Cyclic Peptide Compound Simulating Natural Product Structure, And Method For Preparation Thereof

Abstract

Provided are a cyclic peptide compound simulating a natural product structure- and a method for preparation thereof. The method is: the compound of formula I, a divalent palladium catalyst, and a silver salt undergoing an intramolecular arylation in a solvent under heating and stirring to construct a cyclic peptide, to generate the compound of formula II, in which the arylation sites are diverse, and can be extended to the side chain γ-position methyl or methylene of the majority hydrophobic amino acids to perform intramolecular arylation, thus overcoming the previous defect of the restriction of the types of selectable amino acids, and effectively constructing a novel aromatic ring-supported cyclic peptide compound. The aromatic ring support structure can form a novel 3D structure similar to a natural product, and provide a very favorable support for the subsequent construction of a cyclic peptide molecular library and high-throughput drug screening.

##STR00001##

Claims

1. A precursor of cyclic peptide compound simulating natural product structure, having the following general structural formula I: ##STR00019## wherein DG is a directing group; AA.sub.1 to AA.sub.n represent a peptide chain, n represents length of the peptide chain, and the value range of n is 3-10; wherein a peptide chain segment corresponding to AA.sub.3 to AA.sub.n comprises at least one aryl iodide side chain, and the part comprising the aryl iodide side chain in the peptide chain segment is denoted as ##STR00020## * represents a chiral center and ##STR00021## resents an alkyl side chain.

2. The precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein ##STR00022## in the peptide chain is one selected from the group consisting of 3-iodophenylalanine, 3-iodotyrosine, 3-iodo-p-methoxyphenylalanine, 4-iodophenylalanine and a compound formed by assembling aryl iodobenzene on the side chain of lysine, serine, or glutamic acid.

3. The precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein AX is located at the end of the peptide chain segment corresponding to AA.sub.3 to AA.sub.n.

4. The precursor of cyclic peptide compound simulating natural product structure according to claim 3, wherein ##STR00023## is 3-iodobenzylamine or 3-iodophenethylamine.

5. The precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein the amino acids other than AX in the peptide chain are selected from the group consisting of α-amino acids, 3-aminopropionic acid, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminobutyric acid, 7-aminoheptanoic acid and 8-aminooctanoic acid.

6. The precursor of cyclic peptide compound simulating natural product structure according to claim 5, wherein the α-amino acid is selected from the group consisting of glycine, alanine, proline, N-Me-alanine, 2-aminobutyric acid, 2-aminopentanoic acid, valine, isoleucine, leucine, tert-leucine, phenylalanine, threonine, serine, lysine, arginine, glutamic acid, glutamine, aspartame acid, asparagine, tryptophan, cysteine, methionine, tyrosine, histidine and cyclohexylglycine.

7. The precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein the alkyl side chain is selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl and phenyl.

8. The precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein the DG is any one selected from the following groups: ##STR00024##

9. A cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 1, wherein the cyclic peptide compound having the following general structural formula II is prepared by an intramolecular arylation reaction from the precursor of the cyclic peptide compound, ##STR00025## wherein the peptide chain structure of the cyclic peptide compound corresponds to the peptide chain structure of the precursor of the cyclic peptide compound.

10. The cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 9, wherein the cyclic peptide compound is any one selected from the group consisting of the following groups: ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##

11. A preparation method for cyclic peptide compound from the precursor of cyclic peptide compound simulating natural product structure according to claim 1, comprising the following steps: subjecting a compound of formula I, a divalent palladium catalyst, and a silver salt to intramolecular arylation reaction under heating and stirring in a solvent to construct a cyclic peptide to produce a compound having the following general structural formula II. ##STR00032##

12. The preparation method for cyclic peptide compound simulating natural product structure according to claim 11, wherein the concentration of the compound of formula I in the solvent is 50-200 mM, and the molar ratio of the compound of formula I:the divalent palladium catalyst:the silver salt is 1:0.05-0.15:1.5-3.0.

