4H) 1.75-1.90 (m, 4H) 2.24 (s, 3H) 2.31 (br. s., 3H) 2.34-2.57 (m, 3H) 2.90-3.16 (m, 1H) 3.16-3.30 (m, 4H) 3.37-3.50 (m, 4H) 3.53-3.77 (m, 1H) 4.13 (t, J=5.77 Hz, 1H) 4.95 (d, J=9.54 Hz, 1H) 5.08 (d, J=10.79 Hz, 1H) 5.49-5.67 (m, 2H) 6.02 (d, J=11.04 Hz, 1H) 6.10-6.34 (m, 1H). MS (ES+)=605.5 [MAH].sup.+. [0690] Compound 146 was prepared by the method of Scheme 11

##STR00283## ##STR00284##

Exemplified Protocol for the Synthesis of Urea Compound 146

[0691] Step 1: To a solution of (S)-5-((3-((tert-butyldimethylsily)oxy)-2-methylpropyl)sulfonyl)-1-phenyl-1H-tetrazole (29.3 mg, 0.07 mmol, 2.0 equiv.) in THF (2.0 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.15 mL, 0.07 mmol, 2.0 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde L (24.0 mg, 0.04 mmol, 1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. over 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired diene (EEEE, 15.6 mg, 0.02 mmol, 51.5%).

[0692] Step 2: To a solution of diene EEEE (15.6 mg, 0.02 mmol, 1.0 equiv.) in methanol (2.0 mL, 0.02M) was added p-toluenesulfonic acid (2.3 mg, 0.01 mmol, 0.6 equiv.) at room temperature. The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate. The mixture was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired alcohol (FFFF, 9.0 mg, 0.01 mmol, 60%).

[0693] Step 3: To a solution of alcohol FFFF (7.5 mg, 0.01 mmol, 1.0 equiv.) in dichloromethane (1.0 mL, 0.01M) was added DMAP (1.6 mg, 0.01 mmol, 1.3 equiv.) and tosyl chloride (2.0 mg, 0.01 mmol, 1.0 equiv.) at 0° C. The reaction was warmed up to room temperature and the reaction was stirred for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water and washed with brine. After drying over sodium sulfate, filtration and evaporation of solvent, the crude tosylate (1 equiv.) was then dissolved in DMF (1.0 mL, 0.01M) and sodium azide (2.7 mg, 0.04 mmol, 4.0 equiv.) was added. The reaction was warmed to 70° C. and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the excess of solvent was removed and the crude material was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired azide (GGGG, 6.0 mg, 0.01 mmol, 96%).

[0694] Step 4: To a solution of dichloromethane (1.0 mL, 0.01M) containing azide GGGG (7.5 mg, 0.01 mmol, 1.0 equiv.) was added a trimethylphosphine (0.02 mL, 0.02 mmol, 2.0 equiv.) toluene solution (1M) at room temperature. The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. Paraformaldehyde (1.5 mg, 0.05 mmol, 5.0 equiv.) was added at room temperature and the mixture was stirred for 5 hours, or until the reaction was determined to be complete by LCMS or TLC. Methanol was added (1 mL/1.0 equiv. of GGGG) and the reaction was cooled to 0° C. Sodium borohydride (2.0 mg, 0.05 mmol, 5.0 equiv.) was added and the reaction was stirred at 0° C. for 1 hour or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with sodium bicarbonate, extracted with dichloromethane, and dried over sodium sulfate. After filtration and evaporation, the crude amine (HHHH, 7.4 mg, 0.01 mmol, >95%) was used in the next step without further purification.

[0695] Step 5: To a solution of amine HHHH (7.0 mg, 0.01 mmol, 1 equiv.) in dichloromethane (1.0 mL, 0.01M) was added triethylamine (0.005 mL, 0.04 mmol, 4.0 equiv.) at room temperature. The reaction mixture was then cooled down to 0° C. and then pyrrolidine-1-carbonyl chloride (2.6 mg, 0.02 mmol, 2.0 equiv.) was added slowly. After warming up to room temperature, the reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion of the reaction, excess of solvent was removed and crude material was then purified using silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired urea (IIII, 2.5 mg, 0.003 mmol, 32%).

[0696] Step 6: A solution of urea IIII (2.5 mg, 0.003 mmol, 1.0 equiv.) in methanol (2.0 mL, 0.01M) at room temperature was added p-methoxytoluenesulfonic acid (1.2 mg, 0.006 mmol, 2.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 146, 1.8 mg, 0.003 mmol, 84%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.84-1.08 (m, 10H) 1.25-1.41 (m, 9H) 1.44-1.68 (m, 8H) 1.70-1.85 (m, 5H) 1.88-2.05 (m, 3H) 2.42-2.65 (m, 6H) 2.80-2.95 (m, 6H) 3.08-3.18 (m, 2H) 3.54-3.73 (m, 5H) 3.78 (br. s., 1H) 4.94 (d, J=9.66 Hz, 1H) 5.04 (d, J=10.67 Hz, 1H) 5.54-5.63 (m, 2H) 5.66-5.77 (m, 1H) 6.08 (d, J=11.04 Hz, 1H) 6.31 (dd, J=14.87, 10.98 Hz, 1H), MS (ES+)=701.4 [M+H].sup.+.

TABLE-US-00010 TABLE 7 Compounds 143-146 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00285] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J = 6.78 Hz, 3 H) 0.99-1.08 (d, J = 6.65 Hz, 3 H) 1.27 (d, J = 5.27 Hz, 3 H) 1.30-1.61 (m, 17 H) 1.90 (s, 3 H) 1.60-2.06 (m, 3 H) 2.45-2.67 (m, 4 H) 2.70-2.84 (m, 5 H) 2.84- 2.97 (m, 1 H) 2.95-3.13 (m, 1 H) 3.22-3.36 (m, 4 H) 3.61-3.71 (m, 4 H) 3.73-3.81 (m, 1 H) 5.02 (d, J = 9.41 Hz, 1 H) 5.16 (d, J = 10.67 Hz, 1 H) 5.56-5.75 (m, 3 H) 6.06-6.12 (d, J = 10.92 Hz, 1 H) 6.27 (dd, J = 15.12, 11.11 Hz, 1 H) 687.6 [00286] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.71-0.92 (m, 4 H) 0.93-1.13 (m, 4 H) 1.15- 1.25 (m, 5 H) 1.27 (br. s., 1 H) 1.30- 1.54 (m, 12 H) 1.56-1.67 (m, 7 H) 1.69-1.76 (m, 2 H) 1.80-1.95 (m, 3 H) 2.36-2.57 (m, 8 H) 2.98 (ddd, J = 13.18, 8.03, 4.89 Hz, 1 H) 3.09 (s, 1 H) 3.14-3.33 (m, 3 H) 3.33-3.49 (m, 6 H) 3.57 (d, J = 10.29 Hz, 1 H) 3.61-3.82 (m, 1 H) 3.86-4.13 (m, 1 H) 4.49 (br. s., 1 H) 4.94 (d, J = 9.54 Hz, 2 H) 5.08 (d, J = 10.54 Hz, 1 H) 5.46-5.68 (m, 3 H) 6.02 (d, J = 11.04 Hz, 1 H) 6.20 (dd, J = 15.18, 10.67 Hz, 1 H) 717.7 [00287] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.73-0.89 (m, 3 H) 0.90-1.04 (m, 3 H) 1.08- 1.33 (m, 6 H) 1.40-1.58 (m, 2 H) 1.59-1.71 (m, 4 H) 1.75-1.90 (m, 4 H) 2.24 (s, 3 H) 2.31 (br. s., 3 H) 2.34-2.57 (m, 3 H) 2.90-3.16 (m, 1 H) 3.16-3.30 (m, 4 H) 3.37-3.50 (m, 4 H) 3.53-3.77 (m, 1 H) 4.13 (t, J = 5.77 Hz, 1 H) 4.95 (d, J = 9.54 Hz, 1 H) 5.08 (d, J = 10.79 Hz, 1 H) 5.49- 5.67 (m, 2 H) 6.02 (d, J = 11.04 Hz, 1 H) 6.10-6.34 (m, 1 H) 605.5 [00288] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.84-1.08 (m, 10 H) 1.25-1.41 (m, 9 H) 1.44- 1.68 (m, 8 H) 1.70-1.85 (m, 5 H) 1.88-2.05 (m, 3 H) 2.42-2.65 (m, 6 H) 2.80-2.95 (m, 6 H) 3.08-3.18 (m, 2 H) 3.54-3.73 (m, 5 H) 3.78 (br. s., 1 H) 4.94 (d, J = 9.66 Hz, 1 H) 5.04 (d, J = 10.67 Hz, 1 H) 5.54-5.63 (m, 2 H) 5.66-5.77 (m, 1 H) 6.08 (d, J = 11.04 Hz, 1 H) 6.31 (dd, J = 14.87, 10.98 Hz, 1 H) 701.4
Compound 147 was prepared as shown in Scheme 12.

##STR00289##

Protocol for the Synthesis of Compound 147

[0697] Step 1: To a solution of compound diene EEEE (22.0 mg, 0.03 mmol, 1.0 equiv.) in methanol (2.0 mL, 0.01M) was added p-toluenesulfonic acid (15.5 mg, 0.08 mmol, 3.0 equiv.) at room temperature. The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate. The mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes/ethyl acetate as eluent) to afford the desired diol (JJJJ, 5.0 mg, 0.008 mmol, 32%).

[0698] Step 2: To a solution of diene JJJJ (6.0 mg, 0.01 mmol, 1 equiv.) in dichloromethane (1.0 mL, 0.01M) was added DMAP (1.6 mg, 1.3 equiv.) and tosyl chloride (2.0 mg, 0.01 mmol, 1.0 equiv.) at 0° C. The reaction was warmed up to room temperature and the reaction was stirred for 24 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water, and washed with brine. After drying over sodium sulfate, filtration and evaporation of solvent, the crude tosylate (1 equiv.) was then dissolved in DMF (1.0 mL, 0.01M) and sodium azide (2.6 mg, 0.04 mmol, 4.0 equiv.) was added. The reaction was warmed to 70° C. and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the excess of solvent was removed and the crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired azide (KKKK, 6.0 mg, 0.01 mmol, 96%).

[0699] Step 3: To a solution of product KKKK (5.0 mg, 0.008 mmol, 1.0 equiv.) in water/tert-butanol/dichloromethane (0.1M, 1/2/1, 0.25/0.5/0.25 mL) was added ethynylcyclopropane (2.2 mg, 0.03 mmol, 4.0 equiv.), copper (II) sulfate (2.0 mg, 0.01 mmol, 1.5 equiv.), and sodium (R)-5-((S)-1,2-dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-olate (3.2 mg, 0.02 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 7 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the excess of solvent was removed and the crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired triazole (Compound 147, 2.5 mg, 0.004 mmol, 45%). .sup.1H NMR (400 MHz, METHANOL-d4) 0.78-0.98 (m, 6H) 0.99-1.06 (m, 3H) 1.19-1.28 (m, 4H) 1.28-1.43 (m, 2H) 1.50-1.62 (m, 14H) 1.63-1.75 (m, 6H) 1.85-1.99 (m, 2H) 2.41-2.68 (m, 7H) 2.73-2.89 (m, 1H) 3.39-3.62 (m, 4H) 3.75 (br. s., 2H) 4.07-4.26 (m, 2H) 5.01 (d, J=9.54 Hz, 1H) 5.13 (d, J=10.67 Hz, 1H) 5.55-5.74 (m, 3H) 6.01-6.07 (m, 1H) 6.10-6.20 (m, 1H), MS (ES+)=683.5 [M+H].sup.+.

Compound 148 was prepared by the method of Scheme 13.

##STR00290## ##STR00291##

Protocol for the Synthesis of Compound 148

[0700] Step 1: To a solution of (S)-5-((3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)-1-phenyl-1H-tetrazole (104.0 mg, 0.26 mmol, 2.5 equiv.) in THF (10.0 mL, 0.01M) under nitrogen at −78° C. was added KHMDS (0.52 mL, 0.26 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde E (58.0 mg, 0.1 mmol, 1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired diene (LLLL, 45.0 mg, 0.06 mmol, 59%).

[0701] Step 2: To a solution of diene LLLL (40.0 mg, 0.05 mmol, 1.0 equiv.) in methanol (4.0 mL, 0.01M) was added potassium carbonate (19.1 mg, 0.14 mmol, 2.5 equiv.) and the reaction was stirred at room temperature. After 3 hours, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with ammonium chloride at 0° C. The mixture was then diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired secondary alcohol (MMMM, 40.0 mg, 0.06 mmol, >95%).

[0702] Step 3: To a solution of alcohol MMMM (40.0 mg, 0.06 mmol, 1.0 equiv.) in dichloromethane (6.0 mL, 0.01M) was added triethylamine (0.06 mL, 0.4 mmol, 7.0 equiv.), and DMAP (2.1 mg, 0.02 mmol, 0.3 equiv.) at 0° C. Then a solution of 4-nitrophenyl carbonochloridate (47.2 mg, 0.23 mmol, 4.0 equiv.) in dichloromethane (0.1M) was added slowly. The reaction was warmed up to room temperature and stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude protected carbonate (NNNN) was used in the next step without further purification.

[0703] Step 4: To a solution of carbamate NNNN (1.0 equiv.) in THF (6.0 mL, 0.01M) at room temperature was added N-methyl piperazine (0.07 mL, 0.58 mmol, 10.0 equiv.). After stirring for one hour, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with 1N sodium hydroxide solution and the organic layer was concentrated. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluant) to afford the desired carbamate (0000, 37.0 mg, 0.04 mmol, 78%).

[0704] Step 5: To a solution of carbamate OOOO (37.0 mg, 0.05 mmol, 1.0 equiv.) in methanol (4.0 mL, 0.01M) at room temperature was added p-methoxytoluenesulfonic acid (19.1 mg, 0.1 mmol, 2.2 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired alcohol (PPPP, 18.5 mg, 0.04 mmol, 80%).

[0705] Step 6: To a solution of alcohol PPPP (45.0 mg, 0.09 mmol, 1.0 equiv.) in dichloromethane (1.0 mL, 0.08M) was added triethylamine (0.15 mL, 0.9 mmol, 10.0 equiv.), and DMAP (2.2 mg, 0.02 mmol, 0.2 equiv.) at 0° C. Then a solution of 4-nitrophenyl carbonochloridate (26.7 mg, 0.13 mmol, 1.5 equiv.) in dichloromethane (0.1M) was added slowly. The reaction was warmed up to room temperature and stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude carbonate (QQQQ) was used in the next step without further purification.

[0706] Step 7: To a solution of carbonate QQQQ (1.0 equiv.) in dichloromethane (1.0 mL, 0.03M) at room temperature was added the require amine (5.0 equiv.) at room temperature. After stirring for one hour, or until the reaction was determined to be complete by LCMS or TLC, the mixture was concentrated. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluant) to afford the corresponding carbamate and desired carbonate as a minor by product (compound 148, 1.0 mg, 0.002 mmol, 4.7%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.91 (d, J=6.65 Hz, 3H) 1.09 (d, J=6.78 Hz, 3H) 1.11-1.19 (m, 1H) 1.23 (s, 3H) 1.30-1.46 (m, 3H) 1.50-1.69 (m, 2H) 1.77 (s, 3H) 2.40 (s, 3H) 2.46-2.71 (m, 7H) 3.41-3.70 (m, 4H) 3.75 (s, 3H) 3.78-3.84 (m, 1H) 3.92-4.09 (m, 2H) 4.96 (d, J=9.54 Hz, 1H) 5.07 (d, J=10.67 Hz, 1H) 5.53-5.81 (m, 3H) 6.11 (d, J=10.54 Hz, 1H) 6.38 (dd, J=15.00, 10.85 Hz, 1H), MS (ES+)=566.5 [M+H].sup.+.

Compound 149 was prepared according to Scheme 14.

##STR00292##

Protocol for the Synthesis of Compound 149

[0707] Step 1: To a solution of (R)-methyl 3-hydroxy-2-methylpropanoate RRRR (5.0 g, 42.3 mmol, 1.0 equiv.) in dichloromethane (125 mL, 0.3 M) was added imidazole (4.3 g, 63.5 mmol, 1.5 equiv.) followed by TBS-Cl (6.2 g, 63.5 mmol, 1.2 equiv.) and the reaction was stirred at room temperature for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water. The organic layer was then washed with brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired product to give the desired protected ester (SSSS, 7.0 g, 30.1 mmol, 71%).

[0708] Step 2: To a stirred solution of TBS protected ester SSSS (7.0 g, 30.1 mmol, 1.0 equiv.) in dry dichloromethane (80 mL, 0.2M) at −10° C. was added DIBAL-H (1.0 M solution in toluene, 75.3 mL, 75.3 mmol 2.5 equiv.) under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to room temperature and further stirred for an additional 2 hours, or until the reaction was determined to be complete by LCMS or TLC. After the excess DIBAL-H was decomposed with an excess of methanol, the mixture was poured into a sodium potassium tartrate solution (10 g in 100 mL water) with vigorous stirring until the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired product (TTTT, 4.8 g, 23.5 mmol, 78%).

[0709] Step 3: To a solution of TBS protected alcohol TTTT (1.0 g, 4.9 mmol, 1.0 equiv.) in dichloromethane (20 mL, 0.1M) was added sodium bicarbonate (0.8 g, 9.8 mmol, 2.0 equiv.) at room temperature. Then a solution of DMP (3.1 g, 7.3 mmol, 1.5 equiv.) in dichloromethane (5 mL) was added dropwise. The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The solvent was removed and the crude aldehyde was then quickly purified on a silica plug (hexane/ethyl acetate as eluant). The aldehyde was then dissolved in benzene (25 mL, 0.1M) and methyl (triphenylphosphoranylidene)acetate (1.6 g, 4.9 mmol, 1.0 equiv.) was added to the reaction at room temperature and the reaction was stirred for 10 hours, or until the reaction was determined to be complete by LCMS or TLC. After concentration, the residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired ester (UUUU, 400 mg, 1.6 mmol, 32%).

[0710] Step 4: To a solution of the ester UUUU (200 mg, 0.77 mmol, 1.0 equiv.) in methanol (7 mL, 0.1M) was added palladium/carbon (10%, 82 mg, 0.77 mmol Pd, 0.1 equiv.) under a nitrogen atmosphere. The reaction was then placed under a hydrogen atmosphere and stirred at room temperature for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the hydrogen atmosphere was replaced by a nitrogen atmosphere and then the palladium/carbon was filtered off on a Celite® pad and the excess solvent was removed to give the desired product (VVVV, 101 mg, 0.691 mmol, 89%).

[0711] Step 5: To a solution of ester VVVV (100 mg, 0.68 mmol, 1.0 equiv.) in THF (4 mL, 0.1M) was added triphenylphosphine (206 mg, 0.79 mmol, 1.15 equiv.) followed by 1-phenyl-1H-tetrazole-5-thiol (134 mg, 0.75 mmol, 1.1 equiv.). The reaction was degassed with nitrogen and a solution of DIAD (180 mg, 0.89 mmol, 1.3 equiv.) in THF (2 mL) was added slowly. The reaction was then stirred at room temperature for 1 hour, or until the reaction was determined to be complete by LCMS or TLC. The solvent was removed. The crude residue was then purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired product (WWWW, 110 mg, 0.36 mmol, 53%).

[0712] Step 6: To a solution of sulfide WWWW (25 mg, 0.082 mmol, 1.0 equiv.) in ethanol (1 mL, 0.1M) at 0° C. was added dropwise a premixed yellow solution of ammonium molybdate tetrahydrate (20 mg, 0.016 mmol, 0.2 equiv.) in hydrogen peroxide (33% in water, 0.084 mL, 0.82 mmol, 10.0 equiv.). The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was diluted in ethyl acetate then sodium thiosulfate was added at 0° C. and the reaction was stirred for 20 minutes. The organic layer was then washed with water, brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired sulfone (XXXX, 17 mg, 0.050 mmol, 62%).

[0713] Step 7: To a solution of the sulfone XXXX (23 mg, 0.069 mmol, 1.5 equiv.) in THF (1 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.5 M in toluene, 0.19 mL, 0.092 mmol, 2.0 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde L (30 mg, 0.046 mmol, 1.0 equiv.) (see Scheme 2) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (YYYY, 12 mg, 0.016 mmol, 34%).

[0714] Step 8: To a solution of ester YYYY (11 mg, 0.014 mmol, 1.0 equiv.) in methanol (1.5 mL, 0.01M) at room temperature was added p-methoxytoluenesulfonic acid (8.3 mg, 0.043 mmol, 3.0 equiv.). The reaction was stirred for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 149, 6 mg, 0.0093 mmol, 64%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.19 (s, 4H), 6.04-6.30 (m, 1H), 5.83-6.04 (m, 1H), 5.45-5.71 (m, 3H), 5.08 (d, J=10.8 Hz, 1H), 4.95 (d, J=9.5 Hz, 1H), 3.68 (br. s., 1H), 3.59 (s, 2H), 3.36-3.51 (m, 3H), 3.08-3.36 (m, 2H), 2.37-2.62 (m, 6H), 2.09-2.37 (m, 3H), 1.92-2.04 (m, 1H), 1.87 (br. s., 1H), 1.38-1.67 (m, 15H), 1.10-1.37 (m, 8H), 0.88-1.00 (m, 3H), 0.84 (d, J=6.8 Hz, 3H). MS (ES+)=647.5.

Compound 150 was prepared as shown in Scheme 15.

##STR00293##

Protocol for the Synthesis of Compound 150

[0715] Step 1: To a solution of a azide GGGG (8 mg, 0.013 mmol, 1.0 equiv.) in dichloromethane (1 mL, 0.02M) was added trimethyl phosphine (1.0 molar solution, 0.026 mL, 0.026 mmol, 2.0 equiv) and the reaction was heated at 50° C. for 1 hour, or until the reaction was determined to be complete by LCMS or TLC. Water (1.0 mL, 4.0 equiv.) was added and the reaction mixture was heated at 50° C. for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The solvent was removed to give the crude amine ZZZZ (7.5 mg, 0.013 mmol, 98%).

[0716] Step 2: To a solution of amine ZZZZ (4.0 mg, 0.0068 mmol, 1.0 equiv.) in dichloromethane (0.5 mL, 0.01M) was added triethylamine (0.005 mL, 0.029 mmol, 4.0 equiv.) at room temperature. The reaction mixture was then cooled down to 0° C. and then cyclopentanecarbonyl chloride (0.0015 mL, 0.014 mmol, 2.0 equiv.) was added slowly. After warming up to room temperature, the reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion of the reaction, excess of solvent was removed and crude material was then purified using silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired amide (AAAAA 2.42 mg, 0.0035 mmol, 52%).

[0717] Step 3: To a solution of amide AAAAA (21 mg, 0.026 mmol, 1.0 equiv.) in methanol (1 mL, 0.25M) at room temperature was added p-methoxytoluenesulfonic acid (12.5 mg, 0.066 mmol, 2.5 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 150, 12.9 mg, 0.019 mmol, 72%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J=6.65 Hz, 3H) 1.04 (d, J=6.65 Hz, 3H) 1.27 (s, 3H)) 1.20-1.62 (m, 18H) 1.65-1.78 (m, 5H) 1.79-1.87 (m, 2H) 190-2.01 (m, 2H) 2.37-2.67 (m, 5H) 2.72-2.84 (br.s., 4H) 2.87-2.98 (m, 1H) 3.04-3.14 (m, 1H) 3.25-3.36 (m, 1H) 3.66 (br. s., 4H) 3.71-3.80 (m, 1H) 5.02 (d, J=9.41 Hz, 1H) 5.16 (d, J=10.67 Hz, 1H) 5.43 (t, J=5.34 Hz, 1H) 5.55-5.66 (m, 2H) 5.67 (dd, J=15.06, 9.29 Hz, 1H) 6.09 (d, J=11.17 Hz, 1H) 6.25 (dd, J=15.00, 10.85 Hz, 1H). MS (ES+)=686.6 [M+H].sup.+.

Compound 151 was prepared according to the method of Scheme 16.

##STR00294## ##STR00295##

Protocol for the Synthesis of Compound 151

[0718] Step 1: To a solution of amine WWW (95 mg, 0.38 mmol, 1.0 equiv.) in dichloromethane (4 mL, 0.1M) at 0° C. was added triethylamine (0.21 mL, 1.52 mmol, 4 equiv.) followed by cyclopentanecarbonyl chloride (101 mg, 0.76 mmol, 2 equiv.). The reaction was warmed to room temperature and was stirred for 10 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was concentrated and the crude material was then purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired amide (BBBBB, 49 mg, 0.14 mmol, 37%).

[0719] Step 2: To a solution of product BBBBB (49 mg, 0.14 mmol, 1.0 equiv.) in ethanol (4 mL, 0.03M) at 0° C. was added dropwise a premixed yellow solution of ammonium molybdate tetrahydrate (33 mg, 0.028 mmol, 0.3 equiv.) in hydrogen peroxide (0.15 mL, 1.4 mmol, 10 equiv. 33%). The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was diluted in ethyl acetate then sodium thiosulfate was added at 0° C. and the reaction was stirred for 20 minutes. The organic layer was then washed with water, brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired sulfone CCCCC (49 mg, 0.13 mmol, 92%).

[0720] Step 3: To a solution of sulfone CCCCC (13.6 mg, 0.36 mmol, 2.0 equiv.) in THF (15 mL, 0.01M) under nitrogen at −78° C. was added KHMDS (0.5 M in toluene, 0.14 mL, 0.072 mmol, 4.0 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde E (10 mg, 0.018 mmol, 1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 90 minutes and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (DDDDD, 4 mg, 0.0057 mmol, 31%).

[0721] Step 4: To a solution of product DDDDD (4 mg, 0.0057 mmol, 1.0 equiv.) in methanol (0.5 mL, 0.01M) was added potassium carbonate (1.6 mg, 0.011 mmol, 2.0 equiv.) and the reaction was stirred at room temperature. After 3 hours, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with ammonium chloride at 0° C. The mixture was then diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired secondary alcohol (EEEEE, 4 mg, 0.0048 mmol, 85%).

[0722] Step 5: To a solution of alcohol EEEEE (4 mg, 0.006 mmol, 1.0 equiv.) in dichloromethane (0.7 mL, 0.006M) was added triethylamine (0.0086 uL, 0.06 mmol, 10.0 equiv.), and DMAP (1.4 mg, 0.012 mmol, 2.0 equiv.) at 0° C. Then a solution of 4-nitrophenyl carbonochloridate (4.86 mg, 0.024 mmol, 4.0 equiv.) in dichloromethane (0.3 mL) was added slowly. The reaction was warmed up to room temperature and stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude protected carbonate (FFFFF) was used in the next step without further purification.

[0723] Step 6: To a solution of carbonate FFFFF (1.0 equiv.) in THF (1.0 mL, 0.06M) at room temperature was added N-methyl piperazine (0.0067 uL, 10.0 equiv.). After stirring for one hour, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution, and concentrated. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluant) to afford the desired product (GGGGG, 3 mg, 0.0038 mmol, 63%).

[0724] Step 7: To a solution of carbamate GGGGG (3.0 mg, 0.0038 mmol, 1.0 equiv.) in methanol (1 mL, 0.004M) at room temperature was added p-methoxytoluenesulfonic acid (1.4 mg, 0.0076 mmol, 2.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 151, 1.5 mg, 0.0022 mmol, 58%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: 0.88 (d, J=6.78 Hz, 3H) 1.02 (d, J=6.78 Hz, 3H) 1.21 (m, 3H) 1.27-1.44 (m, 6H) 1.53-1.72 (m, 6H) 1.74 (s, 3H) 1.76-1.84 (m, 2H) 2.35 (s, 3H) 2.41-2.63 (m, 10H) 3.05-3.17 (m, 2H) 3.54 (br.s., 1H) 3.79 (br. s., 1H) 4.94 (d, J=9.66 Hz, 1H) 5.04 (d, J=10.54 Hz, 1H) 5.54-5.64 (m, 2H) 5.65-5.77(m, 1H) 6.02-6.13 (m, 1H) 6.22-6.34 (m, 1H) 7.78-7.86 (m, 1H), MS (ES+)=604.4 [M+H].sup.+. [0725] Compound 152 was prepared according to the method of Scheme 17.

##STR00296##

Protocol for the Synthesis of Compound 152

[0726] Step 1: To a solution of 3-bromo-propan-1-ol HHHHH (2.0 g, 14.4 mmol, 1.0 equiv.) in dimethylformamide (40 mL, 0.3M) was added imidazole (1.47 g, 21.6 mmol, 1.5 equiv.) followed by TBS-Cl (3.3 g, 21.6 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water. The aqueous layer was then extracted with diethyl ether. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired protected alcohol (IIIII, 2.91 g, 10.9 mmol, 76%).

[0727] Step 2: To a suspension of sodium hydride (55% suspension in mineral oil, 0.32 g, 7.9 mmol, 1.0 equiv.) in DMF (15 mL, 0.5M) was added 1-phenyl-1H-tetrazole-5-thiol (1.4 g, 7.9 mmol, 1.0 equiv.) at 0° C. The mixture was stirred for 1 hour. Then a solution of (3-bromopropoxy)(tertbutyl)dimethylsilane IIIII (2.0 g, 7.9 mmol, 1.0 equiv.) was added to the reaction. The reaction was heated to and maintained at 50° C. for 10 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water. The excess of DMF was removed in vacuo. Then the residue was diluted in brine and extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the desired terazole JJJJJ (2.5 g, 7.2 mmol, 91%).

[0728] Step 3: To a solution of the tetrazole JJJJJ (2.5 g, 7.2 mmol, 1.0 equiv.) in ethanol (45 mL, 0.1M) at 0° C. was added dropwise a premixed yellow solution of ammonium molybdate tetrahydrate (0.89 g, 0.72 mmol, 0.1 equiv.) in hydrogen peroxide (7.3 mL, 72 mmol, 10 equiv. 33%). The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was diluted in ethyl acetate, sodium thiosulfate was added at 0° C. and the reaction was stirred for 20 minutes. The organic layer was then washed with water, brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired sulfone (KKKKK, 1.7 g, 4.4 mmol, 62%).

[0729] Step 4: To a solution of the sulfone KKKKK (74 mg, 0.19 mmol, 2.5 equiv.) in THF (4 mL, 0.02M) under nitrogen at −78° C. was added KHMDS (0.5 M in toluene, 0.39 mL, 0.19 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde L (50 mg, 0.077 mmol, 1.0 equiv.) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 2 hours and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (LLLLL, 30.6 mg, 0.038 mmol, 49%).

[0730] Step 5: To a solution of product LLLLL (30.6 mg, 0.038 mol, 1.0 equiv.) in methanol (3 mL, 0.01M) at room temperature was added p-methoxytoluenesulfonic acid (7.2 mg, 0.038 mmol, 1.0 equiv.). The reaction was stirred for 5 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate, diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (MMMMM, 10.7 mg, 0.019 mmol, 49%).

[0731] Step 6 and 7: To a stirred solution of product MMMMM (6.2 mg, 0.011 mmol, 1.0 equiv.) in 1,2-dichloromethane (1 mL, 0.01M) at 23° C. was added DMAP (0.66 mg, 0.054 mmol, 0.5 equiv.) and DIPEA (0.019 mL, 0.107 mmol, 10.0 equiv.). Then, 4-nitrophenyl chloroformate (6.5 mg, 0.032 mmol, 3.0 equiv.) was added to the mixture. After 16 hours, or until the reaction was determined to be complete by LCMS or TLC, pyrrolidine (7.7 mg, 0.11 mmol, 10.0 equiv.) was added and the reaction was stirred for another 4 hours. Dichloromethane was added to the reaction mixture. The organic layer was then washed with water and brine. After drying over sodium sulfate, filtration and evaporation, the crude material was purified by silica gel column chromatography (ethyl acetate/methanol) to give the desired product (compound 152, 2.67 mg, 0.0040 mmol, 37%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.71-0.88 (m, 6H) 0.98-1.06 (m, 1H) 1.13-1.27 (m, 13H) 1.29-1.52 (m, 10H) 1.56 (br. s., 9H) 1.61-1.70 (m, 4H) 1.73 (br. s., 2H) 1.89 (br. s., 2H) 2.34-2.59 (m, 7H) 3.41 (d, J=5.27 Hz, 4H) 3.65-3.78 (m, 2H) 4.11 (t, J=6.78 Hz, 2H) 4.88-5.02 (m, 1H) 5.08 (d, J=10.54 Hz, 1H) 5.43-5.68 (m, 3H) 6.01 (d, J=10.29 Hz, 1H) 6.25 (dd, J=15.06, 11.04 Hz, 1H), MS (ES+)=674.3 [M+14].sup.+. [0732] Compound 153 was prepared according to the method of Scheme 18

##STR00297## ##STR00298##

Protocol for the Synthesis of Compound 153

[0733] Step 1: To a solution of (S)-5-((3-((tert-butyldimethylsily0oxy)-2-methylpropyl)sulfonyl)-1-phenyl-1H-tetrazole (212 mg, 0.54 mmol, 2.5 equiv.) in THF (3 mL, 0.04M) under nitrogen at −78° C. was added KHMDS (0.5 M in toluene, 1.1 mL, 0.54 mmol, 2.5 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde Q (100 mg, 0.21 mmol, 1.0 equiv.) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 2 hours and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (NNNNN, 105 mg, 0.17 mmol, 77%).

[0734] Step 2: To a solution of product NNNNN (101 mg, 0.16 mmol, 1.0 equiv.) in methanol (4 mL, 0.04M) was added potassium carbonate (55 mg, 0.40 mmol, 2.5 equiv.) and the reaction was stirred at room temperature. After 3 hours, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with ammonium chloride at 0° C. The mixture was then diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired secondary alcohol (OOOOO, 52 mg, 0.087 mmol, 55%).

[0735] Step 3: To a solution of alcohol OOOOO (20 mg, 0.034 mmol, 1.0 equiv.) in dichloromethane (4 mL, 0.01M) was added triethylamine (0.033 mL, 0.24 mmol, 7.0 equiv.) and DMAP (1.2 mg, 0.01 mmol, 0.3 equiv.) at 0° C. Then a solution of 4-nitrophenyl carbonochloridate (27.1 mg, 0.13 mmol, 4.0 equiv.) in dichloromethane (1 mL) was added slowly. The reaction was warmed up to room temperature and stirred for 3 hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude protected carbonate (PPPPP) was used in the next step without further purification.

[0736] Step 4: To a solution of carbonate PPPPP (1.0 equiv.) in THF (4 mL, 0.01M) at room temperature was added N-methyl piperazine (34 mg, 0.34 mmol, 10.0 equiv.). After stirring for one hour, or until the reaction was determined to be complete by LCMS or TLC, the reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution concentrated. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluant) to afford the desired product (QQQQQ, 24 mg, 0.033 mmol, 99%).

[0737] Step 5: To a solution of product QQQQQ (24 mg, 0.033 mmol, 1.0 equiv.) in methanol (2 mL, 0.02M) at room temperature was added p-methoxytoluenesulfonic acid (9.5 mg, 0.05 mmol, 1.5 equiv.). The reaction was stirred for 5 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (RRRRR, 14.0 mg, 0.028 mmol, 85%).

[0738] Step 6: To a stirred solution of product RRRRR (4.0 mg, 0.008 mmol, 1.0 equiv.) in 1,2-dichloromethane (1.0 mL, 0.01M) at 23° C. was added DMAP (0.2 mg, 0.0016 mmol, 0.2 equiv.) and DIPEA (0.01 mL, 0.057 mmol, 7.0 equiv.). Then, 4-nitrophenyl chloroformate (2.5 mg, 0.012 mmol, 1.5 equiv.) was added to the mixture. After 12 hours, or until the reaction was determined to be complete by LCMS or TLC, (R)-pyrrolidin-3-ol x (4.0 mg, 0.032 mmol, 4.0 equiv.) was added and stirred for another 4 hours. Dichloromethane was added to the reaction mixture. The organic layer was then washed with water and brine. After drying over sodium sulfate, filtration and evaporation, the crude material was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to give the desired product (compound 153, 3.2 mg, 0.0081 mmol, 65%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J=6.78 Hz, 3H) 0.97-1.03 (m, 6H) 1.44 -1.55 (m, 2H) 1.67-1.85 (m, 5H) 1.86-2.01 (m, 2H) 2.37-2.62 (m, 11H) 3.02 (br. s., 1H) 3.20-3.32 (m, 1H) 3.38-3.63 (m, 9H) 3.68-3.75 (m, 2H) 3.79-4.10 (m, 2H) 4.40-4.48 (m, 1H) 4.86 (t, J=10.10 Hz, 1H) 5.14 (dd, J=10.48, 5.58 Hz, 1H) 5.28-5.41 (m, 2H) 5.55 (dd, J=14.93, 9.91 Hz, 1H) 6.20 (t, J=11.23 Hz, 1H) 6.36 (br. d, J=11.17 Hz, 1H). MS (ES+)=606.5 [MAH].sup.+. [0739] Compound 154 was prepared according to the method of Scheme 19.

##STR00299## ##STR00300##

Protocol for the Synthesis of Compound 154

[0740] Step 1: To a solution of (R)—(S)-2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl 3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate SSSSS (100.0 mg, 0.20 mmol, 1.0 equiv.) in THF (4 mL, 0.04M) was added slowly potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.2 mL, 0.59 mmol, 3 equiv.) at −78° C. The reaction was stirred for 15 minutes and (1H-benzo[d][1,2,3]triazol-1-yl)methanol (58.5 mg, 0.39 mmol, 2.0 equiv.) was added at −78° C. The reaction was stirred for 2 hours at −78° C. and warmed to room temperature over 1 hour. The reaction was quenched with ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was then purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired terminal alkene (TTTTT, 40 mg, 0.13 mmol, 65%).

[0741] Step 2: To a solution of alkene TTTTT (40 mg, 0.13 mmol, 1.0 equiv.) in 1,2-dichloroethane (2.0 mL, 0.1M) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (39.3 mg, 0.26 mmol, 2.0 equiv.). The reaction was purged with nitrogen and Hoveyda-Grubbs II catalyst (8.0 mg, 0.013 mmol, 0.1 equiv.) was added and the reaction was stirred at 50° C. for 16 hours. The mixture was filtered through Celite®, the Celite® was washed with dichloromethane and the filtrate was concentrated in vacuo. The crude material was then purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (UUUUU, 31 mg, 0.063 mmol, 50%).

[0742] Step 3: To a solution of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol DD (240 mg, 0.95 mmol, 1.0 equiv.) in dichloromethane (7 mL, 0.2 M) was added triphenylphosphine (400 mg, 1.5 mmol, 1.6 equiv.) and a solution of NBS (288 mg, 1.6 mmol, 1.7 equiv.) in dichloromethane (1 mL, 0.1M) using a syringe pump at 0° C. The reaction was stirred at 0° C. for 2 hours, or until the reaction was determined to be complete by LCMS or TLC, before being quenched with a sodium sulfite solution. The mixture was extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over sodium sulfate. After evaporation of the solvent in vacuo, the crude material was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired bromo derivative (VVVVV, 270 mg, 0.86 mmol, 90%).

[0743] Step 4: To a solution of bromo derivative VVVVV (270 mg, 0.86 mmol, 1.0 equiv.) in DMF (5 mL, 0.2 M) was added sodium azide (23 mg, 3.4 mmol, 4.0 equiv.). The reaction was heated to and maintained at 50° C. for 1 hour, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was cooled down to room temperature; the mixture was then filtered through a silica gel plug (ethyl acetate). After concentration, the azido derivative (WWWWW, 200 mg, 0.722 mmol, 84%) was used directly in the next step.

[0744] Step 5: To a solution of azide derivative WWWWW (22 mg, 0.079 mmol, 1.0 equiv.) in THF (2 mL, 0.04M) was added trimethylphosphine (1.0 M, 0.16 mL, 0.6 mmol, 2.0 equiv.) at −10° C. The reaction was then warmed to room temperature and stirred at room temperature for 30 minutes or until the reaction was determined to be complete by LCMS or TLC. Then water (4.3 mL, 0.24 mmol, 3.0 equiv.) was added and the reaction was stirred at room temperature for 5 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, non-8-enoic acid (25 mg, 0.16 mmol, 2.0 equiv.), HOBt (13 mg, 0.087 mmol, 1.1 equiv.), Hunig's base (0.047 mL, 0.32 mmol, 4.0 equiv.) and EDCI (16.7 mg, 0.087 mmol, 1.1 equiv.) were added and the mixture was stirred for 3 hours or until the reaction was determined to be complete by LCMS or TLC. The solvent was then evaporated in vacuo, ethyl acetate was added and the organic layer was extracted with sodium bicarbonate and brine. After drying over sodium sulfate, filtration and evaporation of solvent in vacuo, the crude material was purified by silica gel chromatography (hexanes/ethyl acetate as eluent) to afford the desired amide (XXXXX, 11 mg, 0.028 mmol, 36%).

[0745] Step 6: To a degassed solution of amide XXXXX (18 mg, 0.046 mmol, 1.0 equiv.) and benzoquinone (0.25 mg, 0.002 mmol, 0.05 equiv.) in toluene (4.6 mL, 0.01M) was added Hoveyda-Grubbs II catalyst (2.9 mg, 0.0046 mmol, 0.1 equiv.). The mixture was stirred in an oil bath at 65° C. under a nitrogen atmosphere for 12 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction mixture was cooled down to room temperature and filtered through a Celite® and silica gel pad. The solvent was then removed and the crude material was dissolved in dioxane (1 mL, 0.05M), and selenium dioxide (15.4 mg, 0.14 mmol, 3.0 equiv.) was added. The mixture was heated to and maintained at 80° C. for 5 hours or until the reaction was determined to be complete by LCMS or TLC. The mixture was cooled down to room temperature and was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude macrocycle was used in the next step without further purification (YYYYY, 18 mg, 0.048 mmol).

[0746] Step 7: To a solution of macrocycle YYYYY (17 mg, 0.046 mmol , 1.0 equiv.) in 1,2-dichloroethane (2 mL, 0.02 M) was added nitrophenyl chloroformate (23.2 mg, 0.12 mmol, 2.5 equiv.), triethylamine (0.045 mL, 0.322 mmol, 7.0 equiv.), and DMAP (5.6 mg, 0.046 mmol, 1.0 equiv.). The reaction was stirred at room temperature for 12 hours or until the reaction was determined to be complete by LCMS or TLC. N-methyl piperazine (14 mg, 0.14 mmol, 3.0 equiv.) was then added and the reaction was stirred at room temperature for 2 hours, or until the reaction was determined to be complete by LCMS or TLC. The mixture was then directly subjected to purification by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired carbamate (ZZZZZ, 15 mg, 0.029 mmol, 63%).

[0747] Step 8: To a solution of carbamate ZZZZZ (7 mg, 0.014 mmol, 1.0 equiv.) in THF (1 mL, 0.1M) at room temperature was added (R)—(R,E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1 -yl 3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate UUUUU (8 mg, 0.018 mmol, 1.3 equiv.) , monosilver(I) monosilver(III) monooxide (16 mg, 0.07 mmol, 5.0 equiv.), and tetrakis(triphenylphosphine) palladium (0.8 mg, 0.007 mmol, 0.05 equiv.). The reaction mixture was heated to and maintained at 60° C. for 30 minutes or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was cooled down to room temperature, filtered through Celite®, washed with dichloromethane and concentrated in vacuo. The crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired product (AAAAAA, 3.0 mg, 0.0044 mmol, 31%).

[0748] Step 8-2: To a solution of carbamate AAAAAA (3.0 mg, 0.0044 mmol, 1.0 equiv.) in methanol (1 mL, 0.004M) at room temperature was added p-methoxytoluenesulfonic acid (4.1 mg, 0.022 mmol, 5.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 154, 2.4 mg, 0.0042 mmol, 96%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.97 (d, J=6.53 Hz, 3H) 1.07 (d, J=6.78 Hz, 3H) 1.31-1.70 (m, 7H) 1.71 (s, 3H) 1.80-2.06 (m, 3H) 2.21-2.32 (m, 2H) 2.32 (s, 3H) 2.39 (br. s., 4H) 2.56-2.64 (m, 1H) 3.42-3.59 (m, 6H) 3.91-4.02 (m, 2H) 4.15-4.26 (m, 1H) 4.45-4.50 (m, 1H) 5.14 (td, J=10.04, 5.14 Hz, 1H) 5.26-5.40 (m, 2H) 5.58 (dd, J=15.06, 10.04 Hz, 1H) 5.65 (dd, J=15.12, 7.47 Hz, 1H) 6.06 (d, J=10.41 Hz, 1H) 6.27 (dd, J=14.62, 11.23 Hz, 1H). MS (ES+)=575.4 [M+H].sup.+. [0749] Compound 155 was prepared according to the method of Scheme 20.

##STR00301##

Protocol for the Synthesis of Compound 155

[0750] Step 1: To a solution of macrocycle (8R,11S,12S,E)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-11-methyloxacyclododec-9-en-2-one GG (0.20 g, 0.53 mmol, 1.0 equiv.) in dichloromethane (5.3 mL, 0.1M) was added PPh3 (0.28 g, 1.0 mmol, 2.0 equiv.) and CBr4 (0.35 g, 1.0 mmol, 2.0 equiv.) at 0° C. The reaction was stirred at room temperature for 3 hours, or until the reaction was determined to be complete by LCMS or TLC . The reaction mixture was then quenched with water and aqueous layer extracted with dichloromethane. The combined organic layers were then washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was then diluted in DMF (5.3 mL, 0.1M). Sodium azide (0.14 g, 2.1 mmol, 4.0 equiv.) was added and the reaction was warmed to 70° C. for 12 hours, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the solvent was removed and the crude material was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired azide (BBBBBB, 0.17 g, 0.20 mmol, 39%).

[0751] Step 2: To a solution of azide BBBBBB (0.16 g, 0.20 mmol, 1.0 equiv.) in THF (0.1M) was added trimethyl phosphine (0.035 mL, 0.40 mmol, 2.0 equiv.) and the reaction was stirred at 50° C. for 1 hours, or until the reaction was determined to be complete by LCMS or TLC. Water (0.014 mL, 0.8 mmol, 4.0 equiv.) was added and the reaction mixture was heated at 50° C. for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The solvent was removed and the crude material was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired amine (CCCCCC, 0.06 g, 0.16 mmol, 79%).

[0752] Step 3: To a solution of amine CCCCCC (0.08 g, 0.21 mmol, 1.0 equiv.) in dichloromethane (2.0 mL, 0.1M) at 0° C. was added triethylamine (0.12 mL, 0.85 mmol, 4.0 equiv.), DMAP (26.1 mg, 0.21 mmol, 1.0 equiv.) followed by 4-methylpiperazine-1 -carbonyl chloride (0.07 g, 0.43 mmol, 2.0 equiv.). The reaction was warmed to room temperature and was stirred for 7 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate. The organic layer was washed with water and brine. After drying over sodium sulfate and filtration, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired urea (DDDDDD, 0.069 g, 0.14 mmol, 65%).

[0753] Step 4: To a solution of DDDDDD (3.0 mg, 0.006 mmol, 1.0 equiv.) in THF (0.5 mL, 0.1M) at room temperature was added (R,E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl pyrrolidine-1-carboxylate SSSSS (3.7 mg, 0.012 mmol, 2.0 equiv.), monosilver(I) monosilver(III) monooxide (6.9 mg, 0.03 mmol, 5.0 equiv.), triphenylarsine (2.2 mg, 0.007 mmol, 1.2 equiv.), and tetrakis(triphenylphosphine) palladium (0.82 mg, 0.009, 0.15 equiv.). The reaction mixture was heated at 60° C. for 30 minutes, or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was cooled down to room temperature, the mixture was then filtered through Celite®, the Celite® was washed with dichloromethane and concentrated in vacuo. The crude material was purified by silica gel chromatography (dichloromethane/methanol as eluent) to afford the desired product (Compound 155, 2.7 mg, 0.0048 mmol, 81%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.78-0.97 (m, 6H) 1.06 (d, J=6.78 Hz, 3H) 1.16-1.39 (m, 4H) 1.43-1.61 (m, 2H) 1.76-1.87 (m, 2H) 2.22-2.47 (m, 7H) 2.55-2.64 (m, 1H) 3.30-3.41 (m, 8H) 3.90-4.00 (m, 2H) 4.15-4.28 (m, 4H) 5.02 (d, J=10.67 Hz, 1H) 5.14-5.30 (m, 3H) 5.35-5.45 (m, 2H) 5.67 (dd, J=15.06, 7.53 Hz, 1H) 6.10 (d, J=11.42 Hz, 1H) 6.23-6.30 (m, 1H) 6.45 (d, J=0.88 Hz, 1H), MS (ES+)=559.5 [M+H].sup.+. [0754] Compound 156 was prepared according to the method of Scheme 21.

##STR00302## ##STR00303##

Protocol for the Synthesis of Compound 156

[0755] Step 1: To a solution of (S)-5-((3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)-1-phenyl-1H-tetrazole (0.066 g, 0.17 mmol, 2.0 equiv.) in THF (2.0 mL, 0.04M) under nitrogen at −78° C. was added KHMDS (0.33 mL, 0.17 mmol, 2.0 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde D (0.040 g, 0.08 mmol, 1.0 equiv.) in THF (0.2 mL) was added dropwise. The reaction was stirred at −78° C. for 2 hours and then allowed to warm to −20° C. over 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (EEEEEE, 0.036 g, 0.06 mmol, 68%).

[0756] Step 2: To a solution of EEEEEE (0.037 g, 0.06 mmol, 1.0 equiv.) in methanol (2.0 mL, 0.03M) at room temperature was added pyridinium p-toluenesulfonate (0.015 g, 0.06 mmol, 1.0 equiv.). The reaction was stirred for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired primary alcohol (FFFFFF, 0.02 g, 0.04 mmol, 68%).

[0757] Step 3: To a solution of primary alcohol FFFFFF (5.0 mg, 0.009 mmol, 1.0 equiv.) and acid (2R,35)-2-methyl-3-((triethylsilyl)oxy)pentanoic acid (3.5 mg, 0.014 mmol, 1.5 equiv.) in dichloromethane (0.3 mL, 0.03M) was added diisopropylethyamine (0.003 mL, 0.02 mmol, 2.0 equiv.), DMAP (1.1 mg, 0.009 mmol, 1.0 equiv.) and COMU (6.0 mg, 0.014 mmol, 1.5 equiv.) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 hours or until the reaction was determined to be complete by LCMS or TLC. Upon completion, the reaction was diluted with dichloromethane, washed with water, brine and dried over sodium sulfate. After filtration, and evaporation, the crude material was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired ester GGGGGG (5.0 mg, 0.006 mmol, 70%).

[0758] Step 4: To a solution of ester GGGGGG (4.0 mg, 0.005 mmol, 1.0 equiv.) in methanol (0.1 mL, 0.005M) at room temperature was added p-methoxytoluenesulfonic acid (1.0 mg, 0.005 mmol, 1.0 equiv.). The reaction was stirred for 3 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (dichloromethane/methanol as eluent) to afford the desired product (compound 156, 1.2 mg, 0.002 mmol, 40%). .sup.1H NMR (400 MHz, METHANOL, d4) δ: 6.60 (dd, J=15.1, 11.0 Hz, 1H), 6.17 (d, J=11.0 Hz, 1H), 5.86 (dt, J=15.2, 6.3 Hz, 1H), 5.66-5.78 (m, 1H), 4.96-5.19 (m, 2H), 4.67 (d, J=6.5 Hz, 1H), 3.78-4.00 (m, 1H), 3.73 (ddd, J=8.3, 5.8, 4.5 Hz, 1H), 3.15 (s, 1H), 2.44-2.67 (m, 3H), 2.07-2.10 (m, 2H), 1.75-1.86 (m, 2H), 1.57-1.67 (m, 1H), 1.37-1.55 (m, 3H), 1.15-1.24 (m, 4H), 0.82-1.07 (m, 5H), MS (ES+)=561.3 [M+Na].sup.+. [0759] Compound 157 was prepared by the method of Scheme 22.

##STR00304##

[0760] Step 1: Intermediate EEEEEE (40.6 mg, 0.062 mmol, 1.0 equiv) was dissolved in EtOH (2 mL) and PPTS (1.562 mg, 6.217 μmol, 0.1 equiv) was added. The reaction mixture was stirred for 1 hr at rt. Then, the solvent was removed. The residue was purified by silica gel chromatography (25-80% EtOAc/hexanes) to give desired product (Compound 157, 2.7 mg, 6.36 μmol, 10%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.72-0.89 (m, 3H) 0.97 (d, J=6.78 Hz, 3H) 1.11-1.35 (m, 7H) 1.42-1.56 (m, 2H) 1.56-1.71 (m, 4H) 2.02 (s, 3H) 2.34-2.58 (m, 3H) 3.32-3.54 (m, 3H) 3.56-3.83 (m, 1H) 5.01 (d, J=9.03 Hz, 1H) 5.09 (d, J=10.54 Hz, 1H) 5.50-5.65 (m, 3H) 6.03 (d, J=10.79 Hz, 1H) 6.25 (ddd, J=15.06, 10.79, 1.00 Hz, 1H). MS(ES+): 425.30 [M+H].sup.+. [0761] Compounds 158-160 were prepared by the method of Scheme 23.

##STR00305##

General Protocol for the Synthesis of Compounds 158-160

[0762] Step 1: To a solution of the corresponding sulfone (2.5 equiv.) in THF (0.02M) under nitrogen at −78° C. was added KHMDS (2.5 equiv.) dropwise and stirred for 20 minutes. Then aldehyde L (1.0 equiv.) in THF (0.5 M) was added dropwise. The reaction was stirred at −78° C. for 2 hours and then allowed to warm to −20° C. over 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (HHHHHH)

[0763] Step 2: To a solution of carbamate HHHHHH (1.0 equiv.) in methanol (0.1M) at room temperature was added pyridinium p-toluenesulfonate (5.0 equiv.). The reaction was stirred for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired carbamate (compounds 158-160). The two diastereoisomers could be isolated after preparative HPLC. Column: Waters Xbridge C18 5 μm OBD 19×150 mm. Mobile phase A: 0.1% NH.sub.4OH in water (pH 10), Mobile phase B: 0.1% NH.sub.4OH in 100% acetonitrile. Mobile phase conditions: isocratic 45% B in 10 min 30 mL/min.

Exemplified Protocol for the Synthesis of Compound 90 and separation of the two epimers, Compound 159 and Compound 160

[0764] Step 1: To a solution 3-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine (0.15 g, 0.45 mmol, 2.1 equiv.) in THF (4.8 mL, 0.04M) under nitrogen at −78° C. was added KHMDS (0.46 mL, 0.46 mmol, 2.2 equiv.) dropwise and the reaction was stirred for 20 minutes. Then aldehyde L (0.13 g, 0.21 mmol, 1.0 equiv.) in THF (0.2 mL) was added dropwise. The reaction was stirred at −78° C. for 2 hours and then allowed to warm to −20° C. for 1 hour. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (HHHHHH, 0.08 g, 0.11 mmol, 53%).

[0765] Step 2: To a solution of carbamate HHHHHH (0.08 g, 0.11 mmol, 1.0 equiv.) in methanol (1.0 mL, 0.1M) at room temperature was added pyridinium p-toluenesulfonate (0.1 g, 0.55 mmol, 5.0 equiv.). The reaction was stirred for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexanes/ethyl acetate as eluent) to afford the desired carbamate (compound 90, 0.015 g, 0.02 mmol, 22%) as a mixture of epimers at C16. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.70-0.93 (m, 4H) 1.00 (d, J=6.78 Hz, 1H) 1.12-1.21 (m, 5H) 1.24-1.50 (m, 14H) 1.55-1.76 (m, 11H) 1.90 (br. s., 2H) 2.14 (s, 1H) 2.36-2.57 (m, 7H) 3.22-3.43 (m, 5H) 3.43-3.59 (m, 1H) 3.68 (br. s., 1H) 4.94 (d, J=9.54 Hz, 1H) 5.08 (d, J=10.79 Hz, 1H) 5.44-5.72 (m, 2H) 5.82 (dd, J=15.43, 6.90 Hz, 1H) 6.03 (d, J=10.54 Hz, 1H) 6.09-6.25 (m, 1H) 7.16-7.21 (m, 3H) 7.44 (d, J=7.28 Hz, 1H) 8.41 (br. s., 2H), MS (ES+)=638.8 [M+H].sup.+.

[0766] The mixture was then subjected to preparative HPLC separation using the following parameters: Column: Waters Xbridge C18 5 μm OBD 19×150 mm. Mobile phase A: 0.1% NH.sub.4OH in water (pH 10), Mobile phase B: 0.1% NH.sub.4OH in 100% acetonitrile. Mobile phase conditions: isocratic 45% B in 10 min 30 mL/min. fraction 1, rt=5.9 min, fraction 2, rt=6.9 min.

[0767] Compound 159 (fraction 1, WiDr GI.sub.50=13.3 nM, Panc05.04 GI.sub.50=15.0 nM) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.82-1.00 (m, 3H) 1.24-1.31 (m, 4H) 1.34-1.60 (m, 12H) 1.65-1.88 (m, 8H) 1.96-2.12 (m, 1H) 2.45-2.67 (m, 7H) 3.50 (br. s., 4H) 3.59 (t, J=7.03 Hz, 1H) 3.68-3.88 (m, 1H) 4.95-5.10 (m, 1H) 5.17 (d, J=10.54 Hz, 1H) 5.54-5.79 (m, 2H) 5.90 (dd, J=15.06, 7.03 Hz, 1H) 6.12 (d, =10.79 Hz, 1H) 6.27 (ddd, J=15.06, 10.79, 1.25 Hz, 1H) 7.26 (d, J=4.77 Hz, 1H) 7.54 (dt, J=4.51 Hz, 1H) 8.41-8.58 (m, 2H).

[0768] Compound 160 (fraction 2, WiDr GI.sub.50=29.5 nM, Panc05.04 GI.sub.50=15.8 nM) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87-0.97 (m, 3H) 1.23-1.30 (m, 4H) 1.32-1.60 (m, 12H) 1.64-1.78 (m, 7H) 1.78-1.93 (m, 2H) 1.99 (br. s., 1H) 2.42-2.68 (m, 6H) 3.37-3.64 (m, 5H) 3.76 (d, J=6.53 Hz, 1H) 5.03 (d, J=9.54 Hz, 1H) 5.17 (d, J=10.54 Hz, 1H) 5.54-5.78 (m, 2H) 5.91 (dd, J=14.93, 6.90 Hz, 1H) 6.12 (d, J=11.54 Hz, 1H) 6.18-6.40 (m, 1H) 7.27 (s, 1H) 7.41-7.66 (m, 1H) 8.40-8.60 (m, 2H). [0769] Carbamate (Scheme 24) and Heterocycle (Scheme 25) Sidechain Julia Fragments Synthesis

##STR00306##

General Protocol for the Synthesis of Carbamate Julia Fragment

[0770] Step 1: To a solution of (S)-3-bromo-2-methylpropanol SSS (10.0 g, 65.3 mmol, 1.0 equiv.) in dichloromethane (300 mL, 0.1M) at 0° C. was added imidazole (6.7 g, 98.0 mmol, 1.5 equiv.) followed by TBSC1 (11.8 g, 78.4 mmol, 1.2 equiv.). The reaction was allowed to warm to room temperature and stirred at room temperature overnight. Once determined to be complete by TLC or LCMS, the reaction was filtered. The filtrate was washed with water, saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexane/ethyl acetate) to give the desired protected alcohol (IIIIII, 13.5 g, 50.5 mmol, 77%).

[0771] Step 2: To a solution of NaH (2.4 g, 60.6 mmol, 1.2 equiv.) in DMF (200 mL, 0.2M) at 0° C. was added 1-phenyl-1H-tetrazole-5-thiol (9.9 g, 55.6 mmol, 1.1 equiv.) and the reaction was stirred for 1 hour. Next, a solution of bromide HIM (13.5 g, 50.5 mmol, 1.0 equiv.) was added at 0° C. and the reaction was gradually heated to 80° C. for ten hours. Once determined to be complete by TLC or LCMS, the reaction was cooled to 0° C. and quenched with water. The reaction was concentrated and the resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (JJJJJJ, 15.6 g, 42.8 mmol, 85%).

[0772] Step 3: To a solution of tetrazole JJJJJJ (2.4 g, 6.5 mmol, 1.0 equiv.) in ethanol (60 mL, 0.1M) at 0° C. was added ammonium molybdate tetrahydrate (0.8 g, 0.65 mmol, 0.1 equiv.) and hydrogen peroxide (6.6 mL, 64.7 mmol, 10.0 equiv., 30% solution in water). The reaction was allowed to warm to room temperature and stirred at room temperature for four hours or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired sulfone (KKKKKK, 2.2 g, 5.4 mmol, 84%).

[0773] Step 4: To a solution of sulfone KKKKKK (1.0 g, 2.5 mmol, 1.0 equiv.) in methanol (25.0 mL, 0.1M) at room temperature was added p-toluenesulfonic acid (0.1 g, 0.5 mmol, 0.2 equiv.). The reaction was stirred for 1 hour, or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with aqueous sodium bicarbonate solution, and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (LLLLLL, 0.7 g, 2.5 mmol, 100%) was advanced without further purification.

[0774] Step 5: To a solution of alcohol LLLLLL (1.0 equiv.) in dichloromethane (0.1M) at -10° C. was added DMAP (1.1 equiv.), DIEA (1.1 equiv.) and 4-nitrophenylchloroformate (1.1 equiv.). The reaction was allowed to warm to room temperature and stirred at room temperature overnight or until the reaction was determined to be complete by LCMS or TLC. Next, the reaction was cooled to 0° C. and the corresponding amine was added. The reaction was allowed to warm to room temperature and stirred at room temperature for five hours. The reaction was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired sulfone (SSSSS).

Exemplified Protocol for the Synthesis of (S)-2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl pyrrolidine-1-carboxylate

[0775] Steps 1-4 as above.

[0776] Step 5: To a solution of alcohol LLLLLL (0.25 g, 0.89 mmol, 1.0 equiv.) in dichloromethane (1.5 mL, 0.5M) at −10° C. was added DMAP (0.16 g, 1.3 mmol, 1.5 equiv.), DIEA (1.2 mL, 7.09 mmol, 8.0 equiv.) and 4-nitrophenyl chloroformate (0.7 g, 3.5 mmol, 4.0 equiv.). The reaction was allowed to warm to room temperature and stirred at room temperature overnight or until the reaction was determined to be complete by LCMS or TLC. Next, the reaction was cooled to 0° C. and pyrrolidine (0.37 mL, 4.4 mmol, 5 equiv.) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for five hours. The reaction was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (S)-2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl pyrrolidine-1-carboxylate (0.32 g, 0.84 mmol, 95%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.67-7.77 (m, 2H), 7.59-7.67 (m, 3H), 4.18-4.29 (m, 1H), 4.12 (dd, J=14.7, 4.3 Hz, 1H), 3.98 (dd, J=11.0, 7.0 Hz, 1H), 3.58 (dd, J=14.7, 8.2 Hz, 1H), 3.34-3.46 (m, 4H), 2.61-2.74 (m, 1H), 1.83-1.98 (m, 4H), 1.23 (d, J=6.9 Hz, 3H). [0777] Protocol for the Synthesis of 2-(3-methyl-1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)butan-2-yl)pyridine

##STR00307##

[0778] Step 1: NNNNNN (704 mg, 4.657 mmol, 1 equiv) was dissolved in THF (22.100 mL) at 0° C. and sodium tert-butoxide (470 mg, 4.89 mmol, 1.05 equiv) was added. This reaction solution turned bright yellow and was stirred for 30 min at this tempurature. Then, 2-iodopropane (0.931 mL, 9.314 mmol, 2 equiv) was added and the reaction solution was stirred at rt for 3 hrs. The reaction mixture was quenched with sat. aq. ammonium chloride and the THF was evaporated by rotavap. The remaining aqueous was extracted with EtOAc twice and the combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired crude product (SPE-30, 477.5 mg, 2.471 mmol, 53.1%).

[0779] Step 2: SPE-30 (477.5 mg, 2.471 mmol, 1 equiv) was dissolved in THF (25.300 mL) at 0° C. and lithium aluminium hydride (2.97 mL, 2.965 mmol, 1.2 equiv) was added dropwise. The reaction mixture was warmed to rt over 30 min then stirred at rt. The reaction mixture was carefully quenched with water, sodium hydroxide, and water, then stirred for 30 min. The ppt was filtered off and the solvent evaporated. The residue was extracted with ether and the combined organics were washed with water and brine then dried over sodium sulfate, filtered, and concentrated to give the crude desired product (SPE-31, 238 mg, 1.441 mmol, 58%).

[0780] Step 3: SPE-31 (238 mg, 1.44 mmol, 1 equiv) was dissolved in DCM (8805 μL) at 0° C. and triethylamine (221 μl, 1.584 mmol, 1.1 equiv) was added. Mesyl chloride (118 μL, 1.512 mmol, 1.05 equiv) was added dropwise and the reaction mixture stirred at this temperature for 30 min. The reaction was quenched with sat. aq. sodium bicarbonate and the aqueous re-extracted with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give crude desired product (SPE-32, 202 mg, 0.830 mmol, 57.6%).

[0781] Step 4: SPE-32 (202 mg, 0.83 mmol, 1 equiv) was dissolved in DMF (8035 μL) at rt and cesium carbonate (379 mg, 1.162 mmol, 1.4 equiv) was added followed by 1-phenyl-1H-tetrazole-5-thiol (178 mg, 0.996 mmol, 1.2 equiv). The mixture was stirred at 50° C. for 72 hrs. Brine was added and the aqueous layer was extracted 3× with ether. The combined organics were washed with water and brine then dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-100% EtOAc/hexanes) was completed to give the desired product (SPE-33, 130.3 mg, 0.400 mmol, 48.2%).

[0782] Step 5: SPE-33 (130.3 mg, 0.40 mmol, 1 equiv) was suspended in EtOH (2922 μL) at −10° C. and ammonium molybdate tetrahydrate (24.74 mg, 0.02 mmol, 0.05 equiv) was added followed by hydrogen peroxide (204 μL, 2.002 mmol, 5 equiv). The reaction mixture was stirred at this temperature for 3 hrs. Then, 3 mL THF was added and the reaction mixture was stirred at rt for 36 hrs. The mixture was quenched with water and aq. sodium metabisulfite. The reaction was diluted with EtOAc, the layers separated, then the organics washed with aq. sodium thiosulfate and water. The organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-100% EtOAc/hexanes) was completed to give the desired product (SPE-9, 92 mg, 0.257 mmol, 64.3% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.78-0.88 (m, 3H) 0.93-1.02 (m, 3H) 2.02-2.17 (m, 1H) 3.29-3.44 (m, 1H) 3.94-4.06 (m, 1H) 4.59-4.72 (m, 1H) 7.10-7.19 (m, 2H) 7.60 (s, 6H) 8.38-8.47 (m, 1H). MS(ES+): 358.30 [M+H].sup.+. [0783] Protocol for the Synthesis of Compound 161

##STR00308##

[0784] Step 1: To a solution of SPE-9 (93 mg, 0.261 mmol, 1.8 equiv) in 1:4 DMF (247 μL)/ THF (998 pt) at −78° C. was added slowly 0.6 M NaHMDS (375 μl, 0.225 mmol, 1.55M) so as to maintain the reaction temperature below −70° C. This was stirred for 30 min at this temperature. To this cooled yellow solution was added dropwise slowly a solution of aldehyde D (70 mg, 0.145 mmol, 1 equiv) in THF (198 μL). The reaction temperature was maintained below −65° C. The aldehyde vessel was rinsed with THF and added dropwise to the cooled reaction mixture. This was then stirred between −70 to −60° C. for 1 hr (set cryocoil to −65° C.). Then, the cryocoil was set to −50° C. and the reaction mixture was let stir at that temperature o/n. The reaction mixture was warmed to −40° C. and solid ammonium chloride (33.9 mg, 0.634 mmol, 4.37 equiv) was added. The reaction was further warmed to 0° C. and water was added followed by toluene. The aqueous layer was separated and the organic layer was then washed with brine. The organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-40% MTBE/hexanes with long hold at 40% MTBE/hexanes to elute product) was completed to give desired product (SPE-10, 29 mg, 0.047 mmol, 32.6%).

[0785] Step 2: SPE-10 (29 mg, 0.047 mmol, 1 equiv) was dissolved in THF (240 μL) and TBAF (94 pt, 0.094 mmol, 2 equiv) was added. The solution was stirred at rt o/n. The solution was diluted with water and extracted with EtOAc. The organics were then washed with brine and the organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-100% EtOAc/hexanes) was completed to give desired product (Compound 161, 14.4 mg, 0.028 mmol, 61%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: ppm 0.76 (dd, J=6.59, 1.32 Hz, 3H) 0.78-0.87 (m, 1H) 0.91 (d, J=6.65 Hz, 2H) 0.99 (d, J=6.78 Hz, 3H) 1.20 (s, 3H) 1.33-1.43 (m, 2H) 1.55-1.65 (m, 2H) 1.70-1.79 (m, 3H) 2.00-2.04 (m, 1H) 2.05-2.19 (m, 4H) 2.53 (br dd, J=15.75, 3.33 Hz, 3H) 3.11-3.22 (m, 1H) 3.73-3.85 (m, 1H) 5.03-5.09 (m, 2H) 5.51-5.63 (m, 1H) 5.66-5.76 (m, 1H) 5.99 (dd, J=15.00, 9.60 Hz, 1H) 6.13 (br d, J=10.79 Hz, 1H) 6.32-6.43 (m, 1H) 7.23-7.38 (m, 2H) 7.72-7.83 (m, 1H) 8.41-8.52 (m, 1H). MS(ES+): 500.58 [M+H].sup.+. [0786] General Protocol for the Synthesis of (S)-2-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine

##STR00309##

[0787] Step 1: To a solution of 2-(pyridin-2-yl)acetic acid hydrochloride salt MMMMMM (50.0 g, 288.0 mmol, 1.0 equiv.) in methanol (500 mL, 0.5M) at 0° C. was added thionyl chloride (31.5 mL, 432.0 mmol, 1.5 equiv.) dropwise. The reaction was stirred at 0° C. for 60 minutes or until the reaction was determined to be complete by LCMS or TLC. The reaction was carefully quenched with sodium carbonate and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product (NNNNNN, 41.5 g, 275.0 mmol, 95%) was used in the next step without further purification.

[0788] Step 2: To a solution of ester NNNNNN (41.5 g, 275.0 mmol, 1.0 equiv.) in THF (1500 mL, 0.2M) at 0° C. was added sodium 2-methylpropan-2-olate (28.6 g, 288.3 mmol, 1.05 equiv.) and the reaction mixture was stirred for 30 minutes at 0° C. before addition of iodomethane (34.3 mL, 549.1 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 1 hour or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with ammonium chloride and the excess of solvent was removed in vacuo. The crude material was then extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over magnesium sulfate. After filtration and evaporation of the solvent, the mixture was concentrated in vacuo. The resulting methyl ester (OOOOOO, 41.3 g, 250 mmol, 91%) was advanced without purification.

[0789] Step 3: To a solution of methyl ester OOOOOO (43.0 g, 260.3 mmol, 1.0 equiv.) in THF (1500 mL, 0.1M) at 0° C. was added lithium aluminum hydride (312 mL, 312.4 mmol, 1.2 equiv., solution in THF) dropwise. The reaction was allowed to warm gradually to 0° C. for 30 minutes and then to room temperature for 1 hour or until the reaction was determined to be complete by LCMS or TLC. The reaction was carefully quenched with water, sodium hydroxyde and water. After stirring the mixture for 30 minutes, the white precipitate was filtered off and the solvent was removed in vacuo. The reaction was then extracted with diethyl ether and the combined organic fractions were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting alcohol (PPPPPP, 30.0 g, 219.0 mmol, 84%) was advanced without purification.

[0790] Step 4: To a solution of alcohol PPPPPP (30.0 g, 219.0 mmol, 1.0 equiv.) in dichloromethane (700 mL, 0.3M) at 0° C. was added triethylamine (61.5 mL, 437.4 mmol, 2.0 equiv), and DMAP (2.7 g, 21.9 mmol, 0.1 equiv.). Acetic anhydride (24.8 mL, 262.4 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 30 minutes or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with ammonium chloride, and organic layer washed with brine, dried over magnesium sulfate and filtered. The resulting solution was then evaporated and the crude acetate (QQQQQQ, 37.0 g, 206.0 mmol, 94%) was used in the following step without further purification.

[0791] Step 5: A solution of acetate QQQQQQ (39.4 g, 219.8 mmol, 1.0 equiv.) was dissolved in diethyl ether (100 mL) and then 118 g of silica gel was added. The excess of ether was removed in vacuo and the crude solid was then diluted in pH 7 aqueous buffer (1970 mL, 0.1M). (sodium hydroxyde/sodium phosphate monobasic/water) Then porcine pancreatic lipase type II (3.3 g, (15 mg/mmol)) was added and the reaction was stirred at 37° C. for four hours or until determined to be complete by TLC or LCMS. (After four hours, conversion reached 40% according to ELSD and the enantiomeric excess was determined by chiral SFC, and showed an enantiomeric ratio of 13:1 S:R). The silica gel was filtered off and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by silica gel column chromatography (hexanes:ethyl acetate as eluant) to afford the desired alcohol (RRRRRR, 12.5 g, 91 mmol, 41%).

[0792] Step 6: To a solution of alcohol RRRRRR (12.5 g, 91.0 mmol, 1.00 equiv.) in dichloromethane (570 mL, 0.16M) at room temperature was added triethylamine (13.9 mL, 100.1 mmol, 1.1 equiv). The reaction was cooled down to 0° C. and then methanesulfonyl chloride (7.44 mL, 95.5 mmol, 1.05 equiv) was added. The reaction was stirred at 0° C. for 30 minutes or until determined to be complete by TLC or LCMS. The reaction was quenched with sodium bicarbonate and the layers were separated. The aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting sulfonate SSSSSS (19.2 g, 89 mmol, 98%) was advanced without additional purification.

[0793] Step 7: To a solution of sulfonate SSSSSS (19.2 g, 89 mmol, 1.0 equiv.) in DMF (120 mL, 0.1M) at room temperature was added cesium carbonate (40.7 g, 125.0 mmol, 1.4 equiv.) and 1-phenyl-1H-tetrazole-5-thiol (19.1 g, 107.1 mmol, 1.2 equiv.). The resulting mixture was stirred at 50° C. for 48 hours, or until determined to be complete by TLC or LCMS. After cooling the mixture to room temperature, brine was added and the aqueous layer was extracted three times with diethyl ether. The combined organic layers were washed with water, brine, and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified using silica gel column chromatography (hexanes/ethyl acetate) to give the desired product (TTTTTT, 28.9 g, 88 mmol, 99%).

[0794] Step 8: To a solution of sulfide TTTTTT (31.5 g, 105.9 mmol, 1.0 equiv.) in EtOH (700 mL, 0.1M) at −10° C. was added ammonium molybdate tetrahydrate (6.5 g, 5.3 mmol, 0.05 equiv.) and hydrogen peroxide (108 mL, 1060 mmol, 5.0 equiv., 33% aqueous solution). The reaction was stirred at −10° C. for four hours or until determined to be complete by TLC or LCMS. The reaction was quenched with water and sodium metabisulfite solution. The crude product was collected by filtration and was purified by silica gel column chromatography (hexanes:ethyl acetate as eluant) to afford the desired product (UUUUUU, 23.2 g, 70.4 mmol, 66%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.50 (d, J=7.03 Hz, 3H) 1.66 (br. s., 1H) 3.75 (quind, 1H) 3.94 (dd, J=14.81, 5.02Hz, 1H) 4.55 (dd, J=14.68, 7.91 Hz, 1H) 7.14-7.22 (m, 2H) 7.29 (s, 1H) 7.57-7.70 (m, 6H) 8.44-8.49 (m, 1H).

[0795] Racemic 2-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine could be prepared using a similar synthetic strategy as described in scheme 23 by skipping steps 5 and 6 (Lipase resolution).

[0796] Other heterocyclic Julia fragments, including (3-(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine, 4-(1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridine, 4-(2-methyl-3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyrimidine, and 3-(1(1-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propan-2-yl)pyridazine, were prepared in a similar manner (steps 5 and 6 (lipase resolution) were skipped to produce a racemic mixture at C16) starting with the corresponding heterocycle. [0797] Preparation of racemic Compounds 36 and 37

##STR00310##

[0798] Step SN-1: To a stirred solution of sn-2 (2.55 equiv.) in THF (30 mL) at −78° C. under N.sub.2 was added KHMDS (2.55 equiv., 0.5M solution in toluene) slowly. The reaction was stirred at −78° C. for 30 minutes. Next, aldehyde sn-1 (1g, 1.89 mmol, 1.0 equiv.) in THF (10 mL, final conc. 0.047M) was added slowly at −78° C. and the reaction was stirred for 3.5 hours at the same temperature, or until the reaction was determined to be complete by LCMS or TLC. The reaction was allowed to warm to room temperature. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product sn-3 (1.08g, 90%). LCMS data (ES+) M+Na 654.4.

[0799] Step SN-2: A stirred solution of the protected macrolide sn-3 (530 mg, 0.837 mmol, 1.0 equiv.) in acetic acid/water (4:1) (0.042M) was heated at 80° C. for 8 hours under N.sub.2. The reaction mixture was evaporated and the resulting residue was dissolved with water and ethyl acetate. The aqueous solution was adjusted to pH=9 by the addition of saturated aqueous NaHCO.sub.3 solution. The resulting aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product sn-4 (127 mg, 35%). LCMS data (ES+) M+430.2.

[0800] Step SN-3: To a stirred solution of the triol sn-4 (127 mg, 0.296 mmol, 1.0 equiv.) in dichloromethane (0.05M) at 0° C. under N.sub.2, triethylamine (2 equiv.), acetic anhydride (1 equiv.) and 4-dimethylaminopyridine (0.2 equiv.) were added. The resulting mixture was stirred at 0° C. for 1 hour or until the reaction was determined to be complete by LCMS or TLC. The reaction was quenched with saturated aqueous NaHCO.sub.3 solution and ethyl acetate was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the mixture of Compounds 36 and 37 (112 mg, 80%). [0801] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.83-0.96 (m, 3H) 1.17-1.82 (m, 13H) 2.08 (s, 3H) 2.43-2.70 (m, 3H) 3.40-3.83 (m, 3H) 5.07 (d, J=8.8 Hz, 1H) 5.14 (d, J=10.8 Hz, 1H) 5.53-5.73 (m, 2H) 5.92-6.05 (m, 1H) 6.07-6.18 (m, 1H) 6.25-6.38 (m, 1H) 7.06-7.21 (m, 2H) 7.56-7.69 (m, 1H) 8.48-8.60 (m, 1H). [0802] LCMS data (ES+) M+Na 494.1.

[0803] The intermediate of macrolide aldehyde sn-1 was prepared as previously reported (R. M. Kanada and D. Ito et. al., Angew. Chem. Int. Ed. 2007, 46, 4350-4355), and sn-2 was prepared in an analogous manner as described in Scheme 23. [0804] Protocol for Synthesis of Compound 162

##STR00311##

[0805] Step 1: To a solution of E7107 (30 mg, 0.042 mmol, 1.0 equiv) in DCE (1 mL) was added DMAP (1.020 mg, 8.34 μm, 0.2 equiv), Hunig's base (0.037 mL, 0.209 mmol, 5.0 equiv) and acetic anhydride (4.72 μL, 0.05 mmol, 1.2 equiv). After 2 hrs, the reaction mixture was evaporated. Purification by silica gel chromatography (0-10% MeOH/DCM) was completed to give desired product (Compound 162, 24 mg, 0.032 mmol, 76%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.01 (d, J=4.52 Hz, 6H) 0.76-0.88 (m, 14H) 0.99 (d, J=6.78 Hz, 3H) 1.14 (s, 3H) 1.18-1.25 (m, 3H) 1.31-1.59 (m, 8H) 1.63 (d, J=0.75 Hz, 4H) 2.03 (s, 4H) 2.27-2.58 (m, 4H) 2.71-2.86 (m, 3H) 3.10-3.24 (m, 2H) 3.71-3.82 (m, 1H) 3.89 (d, J=6.78 Hz, 2H) 4.89 (d, J=10.67 Hz, 1H) 5.01 (d, J=9.29 Hz, 1H) 5.50-5.65 (m, 3H) 6.05 (s, 1H) 6.12-6.28 (m, 1H). MS(ES+): 761.73 [M+H].sup.+.

TABLE-US-00011 TABLE 8 Compounds 147-162 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00312] .sup.1H NMR (400 MHz, METHANOL- d4) 0.78-0.98 (m, 6 H) 0.99-1.06 (m, 3 H) 1.19-1.28 (m, 4 H) 1.28- 1.43 (m, 2 H) 1.50-1.62 (m, 14 H) 1.63-1.75 (m, 6 H) 1.85-1.99 (m, 2 H) 2.41-2.68 (m, 7 H) 2.73-2.89 (m, 1 H) 3.39-3.62 (m, 4 H) 3.75 (br. s., 2 H) 4.07-4.26 (m, 2 H) 5.01 (d, J = 9.54 Hz, 1 H) 5.13 (d, J = 10.67 Hz, 1 H) 5.55-5.74 (m, 3 H) 6.01- 6.07 (m, 1 H) 6.10-6.20 (m, 1 H) 683.5  [00313] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.91 (d, J = 6.65 Hz, 3 H) 1.09 (d, J = 6.78 Hz, 3 H) 1.11-1.19 (m, 1 H) 1.23 (s, 3 H) 1.30-1.46 (m, 3 H) 1.50-1.69 (m, 2 H) 1.77 (s, 3 H) 2.40 (s, 3 H) 2.46-2.71 (m, 7 H) 3.41- 3.70 (m, 4 H) 3.75 (s, 3 H) 3.78-3.84 (m, 1 H) 3.92-4.09 (m, 2 H) 4.96 (d, J = 9.54 Hz, 1 H) 5.07 (d, J = 10.67 Hz, 1 H) 5.53-5.81 (m, 3 H) 6.11 (d, J = 10.54 Hz, 1 H) 6.38 (dd, J = 15.00, 10.85 Hz, 1 H) 566.5  [00314] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.19 (s, 4H), 6.04-6.30 (m, 1H), 5.83-6.04 (m, 1H), 5.45-5.71 (m, 3H), 5.08 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 9.5 Hz, 1H), 3.68 (br. s., 1H), 3.59 (s, 2H), 3.36-3.51 (m, 3H), 3.08-3.36 (m, 2H), 2.37-2.62 (m, 6H), 2.09-2.37 (m, 3H), 1.92-2.04 (m, 1H), 1.87 (br. s., 1H), 1.38-1.67 (m, 15H), 1.10- 1.37 (m, 8H), 0.88-1.00 (m, 3H), 0.84 (d, J = 6.8 Hz, 3H) 647.5  [00315] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J = 6.65 Hz, 3 H) 1.04 (d, J = 6.65 Hz, 3 H) 1.27 (s, 3 H)) 1.20-1.62 (m, 18 H) 1.65-1.78 (m, 5 H) 1.79-1.87 (m, 2 H) 190-2.01 (m, 2 H) 2.37- 2.67 (m, 5 H) 2.72-2.84 (br. s., 4 H) 2.87-2.98 (m, 1 H) 3.04-3.14 (m, 1 H) 3.25-3.36 (m, 1 H) 3.66 (br. s., 4 H) 3.71-3.80 (m, 1 H) 5.02 (d, J = 9.41 Hz, 1 H) 5.16 (d, J = 10.67 Hz, 1 H) 5.43 (t, J = 5.34 Hz, 1 H) 5.55- 5.66 (m, 2 H) 5.67 (dd, J = 15.06, 9.29 Hz, 1 H) 6.09 (d, J = 11.17 Hz, 1 H) 6.25 (dd, J = 15.00, 10.85 Hz, 1 H) 686.6  [00316] .sup.1H NMR (400 MHz, METHANOL- d4) 0.88 (d, J = 6.78 Hz, 3 H) 1.02 (d, J = 6.78 Hz, 3 H) 1.21 (m, 3 H) 1.27- 1.44 (m, 6 H) 1.53-1.72 (m, 6 H) 1.74 (s, 3 H) 1.76-1.84 (m, 2 H) 2.35 (s, 3 H) 2.41-2.63 (m, 10 H) 3.05- 3.17 (m, 2 H) 3.54 (br. s., 1 H) 3.79 (br. s., 1 H) 4.94 (d, J = 9.66 Hz, 1 H) 5.04 (d, J = 10.54 Hz, 1 H) 5.54-5.64 (m, 2 H) 5.65-5.77 (m, 1 H) 6.02- 6.13 (m, 1 H) 6.22-6.34 (m, 1 H) 7.78-7.86 (m, 1 H) 604.4  [00317] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.71-0.88 (m, 6 H) 0.98-1.06 (m, 1 H) 1.13- 1.27 (m, 13 H) 1.29-1.52 (m, 10 H) 1.56 (br. s., 9 H) 1.61-1.70 (m, 4 H) 1.73 (br. s., 2 H) 1.89 (br. s., 2 H) 2.34-2.59 (m, 7 H) 3.41 (d, J = 5.27 Hz, 4 H) 3.65-3.78 (m, 2 H) 4.11 (t, J = 6.78 Hz, 2 H) 4.88-5.02 (m, 1 H) 5.08 (d, J = 10.54 Hz, 1 H) 5.43-5.68 (m, 3 H) 6.01 (d, J = 10.29 Hz, 1 H) 6.25 (dd, J = 15.06, 11.04 Hz, 1 H) 674.3  [00318] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J = 6.78 Hz, 3 H) 0.97-1.03 (m, 6 H) 1.44-1.55 (m, 2 H) 1.67-1.85 (m, 5 H) 1.86-2.01 (m, 2 H) 2.37-2.62 (m, 11 H) 3.02 (br. s., 1 H) 3.20- 3.32 (m, 1 H) 3.38-3.63 (m, 9 H) 3.68-3.75 (m, 2 H) 3.79-4.10 (m, 2 H) 4.40-4.48 (m, 1 H) 4.86 (t, J = 10.10 Hz, 1 H) 5.14 (dd, J = 10.48, 5.58 Hz, 1 H) 5.28-5.41 (m, 2 H) 5.55 (dd, J = 14.93, 9.91 Hz, 1 H) 6.20 (t, J = 11.23 Hz, 1 H) 6.36 (br. d, J = 11.17 Hz, 1 H) 606.5  [00319] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.97 (d, J = 6.53 Hz, 3 H) 1.07 (d, J = 6.78 Hz, 3 H) 1.31-1.70 (m, 7 H) 1.71 (s, 3 H) 1.80-2.06 (m, 3 H) 2.21-2.32 (m, 2 H) 2.32 (s, 3 H) 2.39 (br. s., 4 H) 2.56-2.64 (m, 1 H) 3.42-3.59 (m, 6 H) 3.91-4.02 (m, 2 H) 4.15- 4.26 (m, 1 H) 4.45-4.50 (m, 1 H) 5.14 (td, J = 10.04, 5.14 Hz, 1 H) 5.26- 5.40 (m, 2 H) 5.58 (dd, J = 15.06, 10.04 Hz, 1 H) 5.65 (dd, J = 15.12, 7.47 Hz, 1 H) 6.06 (d, J = 10.41 Hz, 1 H) 6.27 (dd, J = 14.62, 11.23 Hz, 1 H) 575.4  [00320] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.78-0.97 (m, 6 H) 1.06 (d, J = 6.78 Hz, 3 H) 1.16-1.39 (m, 4 H) 1.43-1.61 (m, 2 H) 1.76-1.87 (m, 2 H) 2.22-2.47 (m, 7 H) 2.55-2.64 (m, 1 H) 3.30- 3.41 (m, 8 H) 3.90-4.00 (m, 2 H) 4.15-4.28 (m, 4 H) 5.02 (d, J = 10.67 Hz, 1 H) 5.14-5.30 (m, 3 H) 5.35- 5.45 (m, 2 H) 5.67 (dd, J = 15.06, 7.53 Hz, 1 H) 6.10 (d, J = 11.42 Hz, 1 H) 6.23-6.30 (m, 1 H) 6.45 (d, J = 0.88 Hz, 1 H) 559.5  [00321] .sup.1H NMR (400 MHz, METHANOL- d4) δ: 0.79 (d, J = 6.8 Hz, 2 H) 0.84 (t, J = 7.5 HZ, 1H) 0.97 (d, J = 6.78 Hz, 1 H) 1.05-1.09 (m, 2 H) 1.14- 1.32 (m, 5 H) 1.36 (dt, J = 7.84, 3.98 Hz, 1 H) 1.44-1.59 (m, 1 H) 1.65 (d, J = 1.00 Hz, 2 H) 1.96 (s, 2 H) 2.16- 2.39 (m, 3 H) 3.03 (dt, J = 3.51, 2.01 Hz, 2 H) 3.38 (dt, J = 3.26, 1.63 Hz, 1 H) 3.46-3.63 (m, 1 H) 3.69 (br. s., 1 H) 3.78-4.04 (m, 1 H) 4.46 (br. s., 1 H) 4.67 (s, 1 H) 4.95 (d, J = 10.04 Hz, 2 H) 5.46-5.65 (m, 2 H) 5.99 (d, J = 12.05 Hz, 1 H) 6.25 (dd, J = 15.94, 10.92 Hz, 1 H) (M + Na) 561.3  [00322] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.72- 0.89 (m, 3 H) 0.97 (d, J = 6.78 Hz, 3 H) 1.11-1.35 (m, 7 H) 1.42-1.56 (m, 2 H) 1.56-1.71 (m, 4 H) 2.02 (s, 3 H) 2.34-2.58 (m, 3 H) 3.32-3.54 (m, 3 H) 3.56-3.83 (m, 1 H) 5.01 (d, J = 9.03 Hz, 1 H) 5.09 (d, J = 10.54 Hz, 1 H) 5.50-5.65 (m, 3 H) 6.03 (d, J = 10.79 Hz, 1 H) 6.25 (ddd, J = 15.06, 10.79, 1.00 Hz, 1 H) 425.30 [00323] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d2) δ: 8.48 (d, J = 3.6 Hz, 2H), 7.14 (d, J = 4.6 Hz, 2H), 6.31 (dddd, J = 15.2, 10.8, 4.5, 1.3 Hz, 1H), 6.10 (dd, J = 10.8, 1.0 Hz, 1H), 5.87 (dd, J = 15.0, 7.5 Hz, 1H), 5.63-5.74 (m, J = 9.7 Hz, 1H), 5.55 (ddd, J = 15.4, 10.2, 1.8 Hz, 1H), 5.13 (d, J = 10.7 Hz, 1H), 4.97 (d, J = 9.7 Hz, 1H), 3.64-3.78 (m, 1H), 3.53 (quin, J = 7.0 Hz, 1H), 3.41 (br. s., 4H), 3.31 (br. d, J = 7.2 Hz, 1H), 2.55 (d, J = 3.5 Hz, 3H), 2.46 (br. s., 4H), 1.74 (d, J = 1.3 Hz, 4H), 1.70- 1.81 (m, 4H), 1.59-1.70 (m, 3H), 1.39 (d, J = 13.3 Hz, 1H), 1.34-1.58 (m, 11H), 1.25-1.34 (m, 3H), 1.20 (s, 3H), 0.88 (dd, J = 8.2, 6.9 Hz, 3H) 638.5  [00324] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.82-1.00 (m, 3 H) 1.24-1.31 (m, 4 H) 1.34- 1.60 (m, 12 H) 1.65-1.88 (m, 8 H) 1.96-2.12 (m, 1 H) 2.45-2.67 (m, 7 H) 3.50 (br. s., 4 H) 3.59 (t, J = 7.03 Hz, 1 H) 3.68-3.88 (m, 1 H) 4.95- 5.10 (m, 1 H) 5.17 (d, J = 10.54 Hz, 1 H), 5.54-5.79 (m, 2 H) 5.90 (dd, J = 15.06, 7.03 Hz, 1 H) 6.12 (d, = 10.79 Hz, 1 H) 6.27 (ddd, J = 15.06, 10.79, 1.25 Hz, 1 H) 7.26 (d, J = 4.77 Hz, 1 H) 7.54 (dt, J = 4.51 Hz, 1 H) 8.41-8.58 (m, 2 H) 638.5  [00325] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.87-0.97 (m, 3 H) 1.23-1.30 (m, 4 H) 1.32- 1.60 (m, 12 H) 1.64-1.78 (m, 7 H) 1.78-1.93 (m, 2 H) 1.99 (br. s., 1 H) 2.42-2.68 (m, 6 H) 3.37-3.64 (m, 5 H) 3.76 (d, J = 6.53 Hz, 1 H) 5.03 (d, J = 9.54 Hz, 1 H) 5.17 (d, J = 10.54 Hz, 1 H) 5.54-5.78 (m, 2 H) 5.91 (dd, J = 14.93, 6.90 Hz, 1 H) 6.12 (d, J = 11.54 Hz, 1 H) 6.18-6.40 (m, 1 H) 7.27 (s, 1 H) 7.41-7.66 (m, 1 H) 8.40-8.60 (m, 2 H) 638.4  [00326] .sup.1H NMR (400 MHz, METHANOL- d4) δ: ppm 0.76 (dd, J = 6.59, 1.32 Hz, 3 H) 0.78-0.87 (m, 1 H) 0.91 (d, J = 6.65 Hz, 2 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.20 (s, 3 H) 1.33-1.43 (m, 2 H) 1.55-1.65 (m, 2 H) 1.70-1.79 (m, 3 H) 2.00-2.04 (m, 1 H) 2.05- 2.19 (m, 4 H) 2.53 (br dd, J = 15.75, 3.33 Hz, 3 H) 3.11-3.22 (m, 1 H) 3.73-3.85 (m, 1 H) 5.03-5.09 (m, 2 H) 5.51-5.63 (m, 1 H) 5.66-5.76 (m, 1 H) 5.99 (dd, J = 15.00, 9.60 Hz, 1 H) 6.13 (br d, J = 10.79 Hz, 1 H) 6.32-6.43 (m, 1 H) 7.23-7.38 (m, 2 H) 7.72-7.83 (m, 1 H) 8.41-8.52 (m, 1 H) 500.58 [00327] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.01 (d, J = 4.52 Hz, 6 H) 0.76-0.88 (m, 14 H) 0.99 (d, J = 6.78 Hz, 3 H) 1.14 (s, 3 H) 1.18-1.25 (m, 3 H) 1.31-1.59 (m, 8 H) 1.63 (d, J = 0.75 Hz, 4 H) 2.03 (s, 4 H) 2.27-2.58 (m, 4 H) 2.71- 2.86 (m, 3 H) 3.10-3.24 (m, 2 H) 3.71-3.82 (m, 1 H) 3.89 (d, J = 6.78 Hz, 2 H) 4.89 (d, J = 10.67 Hz, 1 H) 5.01 (d, J = 9.29 Hz, 1 H) 5.50-5.65 (m, 3 H) 6.05 (s, 1 H) 6.12-6.28 (m, 1 H) 761.73

Synthesis of Compounds 163-174

[0806] Synthesis of Compound 163

##STR00328##

[0807] Step MM-1: To a mixture of macrolide diene x (15 mg, 0.041 mmol, 1.0 equiv.) and commercially available allylic alcohol m-12 (3.0 equiv.) in dichloromethane (0.014M) was added Hoveyda-Grubbs II catalyst (0.1 equiv.). The reaction mixture was stirred at reflux under a nitrogen atmosphere for 1 hour, or until the reaction was determined to be completed by TLC. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate as eluant) to afford the title Compound 163 (12.6 mg, 59%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90(d, J=6.4 Hz, 3H) 1.21(s, 3H) 1.23-1.47(m, 5H) 1.48-1.74(m, 4H) 1.77(s, 3H) 1.79-1.94(m, 2H) 2.10(s, 3H) 2.47-2.74(m, 5H) 3.54(d, J=10.4 Hz, 1H) 3.75(br. s., 1H) 5.09(d, J=8.8 Hz, 1H) 5.18(d, J=10.8 Hz, 1H) 5.58-5.72(m, 2H) 5.86(d, J=15.2 Hz, 1H) 6.13(d, J=10.8 Hz, 1H) 6.48(dd, J=15.2, 10.8 Hz, 1H) 7.10-7.22(m, 3H) 7.23-7.31(m, 2H). LCMS data (ES+) M+Na 537.3.

[0808] The intermediate diene x was prepared as previously reported (R. M. Kanada and D. Ito et. al., Angew. Chem. Int. Ed. 2007, 46, 4350-4355). [0809] Synthesis of Compound 164

##STR00329##

[0810] The title Compound 164 (6.8 mg, 61%) was prepared from commercially available allylic alcohol m-12 (6.0 equiv.) and macrolide diene x (8.4 mg, 0.23 mmol, 1.0 equiv.) in an analogous manner as described for step MM-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.80-0.95(m, 3H) 1.15-1.46(m, 5H) 1.60-1.78(m, 9H) 1.90 (s, 1H) 2.10 (s, 3H) 2.45-2.67 (m, 3H) 3.51 (d, J=10.8 Hz, 1H) 3.76 (br. s., 1H) 5.09 (d, J=8.8 Hz, 1H) 5.17 (d, J=10.4 Hz, 1H) 5.57-5.71 (m, 2H) 6.06 (d, J=14.8 Hz, 1H) 6.14 (d, J=10.0 Hz, 1H) 6.50 (ddd, J=15.2, 10.8, 8.4 Hz, 1H) 7.21-7.30 (m, 1H) 7.31-7.39 (m, 2H) 7.40-7.49 (m, 2H). LCMS data (ES+) M+Na 509.3. [0811] Synthesis of Compound 165

##STR00330##

[0812] The title Compound 165 (5.3 mg, 46%) was prepared from commercially available thiophene sn-5 (29.9 mg, 0.194 mmol, 8.3 equiv.) and macrolide diene x (8.6 mg, 0.0235 mmol, 1.0 equiv.) in an analogous manner as described for MM-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.82-0.98 (m, 3H) 1.15-1.44 (m, 8H) 1.47-1.88 (m, 5H) 1.99-2.26 (m, 5H) 2.44-2.74 (m, 3H) 3.44-3.61 (m, 1H) 3.75 (br. s., 1H) 5.02-5.26 (m, 2H) 5.53-5.75 (m, 2H) 6.00-6.22 (m, 2H) 6.47-6.63 (m, 1H) 6.89-7.03 (m, 2H) 7.17-7.35 (m, 1H). LCMS data (ES+) M+Na 515.1. [0813] Synthesis of Compound 166

##STR00331##

[0814] The title Compound 166 was prepared in an analogous manner to previously described reaction of Julia fragments with aldehydes. The intermediate of macrolide aldehyde sn-1 was prepared as previously reported (R. M. Kanada and D. Ito et. al., Angew. Chem. Int. Ed. 2007, 46, 4350-4355). [0815] The sulfone intermediate m-11 was prepared in the following manner.

##STR00332##

[0816] The sulfone intermediate m-11 (48 mg, 22% in 2 steps) was prepared from commercially available alcohol m-10 in an analogous manner as described in Scheme 23. LCMS data (ES+) M+Na 319.06. [0817] Synthesis of Compound 167

##STR00333##

[0818] Coupling product m-12 (62 mg, 99%) was prepared from aldehyde sn-1 (50 mg, 0.095 mmol, 1.0 equiv.) and sulfone m-9 (2.5 equiv.) in an analogous manner as described for step SN-1. LCMS data (ES+) M+Na 684.31. Triol m-13 (21 mg, 49%) was prepared in an analogous manner as described for step SN-2.

[0819] The title Compound 167 (2.8 mg, 12%) was prepared from triol m-13 in an analogous manner as described for step SN-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.80-0.95(m, 3H) 1.21 (s, 3H) 1.24-1.73 (m, 8H) 1.74 (s, 3H) 2.09 (s, 3H) 2.42-2.67 (m, 3H) 3.48-3.62 (m, 2H) 3.74 (br. s., 1H) 3.93 (s, 3H) 5.08 (d, J=8.40 Hz, 1H) 5.16 (d, J=10.40 Hz, 1H) 5.57-5.70 (m, 2H) 5.99-6.07 (m, 1H) 6.11 (d, J=10.80 Hz, 1H) 6.25-6.34 (m, 1H) 6.54 (d, J=7.20 Hz, 1H) 6.70 (d, J=7.20 Hz, 1H) 7.48 (t, J=8.00 Hz, 1H). LCMS data (ES+) M+Na 524.2. [0820] The sulfone intermediate m-9 was prepared in the following manner.

##STR00334##

[0821] Compound m-8 (426 mg, 63% in 2 steps) was prepared in an analogous manner as described for step mm-3 and step mm-4. LCMS data (ES+) M+Na 189.95.

[0822] Compound m-9 (490 mg, 65% in 2 steps) was prepared in an analogous manner as described in Scheme 23. LCMS data (ES+) M+Na 381.98. [0823] Synthesis of Compound 168

##STR00335##

[0824] Coupling product m-15 (35 mg, 52%) was prepared from aldehyde sn-1 (50 mg, 0.095 mmol, 1.0 equiv.) and sulfone m-6 (2.0 equiv.) in an analogous manner as described for step SN-1. LCMS data (ES+) M+Na 726.40. Triol m-16 (11 mg, 45%) was prepared in an analogous manner as described for step SN-2.

[0825] The title Compound 168 (9.4 mg, 75%) was prepared from m-16 in an analogous manner as described for step SN-3. .sup.11H NMR (400 MHz, CHLOROFORM-d) δ: 0.84-0.94 (m, 3H) 1.00 (s, 3H) 1.02 (s, 3H) 1.21 (s, 3H) 1.22-1.44 (m, 5H) 1.49-1.59 (m, 1H) 1.64-1.76 (m, 4H) 2.04-2.12 (m, 5H) 2.46-2.66 (m, 3H) 3.49-3.58 (m, 2H) 3.68-3.80 (m, 1H) 4.04-4.09 (m, 2H) 5.08 (d, J=8.8 Hz, 1H) 5.16 (d, J=11.2 Hz, 1H) 5.57-5.70 (m, 2H) 5.98-6.06 (m, 1H) 6.11 (d, J=10.8 Hz, 1H) 6.25-6.34 (m, 1H) 6.53 (dd, J=8.4, 4.0 Hz, 1H) 6.67 (dd, J=7.2, 4.0 Hz, 1H) 7.46 (t, J=7.6 Hz, 1H). [0826] The sulfone intermediate m-6 was prepared as described below.

##STR00336##

[0827] Step mm-1: A solution of isobutanol (1.2 equiv.) in DME (2 ml) was added to a suspension of potassium tert-butoxide (1.3 equiv.) in DME (3 ml, final conc. 0.41M) at room temperature. After being stirred at 50° C. for 30 minutes, bromopyridine m-1 (0.5 g, 2.05 mmol, 1.0 equiv.) was added to the mixture. After being stirred at reflux for 2 hours, the reaction mixture was cooled to room temperature, quenched with water and ethyl acetate was added. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product m-2 (0.49 g) was used in the next step without further purification.

[0828] Step mm-2: To a solution of dioxolan m-2 (0.49 g, 2.05 mmol, 1.0 equiv.) in THF (0.27M) was added 5N hydrochloric acid (6.1 equiv.). After being stirred at room temperature for 3 hours, the reaction mixture was quenched with 5N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product m-3 (0.39g) was used in the next step without further purification.

[0829] Step mm-3: To a suspension of methyltriphenylphosphonium iodide (1.3 equiv.) in THF (0.2M) at 0° C. was added n-butyl lithium (1.3 equiv., solution in n-hexane) dropwise. The reaction was stirred at 0° C. for 20 minutes. Next, a solution of pyridine methyl ketone m-3 (0.39 g, 2 mmol, 1.0 equiv) in THF was added dropwise. The reaction was stirred at 0° C. for 30 minutes. The reaction was quenched with water and ethyl acetate was added. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate as eluant) to afford the desired product m-4 (0.35g, 91%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.01 (d, J=6.8 Hz, 6H) 2.06-2.17 (m, 1H) 2.17 (s, 3H) 4.11 (d, J=6.4 Hz, 2H) 5.23 (s, 1H) 5.97 (s, 1H) 6.62 (d, J=8.0 Hz, 1H) 6.99 (d, J=7.6 Hz, 1H) 7.52 (dd, J=8.0, 7.6 Hz, 1H).

[0830] Step mm-4: To a solution of olefin m-4 (0.35 g, 1.82 mmol, 1.0 equiv.) in dichloromethane (0.18M) at 0° C. was added 9-BBN (2.5 equiv., solution in hexane). The reaction was stirred at 50° C. for 4.5 hours. After cooling to 0° C., the reaction was quenched with water, 5N sodium hydroxide solution (4.0 equiv.) and 30% aqueous hydrogen peroxide solution (4.0 equiv.). After being stirred at room temperature for 1 hour, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution, water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (heptane: ethyl acetate as eluant) to afford the desired product m-5 (0.26g, 68%). LCMS data (ES+) M+Na 232.02.

[0831] The desired intermediate m-6 (315 mg, 63% in 2 steps) was prepared in an analogous manner as described for Scheme 23. LCMS data (ES+) M+Na 402.08. [0832] Synthesis of Compound 169

##STR00337##

[0833] The title compound 169 (0.30 mg, 0.8% in 3 steps) was prepared from aldehyde sn-1 (40.0 mg, 0.076 mmol, 1.00 equiv.) and nm-12 (1.81 equiv.) in an analogous manner as described for step SN-1, SN-2 and SN-3. MS(ES+): 522.16 (M+Na.sup.+). [0834] The sulfone intermediate nm-12 was prepared in the following manner.

##STR00338##

[0835] Step NM-10: nm-13 (600 mg) was prepared from 2-methyl-3-buten-1-ol (200 mg, 2.32 mmol, 1.00 equiv.) in an analogous manner as described in Scheme 23. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.16-1.81(m, 3H) 2.65-2.72(m, 1H) 3.40-3.43(m, 2H) 5.03-5.11(m, 2H) 5.71-5.80(m, 1H) 7.27-7.35(m, 1H) 7.51-7.59(m, 4H). Step NM-11: 9-BBN (3.00 equiv., 0.4 M solution in THF) was added dropwise to a solution of nm-13 (300 mg, 1.22 mmol, 1.00 equiv.) in THF (2.5 mL) at 0° C. under N.sub.2. The reaction mixture was stirred at room temperature for 3 h. This mixture was added to a solution of 2-bromopyridine (1.20 equiv.), tetrakis(triphenylphosphine)palladium (0.20 equiv.) and potassium carbonate (4.00 equiv.) in dimethylformamide (4.00 mL) and distilled water (1.50 mL). The reaction mixture was stirred at 90° C. for 4 hours under N.sub.2. The reaction mixture was cooled to room temperature, filtered, extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-14 along with a by-product (254 mg). The crude product nm-14 (254 mg) was used in the next step without further purification.

[0836] Step NM-12: nm-12 (49.0 mg, 11% in 2 steps) was prepared from nm-14 (254 mg, 0.78 mmol, 1.00 equiv.) in an analogous manner as described for Scheme 23. MS(ES+): 379.90 (M+Na.sup.+). [0837] Synthesis of Compound 170

##STR00339##

[0838] The title compound 170 (5.44 mg, 13% in 3 steps) was prepared from aldehyde sn-1 (40.0 mg, 0.085 mmol, 1.00 equiv.) and nm-15 (1.72 equiv.) in an analogous manner as described for step SN-1, SN-2 and SN-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86-0.89 (m, 3H) 1.03 (d, J=6.40 Hz, 3H) 1.21 (s, 3H) 1.24-1.41 (m, 2H) 1.51-1.61 (m, 2H) 1.68 (s, 3H) 2.09 (s, 3H) 2.47-2.54 (m, 2H) 2.60-2.63 (m, 1H) 2.69-2.88 (m, 3H) 3.55 (d, J=10.8 Hz, 1H) 3.71-3.82 (m, 1H) 5.09 (d, J=9.2 Hz, 1H) 5.14 (d, J=10.8 Hz, 1H) 5.58-5.67 (m, 2H) 5.69-5.77 (m, 1H) 6.03-6.06 (m, 1H) 6.12-6.20 (m, 1H) 7.08-7.12 (m, 2H) 7.55-7.60 (m, 1H) 8.54-8.5 (m, 1H). MS(ES+): 508.07(M+Na+). [0839] The sulfone intermediate nm-15 was prepared in the following manner.

##STR00340##

[0840] Step NM-13: nm-16 (2.84 g, 88%) was prepared from methallyl alcohol (1.00 g, 13.9 mmol, 1.00 equiv.) in an analogous manner as described for step #40-6. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.84 (s, 3H) 4.05 (s, 2H) 4.94-4.96 (m, 1H) 5.09-5.10 (m, 1H) 7.54-7.59 (m, 5H).

[0841] Step NM-14: nm-17 (150 mg, 56%) was prepared from nm-16 (200 mg, 0.861 mmol, 1.00 equiv.) in an analogous manner as described for step NM-11. .sup.11-1 NMR (400 MHz, CHLOROFORM-d) δ: 1.01 (d, J=6.80 Hz, 3H) 2.52-2.57 (m, 1H) 2.72-2.78 (m, 1H) 2.97-3.02 (m, 1H) 3.37-3.42 (m, 1H) 3.49-3.54 (m, 1H) 7.11-7.16 (m, 2H) 7.52-7.66 (m, 6H) 8.52-8.54 (m, 1H).

[0842] Step NM-15: nm-15 (50.0 mg, 30%) was prepared from nm-17 (150 mg, 0.482 mmol, 1.00 equiv.) in an analogous manner as described for Scheme 23. MS(ES+): 365.92 (M+Na.sup.+).

[0843] Synthesis of Compound 171

##STR00341##

[0844] The title Compound 171 (2.37 mg, 11.3%) was prepared from diene x (15 mg, 0.041 mmol, 1.0 equiv.) and sn-5 (3.00 equiv.) in an analogous manner as described for step MM-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J=6.80 Hz, 3H) 1.22 (s, 3H) 1.37 (s, 3H) 1.22-1.58 (m, 4H) 1.68-1.74 (m, 1H) 1.78 (s, 3H) 1.81-1.90 (m, 1H) 2.08 (br. s., 1H), 2.10 (s, 3H) 2.50-2.57 (m, 2H), 2.59-2.69 (m, 3H) 3.52 (d, J=10.8 Hz, 1H), 3.73-3.76 (m, 1H) 5.09 (d, J=9.20 Hz, 1H) 5.18 (d, J=10.8 Hz, 1H) 5.59-5.71 (m, 1H) 5.86 (d, J=15.2 Hz, 1H) 6.13 (d, J=10.8 Hz, 1H) 6.47 (d, J=15.2 Hz, 1H) 6.49 (d, J=15.2 Hz, 1H) 7.18-7.19 (m, 2H) 7.25-7.29 (m, 3H). MS(ES+): 537.2 (M+Na.sup.+). [0845] The intermediate allelic alcohol nm-11 was prepared as described in following manner.

##STR00342##

[0846] Step NM-5: To a stirred solution of the triethyl phosphonoacetate (1.30 equiv.) in THF (0.673 M) was added sodium hydride (1.50 equiv., >60% purity) at 0° C. under N.sub.2. The reaction mixture was stirred at room temperature for 60 min. Benzylacetone (3.00 g, 20.2 mmol, 1.00 equiv.) was added to the reaction mixture at room temperature, then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-7 (4.30 g, 98%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.26-1.29 (m, 3H) 2.21 (s, 3H) 2.42-2.46 (m, 2H) 2.76-2.81 (m, 4H) 4.12-4.17 (m, 2H) 5.69 (s, 3H) 7.16-7.31 (m, 5H).

[0847] Step NM-6: To a stirred solution of nm-7 (4.30 g, 19.7 mmol, 1.00 equiv.) in toluene (0.281 M) was added dropwise diisobutylaluminum hydride (2.20 equiv., 1.02 M solution in toluene) at −78° C. under N2. The reaction mixture was stirred at −78° C. for 2.5 hours. The reaction mixture was diluted with water, sat. potassium sodium tartrate, ethyl acetate, and stirred at room temperature for 1 hour. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-8 (1.75 g, 50%). .sup.1H NMR (400 1 MHz, CHLOROFORM-d) δ: 1.72 (s, 3H) 2.30-2.34 (m, 2H) 2.71-2.76 (m, 2H) 4.12-4.13 (m, 2H) 5.38-5.43 (m, 1H) 5.69 (s, 3H) 7.16-7.30 (m, 5H).

[0848] Step NM-7: To a solution of titanium isopropoxide (1.20 equiv.) and 4Å molecular sieves (1.00 g) in dichloromethane (10 mL) was added (−)-diethyl-D-tartrate (1.50 equiv.) in dichloromethane (2.0 mL) at −20° C. under N.sub.2. The reaction mixture was stirred at −20° C. for 10 min. nm-8 (1.75 g, 9.93 mmol, 1.00 equiv.) in dichloromethane (2.0 mL) was added to the reaction mixture at −20° C. The reaction mixture was cooled to −30° C., and tert-butyl hydroperoxide (2.00 equiv., 6.0 M solution in nonane) in dichloromethane (1.0 mL, final conc. 0.66 M) was added to the reaction mixture. The reaction mixture was stirred at −30° C. for 60 min. A solution of water (20 mL), iron sulfate heptahydrate (1.43 equiv.) and D-(−)-tartaric acid (12.0 equiv.) was added to the reaction mixture, then stirred at 0° C. for 20 min. The reaction mixture was diluted with ethyl acetate and further extracted with ethyl acetate. A 1N NaOH aqueous solution (10 mL) was added to the organic layer and the mixture was stirred at room temperature for 30 min. Then, water was added to the mixture. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the mixture of desired product nm-9 and (−)-diethyl-D-tartrate. The crude product nm-9 (1.90 g) was used in the next step without further purification.

[0849] Step NM-8: A mixture of crude product nm-9 (1.90 g, 9.88 mmol, 1.00 equiv.), p-toluenesulfonyl chloride (2.00 equiv.) and triethylamine (5.00 equiv.) in dichloromethane (15 mL, 0.659 M) was stirred at room temperature for 60 min under N.sub.2. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-10 with by-product (3.80 g). The crude product nm-10 (3.80 g) was used in the next step without further purification.

[0850] Step NM-9: Sodium iodide (4.00 equiv.) was added to a mixture of crude product nm-10 (1.00 g, 2.89 mmol, 1.00 equiv.) in THF (20 mL, 0.145 M) at room temperature. The reaction mixture was stirred at 70° C. for 60 min. After nm-10 was no longer detected by TLC, zinc copper couple (5.00 equiv.) was added to the reaction mixture. The reaction mixture was stirred at reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite®, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-11 (249 mg). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 1.35 (s, 3H) 1.82-1.89 (m, 2H) 2.62-2.69 (m, 2H) 5.10-5.13 (m, 1H) 5.25-5.29 (m, 1H) 5.94-6.01 (m, 1H) 7.16-7.30 (m, 5H). [0851] Synthesis of Compound 172

##STR00343##

[0852] Step NM-1: To a stirred solution of nm-2 (50.0 mg, 0.159 mmol, 1.52 equiv.) in THF (2.00 mL) at −78° C. under Na was slowly added KHMDS (1.60 equiv., 0.50 M solution in toluene). The reaction mixture was stirred at −78° C. for 60 minutes. Aldehyde nm-1 (50.0 mg, 0.104 mmol, 1.0 equiv.) in THF (1.00 mL, final conc. 0.035 M) was added slowly at −78° C. At the same temperature, the reaction mixture was stirred for 60 min. The reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethyl acetate as eluent) to afford the desired product nm-3 (32.0 mg, 54%).

[0853] Step NM-2: To a stirred solution of the nm-3 (18.0 mg, 0.032 mmol, 1.0 equiv.) in THF (0.032 M) was slowly added tetrabutylammonium fluoride (2.00 equiv., 1.00 M solution in THF) at room temperature under N.sub.2. The reaction mixture was stirred at room temperature for 60 min. Tetrabutylammonium fluoride (2.00 equiv., 1.00 M solution in THF) was added to the reaction mixture, and then the reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative silica gel column chromatography (ethyl acetate only) to afford the title Compound 172 (3.57 mg, 25%). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J=6.80 Hz, 3H) 1.21 (s, 3H) 1.22-1.70 (m, 4H) 1.74 (s, 3H) 2.10 (s, 3H) 2.48-2.64 (m, 3H) 3.48-3.62 (m, 1H) 3.65 (d, J=6.80 Hz, 2H) 3.72-3.78 (m, 1H) 5.08 (d, J=8.80 Hz, 1H) 5.16 (d, J=10.40 Hz, 1H) 5.57-5.70 (m, 2H) 5.94-6.02 (m, 1H) 6.13 (d, J=11.2 Hz, 1H) 6.34-6.41 (m, 1H) 7.11-7.18 (m, 2H) 7.59-7.63 (m, 1H) 8.53-8.55 (m, 1H). MS(ES+): 480.18 [M+Na.sup.+].

[0854] The aldehyde intermediate nm-1 was prepared as previously described (R. M. Kanada and D. Ito et. al., PCT Int. Appl, 2007, WO2007043621) and sulfone intermediate nm-2 was prepared in the following manner.

##STR00344##

[0855] Step NM-3: Sulfide nm-4 (2.03 g, 88%) was prepared from 2-(2-hydroxylethyl)-pyridine (1.00 g, 8.12 mmol, 1.00 equiv.) in an analogous manner as described in Scheme 23. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 3.37-3.41 (m, 2H) 3.81-3.86 (m, 2H) 7.16-7.25 (m, 2H) 7.52-7.66 (m, 6H) 8.55-8.57 (m, 1H), MS(ES+): 305.98 [M+Na.sup.+].

[0856] Step NM-4: Sulfone nm-2 (132 mg, 40%) was prepared from nm-4 (300 mg, 1.06 mmol, 1.00 equiv.) in an analogous manner as described in Scheme 23. 1H NMR (400 MHz, CHLOROFORM-d) δ: 3.46-3.50 (m, 2H) 4.25-4.29 (m, 2H) 7.16-7.24 (m, 2H) 7.58-7.72 (m, 6H) 8.49-8.50 (m, 1H), MS(ES+): 337.90 [M+Na.sup.+].

Synthesis of Compound 173

[0857] ##STR00345##

[0858] The title compound 173 (0.40 mg, 1.4% in 2 steps) was prepared from nm-1 (30 mg, 0.062 mmol, 1.00 equiv.) and nm-5 (2.55 equiv.) in an analogous manner as described for steps NM-1 and 2. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J=6.80 Hz, 3H) 1.21 (s, 3H) 1.22-1.81 (m, 4H) 1.73 (s, 3H) 2.10 (s, 3H) 2.48-2.65 (m, 3H) 3.44-3.52 (m, 3H) 3.73-3.78 (m, 1H) 5.08 (d, J=9.20 Hz, 1H) 5.16 (d, J=10.8 Hz, 1H) 5.58-5.71 (m, 2H) 5.82-5.89 (m, 1H) 6.10-6.13 (m, 1H) 6.28-6.34 (m, 1H) 7.11-7.13 (m, 2H) 8.50-8.52 (m, 2H). MS(ES+): 480.18 (M+Na.sup.+).

[0859] The sulfone intermediate nm-5 (357 mg, crude) was prepared from 4-(2-hydroxyl-ethyl)pyridine (1.00 g, 8.12 mmol, 1.00 equiv.) in an analogous manner as described for step NM-3 and NM-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 3.29-3.33 (m, 2H) 4.02-4.07 (m, 2H) 7.22-7.23 (m, 2H) 7.44-7.72 (m, 6H) 8.59-8.60 (m, 1H). [0860] Synthesis of Compound 174

##STR00346##

[0861] The title Compound 174 (3.71 mg, 13.0% in 2 steps) was prepared from nm-1 (30 mg, 0.062 mmol, 1.00 equiv.) and nm-6 (2.55 equiv.) in an analogous manner as described for steps NM-1 and NM-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J=6.80 Hz, 3H) 1.21 (s, 3H) 1.22-1.73 (m, 4H) 1.73 (s, 3H) 2.10 (s, 3H) 2.48-2.65 (m, 3H) 3.46 (d, J=6.80 Hz, 2H) 3.51 (d, J=11.2 Hz, 1H) 3.72-3.76 (m, 1H) 5.08 (d, J=8.80 Hz, 1H) 5.15 (d, J=10.8 Hz, 1H) 5.57-5.72 (m, 2H) 5.83-5.90 (m, 1H) 6.09-6.12 (m, 1H) 6.26-6.32 (m, 1H) 7.21-7.26 (m, 1H) 7.48-7.52 (m, 1H) 8.45-8.48 (m, 2H). MS(ES+): 480.18 (M+Na.sup.+).

[0862] The sulfone intermediate nm-6 (2.30 g, crude) was prepared from 3-(2-hydroxylethyl)-pyridine (1.00 g, 8.12 mmol, 1.00 equiv.) in an analogous manner as described for step NM-3 and NM-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 3.28-3.34 (m, 2H) 4.01-4.05 (m, 2H) 7.25-7.31 (m, 2H) 7.44-7.73 (m, 6H) 8.55-8.56 (m, 1H).

TABLE-US-00012 TABLE 9 Compounds 163-174 LCMS Structure, Compound #, and Chemical Name .sup.1H NMR data data (ES+) [00347] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.90 (d, J = 6.4 Hz, 3 H) 1.21 (s, 3 H) 1.23- 1.47 (m, 5 H) 1.48-1.74 (m, 4 H) 1.77 (s, 3 H) 1.79-1.94 (m, 2 H) 2.10 (s, 3 H) 2.47-2.74 (m, 5 H) 3.54 (d, J = 10.4 Hz, 1 H) 3.75 (br. s., 1 H) 5.09 (d, J = 8.8 Hz, 1 H) 5.18 (d, J = 10.8 Hz, 1 H) 5.58-5.72 (m, 2 H) 5.86 (d, J = 15.2 Hz, 1 H) 6.13 (d, J = 10.8 Hz, 1 H) 6.48 (dd, J = 15.2, 10.8 Hz, 1 H) 7.10-7.22 (m, 3 H) 7.23-7.31 (m, 2 H) 537.3  (M + Na.sup.+) [00348] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.80- 0.95 (m, 3 H) 1.15-1.46 (m, 5 H) 1.60- 1.78 (m, 9 H) 1.90 (s, 1 H) 2.1 (s, 3 H) 2.45-2.67 (m, 3 H) 3.51 (d, J = 10.8 Hz, 1 H) 3.76 (br. s., 1 H) 5.09 (d, J = 8.8 Hz, 1 H) 5.17 (d, J = 10.4 Hz, 1 H) 5.57-5.71 (m, 2 H) 6.06 (d, J = 14.8 Hz, 1 H) 6.14 (d, J = 10.0 Hz, 1 H) 6.50 (ddd, J = 15.2, 10.8, 8.4 Hz, 1 H) 7.21-7.30 (m, 1 H) 7.31-7.39 (m, 2 H) 7.40-7.49 (m, 2 H) 509.3  (M + Na.sup.+) [00349] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.82-0.98 (m, 3 H) 1.15-1.44 (m, 8 H) 1.47- 1.88 (m, 5 H) 1.99-2.26 (m, 5 H) 2.44-2.74 (m, 3 H) 3.44-3.61 (m, 1 H) 3.75 (br. s., 1 H) 5.02-5.26 (m, 2 H) 5.53-5.75 (m, 2 H) 6.00-6.22 (m, 2 H) 6.47-6.63 (m, 1 H) 6.89- 7.03 (m, 2 H) 7.17-7.35 (m, 1 H) 515.1  (M + Na.sup.+) [00350] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.82- 0.95 (m, 3H), 1.21 (s, 3 H) 1.21- 1.45 (m, 5H) 1.48-1.49 (m, 2H) 1.63- 1.78 (m, 5 H) 2.09 (s, 3 H) 2.45- 2.68 (m, 3 H), 3.54 (q, J = 7.2 Hz, 1 H), 3.75 (br. s., 1 H) 5.08 (d, J = 9.2 Hz, 1 H) 5.15 (d, J = 10.4 Hz, 1 H) 5.57- 5.72 (m, 2 H) 5.93 (ddd, J = 15.2, 7.2, 2.4 Hz, 1 H) 6.10 (d, J = 10.4 Hz, 1 H) 6.17-6.28 (m, 1H), 7.16-7.32 (m, 5 H) 493.2  (M + Na.sup.+) [00351] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.80- 0.95 (m, 3 H) 1.21 (s, 3 H) 1.24- 1.73 (m, 8 H) 1.74 (s, 3 H) 2.09 (s, 3 H) 2.42-2.67 (m, 3 H) 3.48-3.62 (m, 2 H) 3.74 (br. s., 1 H) 3.93 (s, 3 H) 5.08 (d, J = 8.40 Hz, 1 H) 5.16 (d, J = 10.40 Hz, 1 H) 5.57-5.70 (m, 2 H) 5.99-6.07 (m, 1 H) 6.11 (d, J = 10.80 Hz, 1 H) 6.25-6.34 (m, 1 H) 6.54 (d, J = 7.20 Hz, 1 H) 6.70 (d, J = 7.20 Hz, 1 H) 7.48 (t, J = 8.00 Hz, 1 H) 524.2  (M + Na.sup.+) [00352] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.84- 0.94 (m, 3 H) 1.00 (s, 3 H) 1.02 (s, 3 H) 1.21 (s, 3 H) 1.22-1.44 (m, 5 H) 1.49-1.59 (m, 1 H) 1.64-1.76 (m, 4 H) 2.04-2.12 (m, 5 H) 2.46-2.66 (m, 3 H) 3.49-3.58 (m, 2 H) 3.68- 3.80 (m, 1 H) 4.04-4.09 (m, 2 H) 5.08 (d, J = 8.8 Hz, 1 H) 5.16 (d, J = 11.2 Hz, 1 H) 5.57-5.70 (m, 2 H) 5.98-6.06 (m, 1 H) 6.11 (d, J = 10.8 Hz, 1 H) 6.25-6.34 (m, 1 H) 6.53 (dd, J = 8.4, 4.0 Hz, 1 H) 6.67 (dd, J = 7.2, 4.0 Hz, 1 H) 7.46 (t, J = 7.6 Hz, 1 H) [00353] 522.16 (M + Na.sup.+) [00354] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.86- 0.89 (m, 3 H) 1.03 (d, J = 6.40 Hz, 3 H) 1.21 (s, 3 H) 1.24-1.41 (m, 2 H) 1.51- 1.61 (m, 2 H) 1.68 (s, 3 H) 2.09 (s, 3 H) 2.47-2.54 (m, 2 H) 2.60-2.63 (m, 1 H) 2.69-2.88 (m, 3 H) 3.55 (d, J = 10.8 Hz, 1 H) 3.71-3.82 (m, 1 H) 5.09 (d, J = 9.2 Hz, 1 H) 5.14 (d, J = 10.8 Hz, 1 H) 5.58-5.67 (m, 2 H) 5.69-5.77 (m, 1 H) 6.03-6.06 (m, 1 H) 6.12-6.20 (m, 1 H) 7.08- 7.12 (m, 2 H) 7.55-7.60 (m, 1 H) 8.54-8.55 (m, 1 H) 508.07 (M + Na.sup.+) [00355] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.91 (d, J = 6.80 Hz, 3 H) 1.22 (s, 3 H) 1.37 (s, 3 H) 1.22-1.58 (m, 4 H) 1.68- 1.74 (m, 1 H) 1.78 (s, 3 H) 1.81- 1.90 (m, 1 H) 2.08 (br. s., 1 H), 2.10 (s, 3 H) 2.50-2.57 (m, 2 H), 2.59-2.69 (m, 3 H) 3.52 (d, J = 10.8 Hz, 1 H), 3.73-3.76 (m, 1 H) 5.09 (d, J = 9.20 Hz, 1 H) 5.18 (d, J = 10.8 Hz, 1 H) 5.59-5.71 (m, 1 H) 5.86 (d, J = 15.2 Hz, 1 H) 6.13 (d, J = 10.8 Hz, 1 H) 6.47 (d, J = 15.2 Hz, 1 H) 6.49 (d, J = 15.2 Hz, 1 H) 7.18-7.19 (m, 2 H) 7.25-7.29 (m, 3 H) 537.2  (M + Na.sup.+) [00356] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.80 Hz, 3 H) 1.21 (s, 3 H) 1.22- 1.70 (m, 4 H) 1.74 (s, 3 H) 2.10 (s, 3 H) 2.48-2.64 (m, 3 H) 3.48-3.62 (m, 1 H) 3.65 (d, J = 6.80 Hz, 2 H) 3.72- 3.78 (m, 1H) 5.08 (d, J = 8.80 Hz, 1 H) 5.16 (d, J = 10.40 Hz, 1 H) 5.57- 5.70 (m, 2 H) 5.94-6.02 (m, 1 H) 6.13 (d, J = 11.2 Hz, 1 H) 6.34- 6.41 (m, 1 H) 7.11-7.18 (m, 2H) 7.59-7.63 (m, 1 H) 8.53-8.55 (m, 1 H) 480.18 (M + Na.sup.+) [00357] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.80 Hz, 3 H) 1.21 (s, 3 H) 1.22- 1.81 (m, 4 H) 1.73 (s, 3 H) 2.10 (s, 3 H) 2.48-2.65 (m, 3H) 3.44-3.52 (m, 3 H) 3.73-3.78 (m, 1H) 5.08 (d, J = 9.20 Hz, 1 H) 5.16 (d, J = 10.8 Hz, 1 H) 5.58-5.71 (m, 2 H) 5.82- 5.89 (m, 1 H) 6.10-6.13 (m, 1 H) 6.28-6.34 (m, 1 H) 7.11-7.13 (m, 2H) 8.50-8.52 (m, 2 H) 480.18 (M + Na.sup.+) [00358] 1H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J = 6.80 Hz, 3 H) 1.21 (s, 3 H) 1.22- 1.73 (m, 4 H) 1.73 (s, 3 H) 2.10 (s, 3 H) 2.48-2.65 (m, 3 H) 3.46 (d, J = 6.80 Hz, 2 H) 3.51 (d, J = 11.2 Hz, 1 H) 3.72-3.76 (m, 1H) 5.08 (d, J = 8.80 Hz, 1 H) 5.15 (d, J = 10.8 Hz, 1 H) 5.57-5.72 (m, 2 H) 5.83- 5.90 (m, 1 H) 6.09-6.12 (m, 1 H) 6.26-6.32 (m, 1 H) 7.21-7.26 (m, 1H) 7.48-7.52 (m, 1 H) 8.45- 8.48 (m, 2 H) 480.18 (M + Na.sup.+)

Protocol for Synthesis of Compound 175

[0863] ##STR00359##

[0864] Compound 175 was synthesized in an analogous manner as Compound 163. MS(ES+): 553.35 [M+Na].sup.+. [0865] Protocol for Synthesis of Compound 176

##STR00360##

[0866] Compound 176 was prepared from aldehyde sn-1 (1 equiv) and SPE-21 (1.81 equiv.) in an analogous manner as described for step SN-1, SN-2 and SN-3. MS(ES+): 521.42 (M+Na.sup.+). [0867] Protocol for Synthesis of Compound 177

##STR00361##

[0868] Step 1: To a suspension of sodium hydride (55% oil dispersion in mineral oil, 10.7 mmol, 1 equiv) in DMF (10 mL) at 0° C. was added a solution of SPE-22 (2.0 g, 10.7 mmol, 1 equiv) dropwise at and was stirred for 30 minutes. Then iodomethane (2 ml, 32.1 mmol, 3 equiv) was added dropwise and then allowed to warm up to room temperature over 4 hrs. The reaction was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (SPE-23, 997 mg, 4.96 mmol, 46%).

[0869] Step 2: To a solution of 2-methylbut-3-en-1-ol (651 mg, 3.24 mmol, 1 equiv) in THF (1.25 mL) was added 9-BBN (0.5 M THF solution, 11.6 mL, 5.8 mmol, 1.8 equiv) at 0° C. dropwise. The mixture was then warmed up to room temperature and was stirred for 2.5 hours. To the reaction mixture, was added pre-mixed solution of SPE-23 (651 mg, 3.24 mmol), tetrakis(triphenylphosphine)palladium(0) (189 mg, 0.232 mmol, 0.07) and potassium carbonate (962 mg, 6.96 mmol, 2.14 equiv) in DMF (24 mL) and H.sub.2O (0.75 mL). The resulting mixture was warmed up to 90° C. and was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and water. Phase separated and organic layer was washed with H.sub.2O and brine, then was dried over MgSO.sub.4. Solid was filtered out and solvent was removed in vacuo. The obtained residue was purified by silica gel chromatography (Heptane/EtOAc= 75/25) to give a product (SPE-24, 368 mg, 1.77 mmol, 76% yield).

[0870] Step 3: To a solution of SPE-24 (368 mg, 1.77 mmol, 1 equiv) in THF (4 mL) at 0° C. was added 1-phenyl-1H-tetrazole-5-thiol (378 mg, 2.12 mmol, 1.2 equiv), triphenyl phosphine (557 mg, 2.12 mmol, 1.2 equiv) and diisopropyl azodicarboxylate (452 mg, 2.12 mmol, 1.2 equiv) and was stirred for 3 hours. The reaction was diluted with ethyl acetate and H.sub.2O. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (SPE-25, 310 mg, 0.841 mmol, 48%).

[0871] Step 4: To a solution of SPE-26 (310 mg, 0.84 mmol, 1 equiv) in ethanol (3 mL) was added a solution of ammonium molybdate tetrahydrate (104 mg, 0.084 mmol, 0.1 equiv) in hydrogen peroxide (35% aqueous solution, 1 ml, 12.6 mmol, 15 equiv) at room temperature The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and water. Phase separated and organic layer was washed with H.sub.2O, saturated aq. NaS.sub.2O.sub.3, and brine, then was dried over magnesium sulfate. Solid was filtered out and solvent was removed in vacuo. The obtained residue was purified by silica gel chromatography (Heptane/AcOEt= 2/1) to afford the desired product (SPE-27, 236 mg, 0.589 mmol, 70% yield).

[0872] Step 5: To a solution of SPE-27 (0.035 g, 0.087 mmol, 1.4 equiv) in THF (3.0 mL) under nitrogen at −78° C. was added KHMDS (0.5 M in THF solution, 0.20 mL, 0.10 mmol, 1.6 equiv) dropwise and the reaction was stirred for 1 hour. Then aldehyde D (0.030 g, 0.062 mmol, 1.0 equiv) in THF (0.2 mL) was added dropwise. The reaction was stirred at −78° C. for 3 hours. The reaction was quenched with ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate as eluent) to afford the desired product (SPE-27, 0.024 g, 0.037 mmol, 59%).

[0873] Step 6: To a solution of SPE-27 (24.0 mg, 0.037 mmol, 1.0 equiv.) in THF (2.0 mL, 0.02 M) at room temperature was added tributylammonium fluoride (1.0 M THF solution, 1.1 ml, 1.1 mmol, 30 equiv.) The reaction was stirred for 1 hour. The reaction was diluted with ethyl acetate and H.sub.2O. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (hepatnes/ethyl acetate as eluent) to afford the desired product (Compound 177, 6.8 mg, 0.012 mmol, 34%). .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J=6.8 Hz, 3H) 1.07 (d, J=6.8 Hz, 3H) 1.21 (s, 3H) 1.24-1.38 (m, 3H) 1.51-1.70 (m, 4H) 1.74 (s, 3H) 2.05 (s, 3H) 2.27 (quin, J=6.8 Hz, 1H) 2.49-2.66 (m, 5H) 3.38 (s, 3H) 3.55 (d, J=10.8 Hz, 2H) 3.73-3.78 (m, 1 H) 4.44 (s, 2H) 5.08-5.19 (m, 2H) 5.61-5.73 (m, 3H) 6.09-6.26 (m, 2H) 7.16-7.32 (m, 5 H). MS(ES+): 565.36 [M+Na].sup.+. [0874] Protocol for Synthesis of Compound 178

##STR00362##

[0875] Compound 178 (12.3 mg, 36.4% in 2 steps) was prepared from aldehyde D (30.0 mg, 0.062 mmol, 1.00 equiv.) and sulfone SPE-28 (1.34 equiv.) in an analogous manner as described in Compound 182. .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J=6.8 Hz, 3H) 1.07 (d, J=6.8 Hz, 3H) 1.21 (s, 3H) 1.24-1.41 (m, 3H) 1.51-1.70 (m, 4H) 1.73 (s, 3H) 2.05 (s, 3H) 2.20-2.24 (m, 1H) 2.49-2.66 (m, 5H) 3.38 (s, 3H) 3.56 (d, J=10.8 Hz, 2H) 3.73-3.78 (m, 1 H) 4.42 (s, 2H) 5.08-5.18 (m, 2H) 5.63-5.70 (m, 3H) 6.07-6.22 (m, 2H) 7.15 (d, J=8.0 Hz, 2H) 7.24 (d, J=8.0 Hz, 2H). MS(ES+): 565.37 [M+Na].sup.+. [0876] Protocol for Synthesis of Compound 179

##STR00363##

[0877] Compound 179 (11.5 mg, 34.1% in 2 steps) was prepared from aldehyde D (30.0 mg, 0.062 mmol, 1.00 equiv.) and sulfone SPE-29 (1.34 equiv.) in an analogous manner as described in Compound 177. .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J=6.8 Hz, 3H) 1.05 (d, J=6.8 Hz, 3H) 1.21 (s, 3H) 1.24-1.42 (m, 3H) 1.52-1.72 (m, 4H) 1.74 (s, 3H) 2.10 (s, 3H) 2.20-2.26 (m, 1H) 2.50-2.66 (m, 5H) 3.38 (s, 3H) 3.56 (dd, J=10.8, 3.2 Hz, 2H) 3.72-3.78 (m, 1H) 4.43 (s, 2H) 5.08-5.18 (m, 2H) 5.59-5.71 (m, 3H) 6.08-6.23 (m, 2H) 7.09-7.27 (m, 5H). MS(ES+): 565.41 [M+Na].sup.+. [0878] Protocol for Synthesis of Compound 180

##STR00364##

[0879] To a solution of Pladienolide D (136 mg, 0.246 mmol, 1 equiv) in dichloromethane (4 mL) at room temperature was added Dess-Martin periodinane (209 mg, 0.492 mmol, 2.0 equiv.). The resulting solution was stirred for 10 minutes, and then was diluted with ethyl acetate. The organic layer was washed with water and brine, then was dried over sodium sulfate, solid was filtered off, and solvent was removed in vacuo. The obtained residue was purified by NH-silica gel chromatography (heptane/ethyl acetate as eluent) to afford desired product (Compound 180, 66.1 mg, 0.12 mmol, 49% yield). MS(ES+): 571.36 [M+Na].sup.+. [0880] Protocol for Synthesis of Compound 181

##STR00365## ##STR00366##

[0881] Step 1: E7107 (48.00 g, 66.8 mmol, 1 equiv) was dissolved in DMF (96 mL) and then imidazole (31.8 g, 467 mmol, 7 equiv) was added. Upon complete dissolution of imidazole, the mixture was cooled to 3° C. TBSC1 (30.2 g, 200 mmol, 3 equiv) was added and stirring was continued at 3-5° C. for 2 hours. The mixture was allowed to warm up to room temperature (18-19° C.) and stirring continued for 22 hours. The mixture was diluted with MTBE (192 mL) and cooled to 3° C. Water (192 mL) was added while maintaining T-internal below 15° C. and resultant mixture was transferred to a separation funnel. Water (96 mL) and MTBE (96 mL) were used to rinse the reactor. Rinsate was also transferred to the separation funnel and mixed well. The org layer was separated and set aside. Aqueous layer was extracted with MTBE twice (288 mL×2). All the organic layers were combined, sequentially washed with: (1) water (96 mL), (2) 30 wt % aqueous NaCl (96 mL, 492.79 mmol) and partially concentrated to give 631 g yellow solution (silylation crude mixture), 1.58 g aliquot of which, corresponding to 1/400 of crude mixture, was subjected to purification by silica gel chromatography (25-50% MTBE/heptane) to give the desired product (SPE-13, 172 mg).

[0882] Step 2: Another 1.58 g aliquot of the crude SPE-13 was concentrated, dissolved in acetone (1.6 mL) and diluted with water (0.4 mL). NMO (0.078 g, 0.68 mmol) was added followed by 2.5 wt % O.sub.SO.sub.4 solution in water (0.34 ml, 0.033 mmol). After overnight stirring (16 hr), the mixture was diluted with toluene (0.8 mL), cooled to 0° C. and quenched with 20 wt % aqueous sodium sulfite (0.8 g). The mixture was partially concentrated and extracted with EtOAc twice (4 mL×2). All the organic layers were combined, washed with 36 wt % aqueous NaCl (0.4 mL) and concentrated. Crude product thus obtained was purified by Biotage 25M (EtOAc 100% and EtPAc—MeOh 19:1 v/v) to give the desired product (SPE-14, 117 mg).

[0883] Step 3: SPE-14 (80 mg, 0.082 mmol, 1 equiv) was dissolved in acetonitrile (1.6 mL) and treated with lead tetraacetate (Pb(AcO).sub.4; 74 mg, 0.17 mmol, 2 equiv) at room temperature. After 30 min, mixture was diluted with ethyl acetate (3.2 mL), filtered and washed with a mixture of 20 wt % aqueous sodium sulfite (Na.sub.2SO.sub.3, 0.3 g, 0.5 mmol, 7.3 equiv) and 9 wt % aqueous sodium bicarbonate (0.3 g, 0.3 mmol, 3.6 equiv). The organic layer was separated and set aside. The aqueous layer was extracted with ethyl acetate (3.2 mL). All the organic layers were combined, washed with 36 wt % aqueous sodium chloride (0.60 mL), and concentrated. Brownish crude oil thus obtained was purified by short SiO.sub.2 plug column (EtOAc 100% & EtOAc 100% & EtOAc—MeOH 9:1 v/v) to give the desired product (SPE-15, 30 mg).

[0884] Step 4: (Methyl)triphenylphosphonium bromide (1.28 g, 3.59 mmol, 2.2 equiv) was suspended in THF (10.5 mL) and cooled to —10° C. 1 M potassium tert-butoxide solution in THF (3.2 mL, 3.2 mmol, 2 equiv) was added (T-internal reached —6.1° C.) and the resultant yellow mixture was stirred at −10° C. After 30 min, the mixture was cooled to below —70° C. A solution of SPE-15 (1.049 g, 1.62 mmol, 1 equiv) in THF (2.1 mL) was added (T≤−65° C.). Additional THF (2.1 mL) was used for rinse. Dry ice/acetone bath was replaced with dry ice/acetonitrile bath to have the mixture warmed up to approx. —45° C. After 30 min, 28 wt % aqueous ammonium chloride (1 g) was added and the mixture was allowed to warm up to —10° C., diluted with toluene (31.5 mL) and water (2 mL). The organic layer was separated, washed with 36 wt % aqueous sodium chloride (3 mL), concentrated and purified by Biotage Snap Ultra 100 g (0-100% EtOAc/acetone) to give the desired product (SPE-16, 310 mg).

[0885] Step 5-6: SPE-16 (0.110 g, 0.17 mmol, 1 equiv) was dissolved in 1,2-dichloroethane (2.3 mL). Acrolein dimethyl acetal (0.20 ml, 1.7 mmol, 10 equiv), benzoquinone (0.5 mg) and Hoveyda-Grubbs 2.sup.nd generation catalyst (14 mg, 0.017 mmol, 0.1 equiv) were added. The resultant mixture was heated at 50° C. Additional reagents were charged at the following time points: 1 hr—acrolein dimethyl acetal (0.20 ml, 1.7 mmol, 10 equiv), 2 hr—Acrolein dimethyl acetal (0.20 ml, 1.7 mmol, 10 equiv), 3 hr—Hoveyda-Grubbs 2nd generation catalyst (14 mg, 0.017 mmol, 0.1 equiv) and acrolein dimethyl acetal (0.20 ml, 1.7 mmol, 10 equiv). Heating was continued for extra 5 hr and the mixture was let cool down to ambient temp. The mixture was directly loaded on silica gel column for purification (heptane-MTBE 1:1, heptane-EtOAc 9:1) to give crude SPE-17. This was dissolved in dichloromethane (1 mL) and treated with formic acid (0.1 mL) at room temperature for 10 minutes. 9 wt % aqueous sodium bicarbonate (3 g) was carefully added and the mixture was extracted with ethyl acetate twice (4 mL×2). All the organic layers were combined, concentrated and purified by silica gel chromatography (EtOAc 100% & EtOAc-acetone 3:1) to give the desired product (SPE-18, 10 mg)

[0886] Step 7-8: sn-2 (10.8 mg, 0.033 mmol, 2 equiv) was dissolved in THF (0.1 mL). DMF (0.025 mL) was added and the mixture was cooled to —70° C. 0.5 M solution of 1 M NaHMDS solution in THF (0.037 ml, 0.037 mmol, 2.5 equiv) was added (<−65° C.). A solution of SPE-18 (0.010 g, 0.015 mmol, 1 equiv) in THF (0.1 mL) was added. (<−60° C.). THF (0.2 mL) was used for rinse. After 30 min, dry ice/acetone bath was replaced with dry ice/MeCN bath. The mixture was allowed to warm up to −45° C. to −50° C. After 1 hr, the reaction was quenched with 28 wt % aqueous ammonium chloride (0.1 g). The mixture was warmed up to 0° C., and then diluted with ethyl acetate (6 mL) and water (0.2 mL). The organic layer was separated, washed with 36 wt % aqueous sodium chloride (0.3 mL), concentrated and purified by silica gel chromatography (50-100% EtOAc/heptane) to give the desired product (SPE-19, 10 mg). SPE-19 was dissolved in THF (0.3 mL) and treated with 1 M TBAF solution in THF (0.030 mL, 0.03 mmol) at room temperature. After overnight stirring, the mixture was concentrated and purified by Sift plug (MTBE 100% to MTBE-acetone 2:1) to give the desired product (Compound 181, 3 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) □□ 8.54 (1H, m), 7.60 (1H, m), 7.09-7.17 (2H, m), 6.22-6.36 (2H, m), 6.14 (1H, m), 5.99 (1H, dd, J=7 Hz and 15 Hz), 5.68 (1H, dd, J=10 Hz and 15 Hz), 5.59 (1H, dd, J=10 Hz and 15 Hz), 5.16 (1H, d, J=10 Hz), 5.01 (1H, d, J=10 Hz), 3.6-3.8 (2H, m), 3.4-3.5 (5H, m), 2.4-2.6 (8H, m), 1.96 (1H, s), 1.2-1.8 (16H, m), 1.73 (3H, s), 1.44 (3H, d, J=7 Hz), 1.22 (3H, s), 0.87 (3H, d, J=7 Hz). [0887] Protocol for Synthesis of Compound 182

##STR00367##

[0888] Step 1: To H3B-8800 (55 mg, 0.099 mmol, 1 equiv) in DCE (5 mL), mCPBA (17.08 mg, 0.099 mmol, 1.0 equiv) was added and stirred for 1 hr. The reaction mixture was evaporated and purified by preparative HPLC to give the desired product (Compound 182, 21 mg, 0.037 mmol, 37%). .sup.1H NMR (400 MHz, CDC13) δ: 0.80-1.00 (m, 3H) 1.23-1.48 (m, 6H) 1.50-1.63 (m, 1H) 1.65-1.83 (m, 4H) 2.41-2.68 (m, 5H) 3.19-3.36 (m, 7H) 3.67-3.85 (m, 2H) 3.91 (br s, 2H) 4.02 (br s, 2H), 5.03 (br d, J=9.54 Hz, 1H) 5.17 (d, J=10.54 Hz, 1H) 5.57-5.77 (m, 2H) 6.02 (dd, J=15.18, 7.40 Hz, 1H) 6.13 (br d, J=11.04 Hz, 1H) 6.34 (dd, J=15.06, 10.79 Hz, 1H) 7.14 (t, J=6.18 Hz, 1H) 7.18 (d, J=7.14 Hz, 1H) 7.28 (s, 2H) 7.63 (td, J=7.65, 1.76 Hz, 1H) 8.56 (d, J=5.11 Hz, 1H). MS(ES+): 572.69 [M+H].sup.+. [0889] Compounds 183 and 184 were synthesized according to Scheme 56.

##STR00368##

Exemplified Protocol for Synthesis of Compound 183

[0890] Step 1: To a solution of SPE-1 (246 mg, 0.746 mmol, 1.8 equiv) in a 1:2 ratio DMF (0.5 mL)/THF (1 mL) at −78° C. was added dropwise NaHMDS (0.829 mL, 0.829 mmol, 2.0 equiv) by slow addition to ensure internal does not exceed −60° C. The yellow solution was stirred at −78° C. for 30 mins. Then a solution of D (200 mg, 0.414 mmol, 1 equiv) in THF (1 mL) was added dropwise at such a rate to ensure the reaction temperature remained below −60° C. The flask was rinsed with additional THF (1 mL) and the reaction mixture stirred for 1 hr at −78. The bath temp was increased to −50° C. over 20 mins and then allowed to stir between −50° C. to −45° C. for 2 hrs. Solid ammonium chloride (22.16 mg, 0.414 mmol, 1 equiv) was added in one portion. The bath was slowly allowed to warm to 0° C. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the resulting residue by column chromatography (0-100% EtOAc/hexanes) was completed to give the desired product (SPE-2, 320 mg, 0.382 mmol, 92%).

[0891] Step 2: To a solution of SPE-2 (320 mg, 0.382 mmol, 1 equiv) in MeOH (3 mL) at rt was added solid potassium carbonate (74.0 mg, 0.535 mmol, 1.4 equiv) in one portion. The reaction mixture was stirred at rt for 2.5 hrs. Then, it was cooled to 0° C. and solid ammonium chloride (28.6 mg, 0.535 mmol, 1 equiv) was added along with water (2 mL). This mixture was extracted with EtOAc, washed brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the desired product (SPE-3, 148 mg, 0.272 mmol, 71%).

[0892] Step 3: To a 0° C. solution of SPE-4 (17.87 mg, 0.069 mmol, 1.5) in DCM (1 mL) and Hunig'sBase (0.048 mL, 0.276 mmol, 6.0 equiv) was added phosgene (0.065 ml, 0.092 mmol, 2 equiv) (in Toluene). The reaction mixture was stirred for 30 min at 0° C., then warmed to rt. The reaction mixture was concentrated by rotavap and high vacuum. The residue was dissolved in THF (1 mL) and SPE-3 (25 mg, 0.046 mmol, 1 equiv) and DMAP (22.47 mg, 0.184 mmol, 4 equiv) were added. The reaction mixture was stirred at rt for 1 hr. The reaction mixture was then cooled to 0° C. and a 1M toluene solution of NaHMDS (0.184 ml, 0.184 mmol, 4 equiv) was added. This was stirred for 2 hrs at this temperature. The reaction mixture was quenched with ammonium chloride solution and extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (10% MeOH/EtOAc) was completed to give the desired product (SPE-5, 21 mg, 0.028 mmol, 60%).

[0893] Step 4: To SPE-5 (21 mg, 0.028 mmol, 1 equiv) in methanol (0.5 mL), P-TOLUENESULFONIC ACID MONOHYDRATE (10.6 mg, 0.056 mmol, 2 equiv) was added at rt. After 3 hr, the reaction was quenched with sat. NaHCO3 solution. The aqueous was extracted with EtOAc, followed by washing with brine, driying over sodium sulfate, filtering, and concentration to give the crude product. Purification by silica gel chromatography (0-20% MeOH/EtOAc) was completed to give the desired product (Compound 183, 15.7 mg, 0.024 mmol, 88%). .sup.1H NMR (400 MHz, METHANOL-d4) δ: ppm 0.86-0.92 (m, 3H) 1.14-1.18 (m, 1H) 1.21-1.24 (m, 3H) 1.27 (s, 2H) 1.36-1.48 (m, 7H) 1.57-1.69 (m, 2H) 1.76 (s, 3H) 1.81-1.98 (m, 6H) 2.50-2.62 (m, 6H) 2.72-2.87 (m, 4H) 3.62-3.70 (m, 1H) 3.75-3.84 (m, 1H) 4.91-4.97 (m, 1H) 5.02-5.10 (m, 1H) 5.52-5.64 (m, 1H) 5.67-5.79 (m, 1H) 5.89-6.00 (m, 1H) 6.10-6.19 (m, 1H) 6.32-6.42 (m, 1H) 7.35-7.45 (m, 1H) 7.70-7.81 (m, 1H) 8.37-8.41 (m, 1H) 8.42-8.45 (m, 1H). MS(ES+): 642.64 [M+H].sup.+. [0894] Protocol for the Synthesis of Compound 185

##STR00369##

[0895] Step 1: To a solution of SPE-6 (184 mg, 0.559 mmol, 1.8 equiv) in 1:4 DMF (529 μL)/THF (2139 μL) at −78° C. was added dropwise 1M NaHMDS (482 μL, 0.482 mmol, 1.55 equiv) via slow addition to ensure internal does not exceed −60° C. The yellow solution was stirred at −78° C. for 30 mins. Then a solution of intermediate D (150 mg, 0.311 mmol, 1 equiv) in THF (425 μL) was added dropwise at such a rate as to ensure the temperature remained below −60° C. The aldehyde container was rinsed with additional THF and added to main flask. The reaction mixture was stirred for 1 hr, maintaining bath temp between −70° C. to −60° C. The bath temperature was increased to −50° C. over 20 mins. This was then allowed to stir between −50° C. to −45° C. for 2 hrs in an acetonitrile-dry ice bath. After 2 hrs, solid AMMONIUM CHLORIDE (72.6 mg, 1.358 mmol, 4.37 equiv) was added in one portion and bath was allowed to slowly warm to 0° C. Added toluene and water at 0° C. and the combined organics were washed with brine. The organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-40% MTBE/hexanes with long hold at 40% gave desired product as a mixture with some aldehyde D (SPE-7, 57.8 mg, 0.099 mmol, 31.7%).

[0896] Step 2: To a solution of SPE-7 (29.2 mg, 0.05 mmol, 1 equiv) in MeOH (252 μL) at rt was added solid potassium carbonate (9.64 mg, 0.07 mmol, 1.4 equiv) in one portion. At 2 hours, the reaction mixture was cooled to 0° C. and sat aq ammonium chloride was added. The aqueous was extracted with EtOAc and washed with brine. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product (SPE-8, 12.6 mg, 0.023 mmol, 46.5%) was taken into the next step without further purification.

[0897] Step 3: SPE-8 (24.2 mg, 0.045 mmol, 1 equiv) was dissolved in methanol (225 μL) and tosic acid (16.93 mg, 0.089 mmol, 2 equiv) was added. The reaction mixture was stirred at rt for 1 hr. The reaction was quenched with sat. aq. sodium bicarbonate and extracted with 10% MeOH/DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-20% MeOH/DCM) was completed to give the desired product (Compound 185, 9.2 mg, 0.021 mmol, 48.1% yield) as a crusty oil/white solid. 1H NMR (400 MHz, METHANOL-d4) δ: ppm 0.90 (d, J=6.78 Hz, 3H) 1.28 (s, 4H) 1.35-1.39 (m, 2H) 1.45 (d, J=7.03 Hz, 3H) 1.53-1.62 (m, 2H) 1.76 (d, J=0.88 Hz, 3H) 2.53 (s, 3H) 3.69-3.80 (m, 4H) 5.03-5.08 (m, 1H) 5.34-5.44 (m, 1H) 5.48-5.53 (m, 1H) 5.67-5.78 (m, 1H) 5.92-6.03 (m, 1H) 6.09-6.18 (m, 1H) 6.33-6.44 (m, 1H) 7.23-7.32 (m, 1H) 7.32-7.39 (m, 1H) 7.72-7.84 (m, 1H) 8.40-8.50 (m, 1H). MS(ES+): 430.43 [M+H].sup.+.

TABLE-US-00013 TABLE 10 Compounds 175-185 Structure, Compound #, and Chemical LCMS data Name .sup.1H NMR data (ES+) [00370] 553.35 [00371] 521.42 [00372] .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J = 6.8 Hz, 3 H) 1.07 (d, J = 6.8 Hz, 3 H) 1.21 (s, 3 H) 1.24-1.38 (m, 3 H) 1.51-1.70 (m, 4 H) 1.74 (s, 3 H) 2.05 (s, 3 H) 2.27 (quin, J = 6.8 Hz, 1 H) 2.49-2.66 (m, 5 H) 3.38 (s, 3H) 3.55 (d, J = 10.8 Hz, 2 H) 3.73-3.78 (m, 1 H) 4.44 (s, 2 H) 5.08-5.19 (m, 2 H) 5.61-5.73 (m, 3 H) 6.09- 6.26 (m, 2 H) 7.16-7.32 (m, 5 H) 565.36 [00373] .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J = 6.8 Hz, 3 H) 1.07 (d, J = 6.8 Hz, 3 H) 1.21 (s, 3 H) 1.24-1.41 (m, 3 H) 1.51-1.70 (m, 4 H) 1.73 (s, 3 H) 2.05 (s, 3 H) 2.20-2.24 (m, 1 H) 2.49-2.66 (m, 5 H) 3.38 (s, 3 H) 3.56 (d, J = 10.8 Hz, 2 H) 3.73-3.78 (m, 1 H) 4.42 (s, 2 H) 5.08-5.18 (m, 2 H) 5.63-5.70 (m, 3 H) 6.07- 6.22 (m, 2 H) 7.15 (d, J = 8.0 Hz, 2 H) 7.24 (d, J = 8.0 Hz, 2 H) 565.37 [00374] .sup.1H NMR (400 MHz, CHLOROFORM, d) δ: 0.90 (d, J = 6.8 Hz, 3 H) 1.05 (d, J = 6.8 Hz, 3 H) 1.21 (s, 3 H) 1.24-1.42 (m, 3 H) 1.52-1.72 (m, 4 H) 1.74 (s, 3 H) 2.10 (s, 3 H) 2.20-2.26 (m, 1 H) 2.50-2.66 (m, 5 H) 3.38 (s, 3H) 3.56 (dd, J = 10.8, 3.2 Hz, 2 H) 3.72- 3.78 (m, 1 H) 4.43 (s, 2 H) 5.08- 5.18 (m, 2 H) 5.59-5.71 (m, 3 H) 6.08-6.23 (m, 2 H) 7.09-7.27 (m, 5 H) 565.41 [00375] 571.36 [00376] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.54 (1H, m), 7.60 (1H, m), 7.09-7.17 (2H, m), 6.22-6.36 (2H, m), 6.14 (1H, m), 5.99 (1H, dd, J = 7 Hz and 15 Hz), 5.68 (1H, dd, J = 10 Hz and 15 Hz), 5.59 (1H, dd, J = 10 Hz and 15 Hz), 5.16 (1H, d, J = 10 Hz), 5.01 (1H, d, J = 10 Hz), 3.6-3.8 (2H, m), 3.4-3.5 (5H, m), 2.4-2.6 (8H, m), 1.96 (1H, s), 1.2-1.8 (16H, m), 1.73 (3H, s), 1.44 (3H, d, J = 7 Hz), 1.22 (3H, s), 0.87 (3H, d, J = 7 Hz) [00377] .sup.1H NMR (400 MHz, CDCl3) δ: 0.80- 1.00 (m, 3 H) 1.23-1.48 (m, 6 H) 1.50-1.63 (m, 1 H) 1.65-1.83 (m, 4 H) 2.41-2.68 (m, 5 H) 3.19-3.36 (m, 7 H) 3.67-3.85 (m, 2 H) 3.91 (br s, 2 H) 4.02 (br s, 2 H), 5.03 (br d, J = 9.54 Hz, 1 H) 5.17 (d, J = 10.54 Hz, 1 H) 5.57-5.77 (m, 2 H) 6.02 (dd, J = 15.18, 7.40 Hz, 1 H) 6.13 (br d, J = 11.04 Hz, 1 H) 6.34 (dd, J = 15.06, 10.79 Hz, 1 H) 7.14 (t, J = 6.18 Hz, 1 H) 7.18 (d, J = 7.14 Hz, 1 H) 7.28 (s, 2 H) 7.63 (td, J = 7.65, 1.76 Hz, 1 H) 8.56 (d, J = 5.11 Hz, 1 H) 572.69 [00378] .sup.1H NMR (400 MHz, METHANOL- d4) δ: ppm 0.86-0.92 (m, 3 H) 1.14- 1.18 (m, 1 H) 1.21-1.24 (m, 3 H) 1.27 (s, 2 H) 1.36-1.48 (m, 7 H) 1.57-1.69 (m, 2 H) 1.76 (s, 3 H) 1.81-1.98 (m, 6 H) 2.50-2.62 (m, 6 H) 2.72-2.87 (m, 4 H) 3.62-3.70 (m, 1 H) 3.75-3.84 (m, 1 H) 4.91- 4.97 (m, 1 H) 5.02-5.10 (m, 1 H) 5.52-5.64 (m, 1 H) 5.67-5.79 (m, 1 H) 5.89-6.00 (m, 1 H) 6.10-6.19 (m, 1 H) 6.32-6.42 (m, 1 H) 7.35- 7.45 (m, 1 H) 7.70-7.81 (m, 1 H) 8.37-8.41 (m, 1 H) 8.42-8.45 (m, 1 H) 642.64 [00379] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 0.89- 0.93 (m, 3 H) 1.25 (s, 3 H) 1.26- 1.30 (m, 3 H) 1.32-1.51 (m, 1 H) 1.32-1.41 (m, 1 H) 1.43 (dd, J = 7.03, 2.26 Hz, 4 H) 1.49-1.58 (m, 1 H) 1.62-1.85 (m, 9 H) 1.93- 2.06 (m, 5 H) 2.17-2.22 (m, 2 H) 2.49-2.68 (m, 9 H) 2.73-2.88 (m, 2 H) 3.45-3.54 (m, 1 H) 3.55-3.63 (m, 1 H) 3.70-3.81 (m, 1 H) 4.17- 4.27 (m, 1 H) 4.98-5.04 (m, 1 H) 5.17 (d, J = 10.67 Hz, 1 H) 5.55- 5.66 (m, 1 H) 5.67-5.78 (m, 1 H) 5.86-5.97 (m, 1 H) 6.12 (d, J = 10.79 Hz, 1 H) 6.19-6.32 (m, 1 H) 7.22-7.27 (m, 1 H) 7.47-7.58 (m, 1 H) 8.44-8.54 (m, 1 H) 660.53 [00380] .sup.1H NMR (400 MHz, METHANOL- d4) δ: ppm 0.90 (d, J = 6.78 Hz, 3 H) 1.28 (s, 4 H) 1.35-1.39 (m, 2 H) 1.45 (d, J = 7.03 Hz, 3 H) 1.53-1.62 (m, 2 H) 1.76 (d, J = 0.88 Hz, 3 H) 2.53 (s, 3 H) 3.69-3.80 (m, 4 H) 5.03-5.08 (m, 1 H) 5.34-5.44 (m, 1 H) 5.48-5.53 (m, 1 H) 5.67-5.78 (m, 1 H) 5.92-6.03 (m, 1 H) 6.09- 6.18 (m, 1 H) 6.33-6.44 (m, 1 H) 7.23-7.32 (m, 1 H) 7.32-7.39 (m, 1 H) 7.72-7.84 (m, 1 H) 8.40-8.50 (m, 1 H) 430.43
Compounds 186-196 were synthesized according to Scheme 58. [0898] Protocol for the synthesis of Compound 186

##STR00381##

[0899] Step 1: To a solution of tri-TES Pladienolide D (160 mg, 0.179 mmol) in 1,2-dichloroethane (5 mL) at 20° C. was added DMAP (32.7 mg, 0.268 mmol), triethyl amine (0.75 mL, 5.36 mmol) and 4-nitrophenyl chloroformate (360 mg, 1.787 mmol). The reaction mixture was stirred at 40° C. for 4 days, and at 60° C. for 2 hours. The reaction mixture was diluted with EtOAc and washed with water, then the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were successively washed with water and brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo. Flash chromatography afforded (2S,3S,6S,7R,10R,E)-7-acetoxy-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilypoxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilypoxy)oxacyclododec-4-en-6-yl piperazine-1-carboxylate (150 mg, 79% yield).

[0900] .sup.1H -NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.48-0.71 (m, 24H) 0.78-0.85 (m, 7H) 0.86-0.93 (m, 5H) 0.94-1.03 (m, 34H) 1.18-1.22 (m, 2H) 1.22-1.26 (m, 2H) 1.35-1.43 (m, 4H) 1.43-1.52 (m, 4H) 1.54 (s, 4H) 1.56-1.65 (m, 3H) 1.68-1.72 (m, 3H) 1.75 (br d, J=0.75 Hz, 2H) 1.84-1.95 (m, 1H) 2.01-2.06 (m, 2H) 2.09 (s, 2H) 2.11 (s, 2H) 2.33-2.52 (m, 4H) 2.57 (dd, J=8.09, 2.07 Hz, 2H) 2.80-2.90 (m, 1H) 3.66-3.80 (m, 1H) 3.82-3.93 (m, 2H) 4.92-5.13 (m, 2H) 5.63-5.68 (m, 1H) 5.69-5.74 (m, 1H) 5.75-5.83 (m, 2H) 6.12 (br d, J=10.67 Hz, 1H) 6.41 (ddd, J=15.15, 11.01, 5.08 Hz, 1H) 7.50 (d, J=9.41 Hz, 2H) 8.35 (d, J=9.29 Hz, 2H).

[0901] Step 2: To a solution of (2S,3S,6S,7R,10R,E)-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-6-(((4-nitrophenoxy)carbonyl)oxy)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-7-yl acetate in DCM (1 mL) was added piperazine (0.447 g, 5.195 mmol) and Hunig's base (0.9 mL, 5.195 mmol). The resulting yellowish suspension was stirred for 6 hours. Reaction mixture was concentrated and chromatographed over silica gel to afford (2S,3S,6S,7R,10R,E)-7-acetoxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl piperazine-1-carboxylate (1.0 g, 0.844 mmol, 81% yield). LC/MS (ESI, m/z), 1008.1 [M+H].sup.+.

[0902] Step 3: 2S, 3S,6S,7R,10R,E)-7-acetoxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl piperazine-1-carboxylate (1.09 g, 0.92 mmol), DCM (20.71 mL, 321.826 mmol), and DIPEA (19.91 mL, 114.018 mmol) were combined and cooled to −78° C. Hydrogen fluoride-pyridine (0.518 g, 5.232 mmol) was added and the reaction allowed to warm to RT and stirred overnight. LC/MS suggested de-silylation. the reaction mixture was cooled in an icebath. Saturated NaHCO.sub.3 was added and stirred and extracted with DCM. The organic layers were combined, dried over an. NA.sub.2SO.sub.4 and concentrated and chromatographed to afford (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2S,3S)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (225 mg, 36.8%). LC/MS (ESI, m/z), 665.6 [M+H].sup.+.

[0903] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.87-0.92 (m, 6H) 0.94 (t, J=7.40 Hz, 3H) 1.16-1.31 (m, 1H) 1.35 (s, 3H) 1.40-1.56 (m, 4H) 1.59 (s, 3H) 1.66 (br dd, J=14.68, 7.03 Hz, 3H) 1.76-1.80 (m, 3H) 1.87 (dd, J=14.12, 5.46 Hz, 1H) 2.05 (s, 3H) 2.30-2.41 (m, 1H) 2.50 (d, J=3.76 Hz, 2H) 2.56-2.72 (m, 2H) 2.90 (br d, J=2.01 Hz, 1H) 3.19 (br t, J=5.14 Hz, 4H) 3.50-3.59 (m, 1H) 3.71 (br s, 4H) 3.77-3.89 (m, 1H) 5.01-5.13 (m, 2H) 5.58-5.71 (m, 1H) 5.71-5.81 (m, 1H) 5.88 (d, J=15.31 Hz, 1H) 6.15 (br d, J=10.79 Hz, 1H) 6.53 (dd, J=15.18, 10.92 Hz, 1H). [0904] Protocol for synthesizing Compound 187

##STR00382##

[0905] Step 1: To a solution of tri-TES-Pladienolide D (200 mg, 0.223 mmol) in dichloromethane (2 mL) at 0° C. was added DMAP (409 mg, 3.35 mmol) and 4-nitrophenyl chloroformate (338 mg, 1.675 mmol). The reaction mixture was stirred at RT for 7 days, diluted with EtOAc and water, then the layers were separated. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were washed with brine. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Flash chromatography afforded (2S,3S,6S,7R,10R,E)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-7-(((4-nitrophenoxy)carbonyl)oxy)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate. (170 mg, 72% yield).

[0906] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.54-0.67 (m, 18H) 0.78-1.03 (m, 36H) 1.19-1.32 (m, 1H) 1.39 (s, 3H) 1.43-1.52 (m, 3H) 1.55-1.63 (m, 3H) 1.64 (s, 3H) 1.74 (s, 3H) 1.88 (dd, J=13.80, 5.02 Hz, 1H) 2.13 (s, 3H) 2.23-2.37 (m, 1H) 2.39-2.48 (m, 2H) 2.51-2.63 (m, 2H) 2.84 (s, 1H) 3.69-3.77 (m, 1H) 3.82-4.00 (m, 1H) 5.04 (d, J=10.79 Hz, 1H) 5.24 (d, J=9.03 Hz, 1H) 5.67-5.84 (m, 3H) 6.12 (d, J=10.16 Hz, 1H) 6.42 (dd, J=15.06, 11.04 Hz, 1H) 7.42 (d, J=9.29 Hz, 2H) 8.29 (d, J=9.16 Hz, 2H).

[0907] Step 2: To a solution of (2S,3S,6S,7R,10R,E)-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-7-((4-nitrophenoxy)carbonyl)oxy)-12-oxo-10-((triethylsilypoxy)oxacyclododec-4-en-6-yl acetate (100 mg, 0.094 mmol) in DCM was added piperazine and DMAP. The resulting yellowish suspension was stirred for 6 hours. The reaction mixture was concentrated to give the crude product. Flash chromatography afforded (2S,3S,6S,7R,10R,E)-6-acetoxy-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-7-yl piperazine-1-carboxylate (95 mg, 100%). LC/MS (ESI, m/z), 1008.8 [M+H].sup.+.

[0908] .sup.1-H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.42-0.70 (m, 22H) 0.79-0.84 (m, 7H) 0.86-0.91 (m, 4H) 0.92-1.03 (m, 30H) 1.15-1.30 (m, 2H) 1.37-1.42 (m, 3H) 1.44-1.52 (m, 3H) 1.56-1.62 (m, 2H) 1.62-1.68 (m, 1H) 1.71-1.76 (m, 3H) 1.83-1.93 (m, 1H) 2.03-2.11 (m, 4H) 2.36-2.45 (m, 2H) 2.45-2.53 (m, 2H) 2.54-2.64 (m, 1H) 2.78-2.86 (m, 1H) 2.86-3.07 (m, 4H) 3.32-3.45 (m, 1H) 3.45-3.64 (m, 3H) 3.69-3.78 (m, 1H) 3.79-3.94 (m, 1H) 5.00 (d, J=10.54 Hz, 1H) 5.18 (s, 1H) 5.54-5.79 (m, 3H) 5.98-6.21 (m, 1H) 6.33-6.57 (m, 1H) 6.84-6.96 (m, 3H) 8.02-8.35 (m, 2H) 8.06-8.08 (m, 1H).

[0909] Step 3: To a solution of (2S,3S,6S,7R,10R,E)-6-acetoxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-7-yl piperazine-1-carboxylate in (95 mg, 0.094 mmol) in THF (3 mL) was added TBAF (0.424 mL, 1 M, 0.424 mmol) and stirred at RT for 10 hours. The mixture as concentrated and diluted with EtOAc, washed with water and brine. The organic layer was separated and dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. HPLC purification afforded (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl piperazine-1-carboxylate (16 mg, 26%). LC/MS (ESI, m/z), 665.6 [M+H].sup.+.

[0910] .sup.1-H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.90 (dd, J=6.84, 2.20 Hz, 6H) 0.94 (t, J=7.40 Hz, 3H) 1.20-1.30 (m, 1H) 1.34 (s, 3H) 1.39-1.54 (m, 3H) 1.55 (s, 3H) 1.59-1.73 (m, 3H) 1.78 (d, J=0.88 Hz, 3H) 1.86 (dd, J=13.99, 5.46 Hz, 1H) 2.05 (s, 3H) 2.39-2.53 (m, 3H) 2.55-2.65 (m, 1H) 2.67 (dd, J=8.03, 2.26 Hz, 1H) 2.89 (s, 1H) 3.22 (br s, 4H) 3.50-3.57 (m, 1H) 3.58-3.90 (m, 5H) 5.08 (d, J=10.67 Hz, 1H) 5.18 (d, J=9.03 Hz, 1H) 5.58-5.78 (m, 2H) 5.88 (d, J=15.31 Hz, 1H) 6.10-6.23 (m, 1H) 6.53 (dd, J=15.25, 10.98 Hz, 1H).

TABLE-US-00014 TABLE 11 Compounds 175-185 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00383] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.87-0.92 (m, 6 H) 0.94 (t, J = 7.40 Hz, 3 H) 1.16-1.31 (m, 1 H) 1.35 (s, 3 H) 1.40-1.56 (m, 4 H) 1.59 (s, 3 H) 1.66 (br dd, J = 14.68, 7.03 Hz, 3 H) 1.76-1.80 (m, 3 H) 1.87 (dd, J = 14.12, 5.46 Hz, 1 H) 2.05 (s, 3 H) 2.30-2.41 (m, 1 H) 2.50 (d, J = 3.76 Hz, 2 H) 2.56-2.72 (m, 2 H) 2.90 (br d, J = 2.01 Hz, 1 H) 3.19 (br t, J = 5.14 Hz, 4 H) 3.50- 3.59 (m, 1 H) 3.71 (br s, 4 H) 3.77- 3.89 (m, 1 H) 5.01-5.13 (m, 2 H) 5.58-5.71 (m, 1 H) 5.71-5.81 (m, 1 H) 5.88 (d, J = 15.31 Hz, 1 H) 6.15 (br d, J = 10.79 Hz, 1 H) 6.53 (dd, J = 15.18, 10.92 Hz, 1 H) LC/MS (ESI, m/z), 665.6 [M + H].sup.+ [00384] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.90 (dd, J = 6.84, 2.20 Hz, 6 H) 0.94 (t, J = 7.40 Hz, 3 H) 1.20-1.30 (m, 1 H) 1.34 (s, 3 H) 1.39-1.54 (m, 3 H) 1.55 (s, 3 H) 1.59-1.73 (m, 3 H) 1.78 (d, J = 0.88 Hz, 3 H) 1.86 (dd, J = 13.99, 5.46 Hz, 1 H) 2.05 (s, 3 H) 2.39-2.53 (m, 3 H) 2.55- 2.65 (m, 1 H) 2.67 (dd, J = 8.03, 2.26 Hz, 1 H) 2.89 (s, 1 H) 3.22 (br s, 4 H) 3.50-3.57 (m, 1 H) 3.58-3.90 (m, 5 H) 5.08 (d, J = 10.67 Hz, 1 H) 5.18 (d, J = 9.03 Hz, 1 H) 5.58-5.78 (m, 2 H) 5.88 (d, J = 15.31 Hz, 1 H) 6.10- 6.23 (m, 1 H) 6.53 (dd, J = 15.25, 10.98 Hz, 1 H) LC/MS (ESI, m/z), 665.6 [M + H].sup.+ [00385] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm 0.87-1.01 (m, 10 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.27-1.63 (m, 12 H) 1.66-1.74 (m, 1 H) 1.76 (s, 3 H) 1.97-2.10 (m, 3 H) 2.35-2.57 (m, 5 H) 2.58-2.65 (m, 1 H) 2.65- 2.71 (m, 1 H) 2.77 (td, J = 5.93, 2.32 Hz, 1 H) 2.89-3.05 (m, 4 H) 3.07- 3.34 (m, 8 H) 3.50-3.68 (m, 5 H) 3.72-3.88 (m, 1 H) 4.88-5.09 (m, 1 H) 5.18 (d, J = 10.67 Hz, 1 H) 5.50-5.84 (m, 3 H) 6.01-6.13 (m, 1 H) 6.19-6.36 (m, 1 H). LC/MS (ESI, m/z), 649.7 [M + H].sup.+ [00386] .sup.1H NMR (400 MHz, METHANOL-d4) δ ppm 0.76- 0.87 (m, 9H), 1.03-1.09 (m, 3H), 1.10-1.13 (m, 3H), 1.13-1.19 (m, 1H), 1.20-1.27 (m, 3H), 1.29- 1.48 (m, 6H), 1.51-1.59 (m, 1H), 1.65-1.71 (m, 3H), 1.73-1.81 (m, 1H), 2.20 (s, 3H), 2.27-2.34 (m, 4H), 2.34-2.44 (m, 2H), 2.44- 2.53 (m, 1H), 2.53-2.59 (m, 1H), 2.76-2.83 (m, 1H), 3.23-3.26 (m, 1H), 3.34-3.52 (m, 7H), 3.67- 3.75 (m, 1H), 4.86-4.92 (m, 1H), 4.92-4.99 (m, 1H), 5.41-5.51 (m, 1H), 5.60-5.71 (m, 1H), 5.72- 5.82 (m, 1H), 6.00-6.07 (m, 1H), 6.37-6.48 (m, 1H). LC/MS (ESI, m/z): 665.73 [M + H].sup.+ [00387] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 0.84-1.01 (m, 11 H) 1.08 (d, J = 6.78 Hz, 3 H) 1.29-1.64 (m, 10 H) 1.63-1.73 (m, 1 H) 1.76 (s, 3 H) 1.94-2.12 (m, 4 H) 2.37-2.58 (m, 4 H) 2.59-2.65 (m, 1 H) 2.68 (dd, J = 7.40, 2.26 Hz, 1 H) 2.77 (td, J = 5.93, 2.32 Hz, 1 H) 3.01-3.30 (m, 4 H) 3.49 (s, 1 H) 3.54-3.67 (m, 2 H) 3.69-3.92 (m, 5 H) 4.13- 4.78 (m, 11 H) 5.13-5.24 (m, 2 H) 5.48-5.61 (m, 1 H) 5.62-5.74 (m, 2 H) 6.04-6.13 (m, 1 H) 6.18- 6.32 (m, 1 H) LC/MS (ESI, m/z), 649.6 [M + H].sup.+ [00388] .sup.1H-NMR (400 MHz, MeOH-d4): δ ppm 0.88-0.99 (m, 9 H) 1.10 (d, J = 6.78 Hz, 3 H) 1.24 (s, 4 H) 1.42- 1.69 (m, 8 H) 1.77 (d, J = 0.88 Hz, 3 H) 2.43-2.63 (m, 4 H) 2.64- 2.70 (m, 1 H) 2.71-2.82 (m, 5 H) 3.34 (br s, 3 H) 3.37 (s, 2 H) 3.42- 3.57 (m, 5 H) 3.79-3.89 (m, 1 H) 5.06 (s, 2 H) 5.54-5.63 (m, 1 H) 5.64-5.80 (m, 2 H) 6.07-6.16 (m, 1 H) 6.29-6.40 (m, 1 H) LC/MS (ESI, m/z), 621.6 [M + H].sup.+ [00389] .sup.1H-NMR (400 MHz, MeOH-d4): δ ppm 0.88-1.00 (m, 9 H) 1.10 (d, J = 6.65 Hz, 3 H) 1.16-1.27 (m, 4 H) 1.40-1.70 (m, 8 H) 1.77 (d, J = 0.88 Hz, 3 H) 2.28-2.36 (m, 3 H) 2.42 (br t, J = 5.08 Hz, 3 H) 2.47- 2.61 (m, 4 H) 2.68 (dd, J = 8.22, 2.20 Hz, 1 H) 2.74 (td, J = 5.99, 2.20 Hz, 1 H) 3.13-3.17 (m, 1 H) 3.34-3.38 (m, 3 H) 3.47-3.58 (m, 5 H) 3.81-3.87 (m, 1 H) 5.01- 5.10 (m, 2 H) 5.54-5.81 (m, 3 H) 6.06-6.15 (m, 1 H) 6.34 (dd, J = 15.00, 10.98 Hz, 1 H) LC/MS (ESI, m/z), 635.8 [M + H] [00390] .sup.1H-NMR (400 MHz, MeOH-d4): δ ppm 0.92 (br d, J = 6.53 Hz, 9 H), 1.25 (br s, 4 H), 1.36 (s, 3 H), 1.41- 1.74 (m, 6 H), 1.45-1.59 (m, 1 H), 1.64-1.72 (m, 1 H), 1.80 (s, 3 H), 1.85-1.94 (m, 1 H), 2.42 (s, 3 H), 2.50-2.63 (m, 3 H), 2.65-2.73 (m, 1 H), 2.73-2.80 (m, 2 H), 2.88-3.01 (m, 4 H), 3.35-3.38 (m, 3 H), 3.35- 3.40 (m, 3 H), 3.41-3.48 (m, 2 H), 3.52-3.57 (m, 1 H), 3.78-3.89 (m, 1 H), 5.00-5.13 (m, 2 H), 5.53-5.64 (m, 1 H), 5.71-5.82 (m, 1 H), 5.84- 5.94 (m, 1 H), 6.12-6.19 (m, 1 H), 6.49-6.61 (m, 1 H) LC/MS (ESI, m/z), 639.7 [M + H].sup.+ [00391] LC/MS (ESI, m/z), 653.79 [M + H].sup.+ [00392] .sup.1H-NMR (400 MHz, DMSO-d6): δ ppm 0.71-0.77 (m, 9 H), 1.03 (s, 5 H), 1.14-1.20 (m, 6 H), 1.23-1.33 (m, 5 H), 1.36-1.48 (m, 5 H), 1.63 (s, 3 H), 1.67-1.75 (m, 1 H), 2.13- 2.24 (m, 4 H), 2.58-2.64 (m, 1 H), 2.68-2.81 (m, 2 H), 3.20-3.20 (m, 3 H), 3.61-3.77 (m, 4 H), 4.28-4.39 (m, 1 H), 4.44-4.53 (m, 1 H), 4.79- 4.88 (m, 2 H), 5.28-5.43 (m, 1 H), 5.52-5.66 (m, 1 H), 5.73-5.85 (m, 1 H), 5.94-6.04 (m, 1 H), 6.27-6.41 (m, 1 H), 6.43-6.53 (m, 2 H), 8.19- 8.29 (m, 1 H) LC/MS (ESI, m/z), 709.5 [M + H].sup.+ [00393] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 0.75 (s, 9H), 1.03 (s, 3H), 1.16 (s, 3H), 1.16-1.17 (m, 1H), 1.23-1.33 (m, 4H), 1.36-1.47 (m, 2H), 1.53-1.60 (m, 2H), 1.63 (s, 3H), 1.67-1.75 (m, 1H), 2.10- 2.35 (m, 10H), 2.47-2.53 (m, 2H), 2.65-2.73 (m, 1H), 3.15 (s, 3H), 3.27-3.32 (m, 4H), 3.58-3.68 (m, 1H), 4.25-4.39 (m, 1H), 4.45- 4.52 (m, 1H), 4.69-4.78 (m, 1H), 4.80-4.88 (m, 2H), 5.29-5.42 (m, 1H), 5.53-5.66 (m, 1H), 5.72- 5.84 (m, 1H), 5.93-6.05 (m, 1H), 6.27-6.41 (m, 1H), 8.38-8.46 (m, 1H) LC/MS (ESI, m/z), 723.43 [M + H].sup.+
Compounds 197-200 were synthesized according to Scheme 60.

##STR00394##

Step 1

[0911] To a solution of tri-TES Pladienolide D (1.0 equiv.) in 1,2-dichloroethane (0.2 M) at 20° C. was added DMAP (1.5 equiv.), triethylamine (30 equiv.) and 4-nitrophenyl chloroformate (10 equiv.). The reaction mixture was stirred at 40° C. for 4 days, and then for 2 h at 60° C. The reaction mixture was diluted with EtOAc and washed with water, then the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were successively washed with water and brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. Flash column chromatography (EtOAc in Hexane; silica gel) afforde the intermediate carbonate. To a mixture of the intermediate carbonate (1.0 equiv.) in DCM (0.2 M) were added triethylamine (3.0 equiv.) and amine (2.0 equiv.) and the resulting mixture was stirred at RT for 1 hour. The reaction mixture was then concentrated and chromatographed (DCM/MeOH; silica gel) to afford the carbamate intermediate as a mixture of regio-isomers.

Step 2

[0912] The regio-isomeric mixture of carbamate intermediate (1.0 equiv.) was dissolved in DCM (0.04 M). Hünig's base (124 equiv.) was added and the reaction mixture was cooled to −78° C. and hydrogen fluoride pyridine (30 equiv.) was added dropwise before warming the mixture to rt and stirring overnight at rt. The reaction mixture was then cooled to −78° C. and saturated sodium bicarbonate was added dropwise. After addition of sodium bicarbonate, the mixture was warmed to rt. The organic layer was isolated and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC purification to afford the each of desired regio-isomeric products.

TABLE-US-00015 TABLE 12 Compounds 197-200 LCMS data Structure, Compound #, and Chemical Name .sup.1H NMR data (ES+) [00395] .sup.1H-NMR (400 MHz, MeOH-d.sub.4): δ ppm 0.85- 0.98 (m, 9 H) 1.25 (td, J = 7.40, 4.14 Hz, 1 H) 1.34 (s, 3 H) 1.42-1.69 (m, 9 H) 1.79 (s, 4 H) 1.82-1.96 (m, 2 H) 2.04 (d, J = 9.29 Hz, 3 H) 2.33 (br d, J = 10.04 Hz, 1 H) 2.47-2.54 (m, 2 H) 2.57-2.72 (m, 2 H) 2.87-2.92 (m, 1 H) 3.03 (br s, 2 H) 3.33-3.43 (m, 2 H) 3.43-3.57 (m, 2 H) 3.77-3.84 (m, 1 H) 3.86-3.94 (m, 1 H) 4.50 (br s, 1 H) 4.97-5.11 (m, 2 H) 5.60-5.68 (m, 1 H) 5.73-5.82 (m, 1 H) 5.88 (d, J = 15.31 Hz, 1 H) 6.15 (br d, J = 11.04 Hz, 1 H) 6.53 (dd, J = 15.25, 10.98 Hz, 1 H) 8.54 (s, 1 H) LC/MS (ESI, m/z), 677.6 [M + H].sup.+ [00396] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm LC/MS (ESI, m/z), 677 [M + H].sup.+ [00397] .sup.1H-NMR (400 MHz, MeOH-d.sub.4): δ ppm 0.88- 0.98 (m, 9 H) 1.26 (td, J = 7.40, 4.27 Hz, 1 H) 1.32-1.39 (m, 3 H) 1.44- 1.70 (m, 9 H) 1.80 (s, 3 H) 1.83-1.92 (m, 1 H) 2.05 (s, 3 H) 2.32-2.46 (m, 1 H) 2.47-2.70 (m, 11 H) 2.91 (td, J = 5.77, 2.26 Hz, 1 H) 3.43-3.61 (m, 5 H) 3.69 (t, J = 5.83 Hz, 2 H) 3.81 (br dd, J = 9.79, 3.39 Hz, 1 H) 5.00- 5.11 (m, 2 H) 5.64 (dd, J = 15.18, 9.66 Hz, 1 H) 5.73-5.81 (m, 1 H) 5.86- 5.94 (m, 1 H) 6.15 (br d, J = 10.29 Hz, 1 H) 6.54 (dd, J = 15.25, 10.98 Hz, 1 H) LC/MS (ESI, m/z), 709.7 [M + H].sup.+ [00398] .sup.1H-NMR (400 MHz, CHCl.sub.3-d): δ ppm LC/MS (ESI, m/z), 709.8 [M + H].sup.+

EXAMPLE 201

[0913] ##STR00399##

[0914] To a mixture of (2 S,3 S,6 S,7R,10R,E)-6-acetoxy -10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl piperazine-1-carboxylate (230 mg, .346 mmol; Example 187) in DCM (8 mL) was added sodium triacetoxyborohydride (4 equiv.) and then formaldehyde (104 mg, 3.459 mmol) as an aqueous solution. The mixture was stirred for 20 minutes at rt. After stirring, the mixture was diluted with methanol and then concentrated in vacuo onto silica and purifed by silica gel chromatography (0-15% MeOH/DCM) and concentrated in vacuo to afford (2 S,3S,6 S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl 4-methylpiperazine-1-carboxylate (160 mg, 0.236 mmol, 68.1% yield) as a colorless oil. [0915] LCMS (ESI, m/z), [M+H].sup.+679.2.

EXAMPLE 202

[0916] ##STR00400##

[0917] To a mixture of (2 S,3S,6 S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (55 mg, 0.083 mmol; Example 186) in DCM (3 mL) was added (9H-fluoren-9-yl)methyl (2-oxoethyl)carbamate (46.5 mg, 0.165 mmol) and sodium triacetoxyborohydride (52.6 mg, 0.248 mmol). The mixture was stirred at rt for 20 minutes and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) and concentrated in vacuo. The isolated material was diluted with DMF (3 mL) and to that mixture was added diethylamine (121 mg, 1.655 mmol). The mixture was stirred until it the starting material was consumedat rt before concentrating in vacuo. The resulting residue was purified via reverse phase HPLC to afford (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-(2-aminoethyl)piperazine-1-carboxylate (6 mg, 8.48 umol, 10.25% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6): δ ppm 0.74-0.86 (m, 9H) 1.04-1.15 (m, 1H) 1.23 (s, 3H) 1.26-1.40 (m, 3H) 1.45 (s, 4H) 1.47-1.51 (m, 1H), 1.52-1.63 (m, 1H) 1.69 (s, 3H) 1.73-1.82 (m, 1H) 1.99 (s, 3H) 2.13-2.42 (m, 9H) 2.53-2.65 (m, 4H) 2.72-2.80 (m, 1H), 3.35-3.41 (m, 3H) 3.65-3.76 (m, 1H) 4.36-4.46 (m, 1H) 4.57-4.66 (m, 1H) 4.79-4.85 (m, 1H) 4.87-4.95 (m, 2H) 5.43-5.56 (m, 1H) 5.64-5.77 (m, 1H) 5.80-5.91 (m, 1H) 6.01-6.12 (m, 1H) 6.33-6.49 (m, 1H). LCMS (ESI, m/z), 708.2 [M+H].sup.+

EXAMPLE 203

[0918] ##STR00401##

[0919] To a solution of (2S,3S ,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (25 mg, 0.038 mmol; Example 186) in acetone (2 mL) was added ethyl 2-bromoacetate (7.54 mg, 0.045 mmol) and potassium carbonate (3 equiv.). The resulting mixture was stirred for 25 minutes before adding additional bromo acetate (2 equiv.) and stirring at rt for 1 hour. Subsequently, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was isolated, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (0-15% MeOH/DCM) to provide (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3 S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (12 mg, 0.016 mmol, 42.5% yield) as a colorless oil. LCMS (ESI, m/z), [M+H].sup.+751.3

EXAMPLES 204 and 205

[0920] Examples 204 and 205 were prepared via the sequence outlined in Scheme 61.

##STR00402##

Step 1:

[0921] A mixture of (2S,3S,6S,7R,10R,E)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate (0.626 g, 0.699 mmol), THF (4.58 mL, 55.925 mmol), ethyl vinyl ether (2.69 ml, 27.963 mmol), PPTS (0.044 g, 0.175 mmol) was stirred overnight. Triethylamine (0.8 eq) was added to the reaction mixture and stirred for several minutes before extracting with saturated aqueous sodium bicarbonate. The aqueous layer was isolated and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and contrated in vacuo to afford (2S,3S,6S,7R,10R,E)-7-(1-ethoxyethoxy)-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate as a mixture of diastereomers (636 mg, 0.657 mmol, 94% yield).

[0922] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.60 (q, J=7.65 Hz, 19H) 0.78-0.92 (m, 10H) 0.96 (t, J=7.91 Hz, 28H) 1.16-1.30 (m, 8H) 1.32-1.35 (m, 1H) 1.38 (br s, 5H) 1.43-1.62 (m, 7H) 1.71 (d, J=6.65 Hz, 4H) 2.02-2.08 (m, 3H) 2.33-2.53 (m, 3H) 2.53-2.59 (m, 1H) 2.79-2.87 (m, 1H) 3.42-3.67 (m, 2H) 3.68-3.76 (m, 1H) 3.78-3.86 (m, 1H) 4.94-5.13 (m, 2H) 5.14-5.20 (m, 1H) 5.57-5.78 (m, 3H) 6.03-6.13 (m, 1H) 6.35-6.47 (m, 1H).

Step 2:

[0923] A mixture of (2S,3S,6S,7R,10R,E)-7-(1-ethoxyethoxy)-3,7-dimethyl-2-4R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate (1.4 g, 1.447 mmol), potssium carbonate (0.300 g, 2.17 mmol), and methanol (14.47 mL, 1.447 mmol) was stirred for 1 hr. EtOAc and saturated aqueous ammonium chloride were added to the mixture and the organic layer was isolated. The aqueous layer was then extraxted three times with EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford (4R,7R,8S ,11S ,12S,E)-7-(1-ethoxyethoxy)-8-hydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-4-((triethylsilyl)oxy)oxacyclododec-9-en-2-one (1 g, 1.080 mmol, 74.7% yield).

Step 3:

[0924] (4R,7R,8S,11S,12S,E)-7-(1-ethoxyethoxy)-8-hydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-4-((triethylsilyl)oxy)oxacyclododec-9-en-2-one (1 g, 1.08 mmol), DCM (0.1 M), Hünig's Base (5.0 equiv.), DMAP (1.0 equiv.), and 4-nitrophenyl chloroformate (1.8 equiv.) were combined and stirred overnight. Aqueous sodium hydroxide (1N) was added to the resulting mixture and the organic layer was isolated. The aqeous layer was then extracted three times with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was diluted with DCM (0.1 M), and to that mixture was added Hünig's Base (5.0 equiv.) and amine (3.0 equiv.), followed by stirring for 2 hours. The resulting mixture was then purified by silica gel chromatography (1-10% MeOH in DCM) to afford carbamate intermediate.

[0925] Carbamate Intermediate #1:

##STR00403##

[0926] (2S,3S,6S,7R,10R,E)-7-(1-ethoxyethoxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (700 mg, 0.666 mmol, 61.6% yield). LCMS (ESI, m/z), 1052.6 (M+H).sup.+

[0927] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm 0.60-0.70 (m, 18H) 0.82-1.03 (m, 38H) 1.12-1.26 (m, 5H) 1.26-1.36 (m, 6H) 1.43 (s, 3H) 1.45-1.64 (m, 7H) 1.77 (s, 4H) 1.88-1.99 (m, 1H) 2.30 (s, 3H) 2.36-2.46 (m, 5H) 2.46-2.65 (m, 3H) 2.82-2.93 (m, 1H) 3.55 (s, 6H) 3.71-3.81 (m, 1H) 3.84-3.98 (m, 1H) 4.88-5.00 (m, 2H) 5.09-5.18 (m, 1H) 5.52-5.63 (m, 1H) 5.72-5.88 (m, 2H) 6.09-6.19 (m, 1H) 6.45-6.57 (m,1H).

[0928] Carbamate Intermediate #2

##STR00404##

[0929] (2S,3S ,6S,7R,10R,E)-7-(1-ethoxyethoxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl piperazine-1-carboxylate (330 mg, 0.318 mmol, 69.4% yield).

Step 4:

[0930] Tert-butanol (0.16 M), THF (0.08 M), and PPTS (3.0 equiv.) were combined and stirred at RT. (2S,3S,6S ,7R,10R,E)-7-(1-ethoxyethoxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (1.0 equiv.) was added to the mixture and it was stirred overnight. Subsequently, saturated brine was added and the mixture was stirred for 30 minutes. The organic layer was isolated and the aqueous layer was extracted three times with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (0-100% EtOAc in Hexane) to afford tri-TES protected intermediate.

[0931] Tri-TES Protected Intermediate #1:

##STR00405##

[0932] (2S,3S,6S,7R,10R,E)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (172 mg, 0.176 mmol, 41.1% yield) LCMS (ESI, m/z), 980.144 (M+H).sup.+

[0933] Tri-TES Protected Intermediate #2:

##STR00406##

[0934] (2S,3S,6S,7R,10R,E)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl piperazine-1-carboxylate (0.49 g, 96%) LCMS (ESI, m/z), 966.1 (M+H).sup.+.

[0935] Step 5:

[0936] (2S,3S ,6S,7R,10R,E)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2S,3S)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hepta-2,4-dien-2-yl)-12-oxo-10-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (100 mg, 0.102 mmol), DCM (371 equiv.), and DIPEA (191 equiv.) were combined and cooled to −78° C. Hydrogen fluoride-pyridine (30 equiv) was added and the mixture was warmed to RT and stirred overnight. The mixture was then cooled in an icebath, and then saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with DCM and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel (MeOH/DCM) to afford the desired compound.

EXAMPLE 204

[0937] ##STR00407##

[0938] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (31.6 mg, 0.050 mmol, 48.6% yield)

[0939] MS (ESI, m/z), 637.6 (M+H).sup.+

[0940] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm 0.86-0.98 (m, 9H) 1.20-1.23 (m, 3H) 1.23-1.32 (m, 2H), 1.34 (s, 3H) 1.35-1.70 (m, 7H) 1.78 (d, J=0.75 Hz, 3H) 1.83-1.93 (m, 1H) 2.30 (s, 3H) 2.41 (br t, J=4.77, Hz, 4H) 2.52 (dd, J=3.39, 1.63 Hz, 3H) 2.65-2.72 (m, 1H) 2.86-2.95 (m, 1H) 3.38-3.73 (m, 5H) 3.76 -3.88 (m, 1H) 4.95 (s, 1H) 5.03-5.13 (m, 1H) 5.51-5.63 (m, 1H) 5.66-5.78 (m, 1H) 5.82-5.93 (m, 1H), 6.08-6.20 (m, 1H) 6.48-6.61 (m, 1H).

EXAMPLE 205

[0941] ##STR00408##

[0942] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (50 mg, 78% yield)

[0943] MS (ESI, m/z), 623.7 (M+H).sup.+

[0944] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm 0.88-0.99 (m, 9H) 0.98-1.05 (m, 2H) 1.25 (s, 4H) 1.21-1.27 (m, 1H) 1.34-1.37 (m, 4H) 1.48-1.73 (m, 5H) 1.76-1.83 (m, 3H) 1.85-1.93 (m, 1H) 2.46-2.74 (m, 4H) 2.88-2.95 (m, 1H) 3.21 (s, 4H) 3.51-3.60 (m, 1H) 3.78 (s, 5H) 4.94-5.01 (m, 1H) 5.05-5.11 (m, 1H) 5.56-5.66 (m, 1H) 5.70-5.79 (m, 1H) 5.86-5.93 (m, 1H) 6.08-6.24 (m, 1H) 6.45-6.63 (m, 1H)

[0945] Biological Assays

[0946] Cell Viability Assay Protocol

[0947] Cells (WiDr and Panc05.04 obtained from ATCC) were seeded in 96-well plates, with 2000 cells/100 μL/well, and incubated overnight. Spent media was removed, and fresh media containing 9 different concentrations of compound (100 μL/well) were added, with DMSO concentration from compound stock solution adjusted to be 0.1%. Each compound treatment was done in duplicate or triplicate at each concentration.

[0948] Another plate with cells seeded was dedicated as a time zero (Tz) plate, to which was added 0.1% DMSO in media (100 μL/well) followed by CellTiter-Glo® reagent (Promega Corporation, Madison, Wis.) (50 μL/well) for ATP measurement as a surrogate of cell viability. Average value from measurement of multiple wells of this plate is used as Tz. Compound-treated plates were incubated for 72 hr at 37° C. Then, CellTiter-Glo® reagent (50 μL/well) was added and ATP was measured. Average value from measurement of the duplicate or triplicate compound-treated wells is used as Ti, and seeded plates with medium having 0.1% DMSO without compound is used as control growth (C).

[0949] Percentage growth inhibition/Percentage viability was calculated as:

[0950] [(Ti−Tz)/(C−Tz)]×100 for concentrations for which Ti>/=Tz

[0951] [(Ti−Tz)/Tz]×100 for concentrations for which Ti<Tz. [0952] *time zero (Tz), control growth (C), and test growth in the presence of compound (Ti) Percentage growth inhibition/Percentage viability are plotted versus compound concentration to determine E.sub.max.

[0953] Growth inhibition of 50% (GI.sub.50) was calculated from [(Ti−Tz)/(C−Tz)]×100=50, which is the drug concentration resulting in a 50% reduction in the net increase of ATP in control growth (C) during the compound treatment.

[0954] In Vitro Splicing (biochemical) Assay Protocol

[0955] Biotin-labeled pre-mRNA of an adenovirus type 2 construct with a deletion of intervening sequence (Ad2) (Berg, M. G., et al. 2012 Mol. Cell Bio., 32(7):1271-83) was prepared by in vitro transcription. The Ad2 construct containing Exon 1 (41 nucleotides), Intron (231 nucleotides), and Exon 2 (72 nucleotides) was generated by gene synthesis and cloned into the EcoRI and XbaI sites of pGEM®-3Z vector (Promega) by Genewiz® (South Plainfield, N.J). The plasmid was then linearized by XbaI digestion and purified. In vitro transcription and purification of transcribed pre-mRNA were performed using the MEGAscript® T7 transcription kit (Invitrogen™, Life Technologies™, Grand Island, N.Y.) and MEGAclear™ transcription clean-up kit (Invitrogen™, Life Technologies™, Grand Island, N.Y.), respectively, following the manufacturer's instructions. The ratio of biotin-16-UTP (Roche Diagnostics Corporation, Indianapolis, Ind.) to cold UTP was 1:13 to incorporate approximately two biotin molecules per spliced Ad2 mRNA.

[0956] In vitro splicing assay was performed at 30° C. in 25 μL reaction mixtures containing 95 μg HeLa nuclear extract (Promega Corporation, Madison, Wis.), 47 nM Ad2 pre-mRNA, 25U RNasin RNase inhibitor (Promega Corporation, Madison, Wis.), 1× SP buffer (0.5 mM ATP, 20 mM creatine phosphate, 1.6 mM MgCl.sub.2), and compounds in DMSO (with 1% final concentration of DMSO). After 90 min of incubation, the reaction was stopped by addition of 18 μL of 5M NaCl, and the mixtures were incubated with 10 μL of M-280 streptavidin-coated magnetic beads (Invitrogen™, Life Technologies, Grand Island, N.Y.) for 30 min at room temperature to capture Ad2 pre- and spliced mRNA. The beads were washed twice with 100 uL buffer containing 10 mM Tris pH=7.5, 1mM EDTA and 2M NaCl, and then incubated in RNA gel loading buffer containing 95% formamide at 70° C. for 10 min to elute the RNAs. Ad2 RNAs were resolved by 6% TBE-UREA gel, transferred to a nylon membrane, UV cross-linked, and probed with an IRDye® labeled streptavidin (LI-COR, Lincoln, Nebr.). The amount of spliced RNA was quantified by measuring the band fluorescent intensity using LI-COR Image Studio software.

[0957] Results

[0958] Data are reported in Table 13 below. E.sub.max refers to the maximum achievable response to a compound in a tested dose range, with a negative value indicating cellular lethality. A larger negative E.sub.max value indicates greater cellular lethality for a particular compound. For example, in Panc 05.04 cells, a mutant SF3B1 cell line, the larger negative Emax value indicates that Compound 1 had greater cellular lethality than Compound 7.

[0959] WiDr-R cells are colon cancer cells which have a chemically-induced R1074H mutation and have been shown to be resistant to pladienolide B in terms of growth inhibition (Yokoi, A., et al., 2011 FEBS Journal, 278:4870-4880). The counter-screening of compounds in this viability assay with a “resistant” WiDr-R cell line may indicate whether these compounds have off-target effect(s). Compounds that lack growth inhibitory (GI.sub.50) activity in the resistant WiDr-R cell line but maintain activity in the parental WiDr cell line suggests that on-mechanism splicing modulation is responsible for the growth inhibition which is observed in the parental WiDr cell line.

[0960] Scintillation Proximity Assay (SPA) with [.sup.3H]-labelled Pladienolide Probe

[0961] Batch immobilization of anti-SF3B1 antibody (MBL) to anti-mouse PVT SPA scintillation beads (PerkinElmer) was prepared as follows: for every 2.5 mg of nuclear extracts, 5 μg anti-SF3B1 antibody and 1.5 mg of beads were mixed in 150 μl PBS. The antibody-bead mixture was incubated for 30 min at RT and centrifuged at 18,000 g for 5 min. 150 p1 PBS was used to resuspend every 1.5 mg antibody-bead mixture. The beads were suspended and added to the prepared nuclear extracts. The slurry was incubated for 2 h at 4° C. with gentle mixing. The beads were then collected by centrifuging at 18,000 g for 5 min, and washed twice with PBS+0.1% Triton X-100. After a final centrifugation step, every 1.5 mg of beads was suspended with 150 μl of PBS. The SF3b complexes were tested for [.sup.3H]-labelled pladienolide probe binding ([.sup.3H]-PB), synthesized as previously described (Kotake et al., 2007). 100 μL binding reactions were prepared with 50 μl bead slurry and by adding varying concentrations of PB or PB—OH, and after 30 min pre-incubation, 2.5 nM [.sup.3H]—PB was added. The mixture was incubated for 30 min, and luminescence signals were read using a MicroBeta2 Plate Counter (PerkinElmer). Prism 6 (Graphpad) was used for non-linear regression curve fitting of the data.

[0962] Key for Table 13: [0963] WiDr cells=Colon cancer cells; wildtype SF3B1 [0964] WiDr-R cells=Colon cancer cells; chemically-induced SF3B1 mutant which is resistant to E7107 (R1074H mutation) Panc 05.04 cells=Pancreatic cancer cells; Q699H and K700E mutations in SF3B1 [0965] SPA=Scintillation proximity assay

TABLE-US-00016 TABLE 13 Biological Activity of Example Compounds Panc Panc 05.04 05.04 SPA (mt (mt (wt SF3B1 SF3B1 WiDr- SF3B1 cells) cells), WiDr R cells) E.sub.max GI.sub.50 GI.sub.50 GI.sub.50 IC.sub.50 Structure and Compound # (%) (nM) (nM) (nM) (nM) [00409] −87.275 27.349 26.401 >1000 4.355 [00410] −92.825 326.677 554.751 >10000 53.368 [00411] 40.550 4589.385 1941.512 >10000 472.770 [00412] −91.760 42.549 39.130 >1000 6.215 [00413] −94.128 20.087 4.826 >1000 2.746 [00414] −94.410 250.128 172.085 >10000 [00415] −91.152 74.414 46.727 >10000 17.965 [00416] −92.151 25.017 21.224 >10000 2.397 [00417] −87.370 54.563 32.637 >10000 4.853 [00418] 198.03 86.457 >10000 [00419] 587.41 307.763 >10000 [00420] 40.097 2090.471 8131.147 >10000 [00421] −90.898 76.514 71.613 >1000 60.673 [00422] −96.801 64.282 246.764 >1000 [00423] −91.832 44.669 137.681 >10000 10.740 [00424] −89.983 52.598 38.111 >10000 27.299 [00425] −79.344 2.110 0.983 >1000 2.721 [00426] −74.649 82.242 49.693 >10000 15.049 [00427] −83.432 35.134 24.651 >10000 80.359 [00428] −89.552 45.075 51.472 >10000 96.546 [00429] 15.45 91.252 >10000 [00430] −88.833 203.085 105.995 >1000 235.639 [00431] 67.97 62.92 >1000 [00432] −90.269 3.051 3.832 >1000 2.103 [00433] −94.750 88.064 89.925 >1000 [00434] −77.223 20.340 29.407 >1000 14.018 [00435] −56.00 35.40 33.788 >1000 [00436] −92.84 30.49 36.628 >1000 [00437] −85.416 10.054 14.697 >1000 [00438] −93.737 7.817 9.605 >1000 3.729 [00439] −68.065 1.123 1.035 >1000 2.772 [00440] −97.033 16.654 19.777 >1000 [00441] −90.19 4.86 2.844 >1000 [00442] −82.07 2.25 1.697 >1000 [00443] 90.700 31.462 47.213 >1000 9.557 [00444] 1.960 545.544 204.979 >10000 234.867 [00445] −16.082 537.655 230.686 >10000 45.128 [00446] −28.235 408.252 343.407 >10000 [00447] 6.969 1288.909 252.246 >1000 [00448] −49.209 53.638 34.307 >1000 5.693 [00449] −90.908 59.215 18.672 >1000 9.201 [00450] −22.224 155.424 60.103 >1000 38.444 [00451] −90.107 26.610 31.754 >1000 6.373 [00452] −78.056 65.979 76.010 >1000 13.057 [00453] −89.491 27.891 19.587 >1000 8.756 [00454] −87.701 37.193 53.113 >1000 8.560 [00455] −41.858 114.631 129.855 >1000 71.254 [00456] −60.371 126.216 132.822 >1000 [00457] −83.573 38.919 36.709 >1000 7.230 [00458] −60.16 25.08 16.250 >1000 [00459] 35.309 2545.788 >1000.000 >1000 479.605 [00460] −29.357 56.386 41.521 >1000 12.258 [00461] −95.714 64.987 51.978 >1000 [00462] −23.122 84.867 33.109 >1000 6.869 [00463] −94.348 21.406 21.202 >1000 3.325 [00464] −76.515 39.538 15.971 >1000 26.868 [00465] −12.670 103.826 74.907 >1000 7.317 [00466] 35.115 1389.178 1145.992 >10000 [00467] −93.786 13.556 7.178 >1000 2.347 [00468] −90.314 76.078 47.340 [00469] −86.908 3.254 12.669 >1000 5.114 [00470] −92.429 278.544 43.378 >1000 [00471] −87.256 1.658 2.545 >1000 2.825 [00472] −84.513 5.509 5.562 >1000 7.661 [00473] −70.370 2.394 2.735 40.140 7.033 [00474] 80.11 77.26 >1000 [00475] 2.52 1.424 21.764 [00476] −86.642 1.198 3.934 >1000 [00477] −93.599 2.593 6.204 >1000 [00478] −92.870 40.226 32.782 >1000 [00479] −89.146 11.933 29.094 >1000 16.761 [00480] −68.88 4.52 2.392 14.819 [00481] −92.218 22.502 7.641 >1000 [00482] −79.385 1.764 4.297 >1000 1.929 [00483] −92.980 10.383 28.938 >1000 [00484] −79.728 4.434 3.462 221.390 5.142 [00485] −92.417 86.299 41.399 1879.784 [00486] 35.028 2635.026 >1000.000 >1000 36.054 [00487] −93.610 2.845 4.774 449.450 [00488] −76.42 7.98 6.393 602.820 [00489] −93.540 11.681 11.789 861.860 11.552 [00490] −24.659 302.087 137.820 >1000 [00491] −95.353 74.626 294.340 >1000 [00492] −58.256 108.430 691.610 >1000 2.255 [00493] −85.429 33.049 30.233 3992.400 9.701 [00494] −89.812 3.676 22.230 >1000 3.679 [00495] −72.713 1.745 1.235 >1000 4.234 [00496] −59.56 59.43 28.047 >1000 [00497] −84.18 18.62 8.277 >1000 [00498] −95.447 10.381 19.662 >1000 2.514 [00499] −90.025 71.754 65.037 >1000 5.952 [00500] 63.471 >4000.000 148.414 >1000 [00501] −96.595 147.043 22.977 4310.192 [00502] −93.732 22.057 31.918 >10000 6.375 [00503] −94.489 98.272 40.135 >10000 16.134 [00504] −92.260 21.238 15.850 >1000 6.265 [00505] −92.395 59.861 58.701 >1000 6.791 [00506] −91.588 30.954 45.936 >1000 11.891 [00507] −94.716 22.005 15.089 >1000 3.382 [00508] −26.648 955.710 531.915 >1000 503.624 [00509] −92.893 29.505 33.604 >1000 8.103 [00510] −93.100 34.531 38.061 >1000 6.573 [00511] −76.743 100.995 124.520 >1000 9.698 [00512] −95.264 121.789 320.244 >1000 21.857 [00513] −90.949 10.781 8.393 >1000 [00514] −77.841 10.825 8.272 >1000 5.670 [00515] −86.024 1.364 3.805 >1000 2.961 [00516] −83.342 3.374 4.863 >1000 5.435 [00517] −78.99 4.36 2.656 >1000 [00518] −77.71 6.76 5.055 >1000 [00519] −79.107 0.339 2.198 >1000 [00520] 28.067 2890.203 420.641 >10000 538.320 [00521] −96.287 43.969 33.240 2428.955 10.560 [00522] −94.255 8.070 15.318 >10000 3.784 [00523] 23.951 1717.435 478.606 >10000 142.021 [00524] −65.323 4.885 2.140 821.510 5.281 [00525] −93.253 170.176 74.629 929.153 [00526] −90.468 6.738 7.836 2443.625 3.712 [00527] −94.777 155.862 135.293 6382.117 71.129 [00528] −83.689 139.143 154.043 −10000 [00529] −87.001 6.480 8.588 2835.605 5.422 [00530] −65.34 7.73 3.440 680.844 [00531] −62.754 2.897 2.519 422.835 3.608 [00532] −81.612 35.234 45.539 >1000 40.193 [00533] −85.578 54.749 65.541 >1000 113.381 [00534] >10000 >10000 >10000 [00535] −40.649 882.501 258.063 3819.588 [00536] −93.548 75.129 67.116 >10000 7.896 [00537] 48.162 5794.861 1064.595 7760.310 >1200.000 [00538] 52.01 >10000 4284.737 >10000 [00539] 51.96 >10000 810.247 4077.331 [00540] >1000.000 >10000 [00541] −94.806 474.937 454.567 >10000 [00542] −72.647 40.380 45.671 >1000 [00543] −91.386 2.385 4.925 >1000 1.667 [00544] −72.301 2.068 1.742 >1000 2.543 [00545] −94.561 4.443 11.236 >1000 [00546] −94.92 37.27 31.612 >1000 [00547] −90.189 6.549 15.226 >1000 47.804 [00548] −83.721 3.139 7.117 >1000 5.692 [00549] −75.710 33.924 31.569 >1000 [00550] −95.426 12.251 24.983 >1000 [00551] −90.892 19.831 27.644 >1000 5.244 [00552] −85.001 77.295 95.904 >1000 40.798 [00553] −90.365 54.083 76.622 >1000 7.619 [00554] −94.475 23.520 145.219 >1000 [00555] −94.521 38.566 51.840 >1000 14.147 [00556] −95.852 5.109 14.700 >1000 [00557] −96.911 51.275 103.451 >1000 4.542 [00558] −88.360 53.333 72.976 >1000 11.236 [00559] −56.978 136.788 262.578 >1000 [00560] 58.44 63.59 >5500 [00561] −90.353 6.672 4.508 >1000 2.153 [00562] 19.145 1179.770 375.699 >10000 267.299 [00563] −93.574 18.961 18.526 >1000 14.419 [00564] −90.53 31.10 42.835 >10000 [00565] 47.525 6919.552 4039.541 >10000 326.162 [00566] −95.148 6.627 13.974 >1000 2.744 [00567] −95.570 10.952 13.246 >1000 2.342 [00568] −94.237 20.415 29.403 >1000 2.562 [00569] 20.875 [00570] −78.560 2.407 2.000 132.081 5.851 [00571] −41.520 353.724 194 >10000 [00572] 13.281 1501.265 657 >10000 [00573] 32.802 3786.286 473 >10000 [00574] 12.322 932.044 382 >10000 [00575] −12.662 554.116 282 >10000 [00576] −27.091 841.978 440 >10000 [00577] 0.954 971.633 593 >10000 [00578] 20.264 1667.412 911 >10000 [00579] −55.378 313.799 167 >10000 [00580] 87.197 >10000 559 >10000 >1200 [00581] 76.538 >6400 610 >10000 [00582] 84.545 >6400 538 >10000 [00583] −70.521 248.761 [00584] −26.377 827.322 [00585] −39.524 427.157 [00586] −67.307 320.764 [00587] −32.036 508.411 [00588] −81.709 97.681 [00589] 11.003 720.201 119.866 [00590] −81.172 45.423 5.891 [00591] 12.455 861.913 [00592] −2.901 94.839 30.921 [00593] 49.481 3980.021 >1200 [00594] −73.192 26.834 8.778 [00595] −74.150 23.547 5.921 [00596] −47.060 2.051 2.117 [00597] −75.410 1.759 9.228 [00598] −78.918 0.860 2.085 [00599] 0.990 [00600] 1.521 [00601] 18.251 [00602] −64.413 3.485 [00603] 29.188 [00604] 14.557 [00605] 16.0 [00606] 24.3
Administration of at least one compound chosen from compounds of Formula I, compounds of Formula II, compounds of Formula III, and pharmaceutically acceptable salts of any of the foregoing [0966] CT26 colon cancer cells (0.25×10.sup.6; ATCC Cat. # CRL-2638) are implanted subcutaneously into the right flank of eight-week old female Balb/c mice (Envigo) in 100 μL of PVS lacking Matrigel. CT26 tumors are allowed to grow to an average of ˜100 mm.sup.3 before animals are enrolled into the efficacy study. Each treatment group contains 12 mice. Mice are treated with at least one compound chosen from compounds of Formula I, compounds of Formula II, compounds of Formula III, and pharmaceutically acceptable salts of any of the foregoing, an anti-CTLA4 antibody, or a combination thereof, at various doses and via various routes of administration. The at least one compound chosen from compounds of Formula I, compounds of Formula II, compounds of Formula III, and pharmaceutically acceptable salts of any of the foregoing is formulated in a composition containing 5% ethanol and 95% methylcellulose solution (0.5% methylcellulose). The anti-CTLA4 antibody is formulated in PBS at pH 7. Tumors are measured 3 times per week for up to 19 days. Tumor volumes are calculated using the ellipsoid formula: Tumor Volume=(length×width.sup.2)/2.