13. The preparation method for cyclic peptide compound simulating natural product structure according to claim 11, wherein the solvent is any one selected from the group consisting of hexafluoroisopropanol, chlorobenzene, trifluoroethanol, dichloroethane, tert-amyl alcohol, water, and a mixed solvent of hexafluoroisopropanol and water at a volume ratio of 1:0-1:2.

14. The preparation method for cyclic peptide compound simulating natural product structure according to claim 11, wherein the divalent palladium catalyst is one selected from the group consisting of Pd(CH.sub.3CN).sub.4(BF.sub.4).sub.2, Pd(OAc).sub.2, Pd(TFA).sub.2, Pd(OPiv).sub.2 and Pd(CH.sub.3CN).sub.2Cl.sub.2; and the silver salt is one selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver oxide and silver phosphate.

15. The preparation method for cyclic peptide compound simulating natural product structure according to claim 11, wherein reaction condition of the intramolecular arylation reaction includes a heating temperature of 110-130° C. and a reaction time of 6-48 hours.

16. The precursor of cyclic peptide compound simulating natural product structure according to claim 3, wherein ##STR00033## in the peptide chain is one selected from the group consisting of 3-iodophenylalanine, 3-iodotyrosine, 3-iodo-p-methoxyphenylalanine, 4-iodophenylalanine and a compound formed by assembling aryl iodobenzene on the side chain of lysine, serine, or glutamic acid.

17. The cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 3, wherein the cyclic peptide compound having the following general structural formula II is prepared by an intramolecular arylation reaction from the precursor of the cyclic peptide compound, ##STR00034## wherein the peptide chain structure of the cyclic peptide compound corresponds to the peptide chain structure of the precursor of the cyclic peptide compound.

18. The cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 7, wherein the cyclic peptide compound having the following general structural formula II is prepared by an intramolecular arylation reaction from the precursor of the cyclic peptide compound, ##STR00035## wherein the peptide chain structure of the cyclic peptide compound corresponds to the peptide chain structure of the precursor of the cyclic peptide compound.

19. The cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 8, wherein the cyclic peptide compound having the following general structural formula II is prepared by an intramolecular arylation reaction from the precursor of the cyclic peptide compound, ##STR00036## wherein the peptide chain structure of the cyclic peptide compound corresponds to the peptide chain structure of the precursor of the cyclic peptide compound.

20. The cyclic peptide compound prepared from the precursor of cyclic peptide compound simulating natural product structure according to claim 16, wherein the cyclic peptide compound having the following general structural formula II is prepared by an intramolecular arylation reaction from the precursor of the cyclic peptide compound, ##STR00037## wherein the peptide chain structure of the cyclic peptide compound corresponds to the peptide chain structure of the precursor of the cyclic peptide compound.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 shows the structural formula of the specific compound corresponding to the compound of general formula I (precursor of cyclic peptide compound) of the present invention;

[0042] FIG. 2 shows the structural formula of the specific compound corresponding to the compound of general formula II (cyclic peptide compound) of the present invention;

[0043] FIG. 3 shows the reaction equation of the compound of formula I to the compound of formula II.

DETAILED EMBODIMENTS

[0044] The present invention will be further described through the following embodiments.

[0045] I. Preparation of the Ring-Closure Precursor Linear Peptide (i.e. the Compound of Formula I)

[0046] General preparation method 1: Preparation of the linear peptide with methyl ester at C-terminus (Albericio, F. Angew. Chem., Int. Ed. 2017, 56, 314., Stapled Peptides by Late-Stage C(sp3)-H Activation.)

##STR00009##

[0047] i) Loading of 2-Cl-trt resin: 2-Cl-trt resin was weighed in a solid phase synthesis tube, 5% DIPEA/DCM solution was added to swell the resin for 10 minutes, and then the solvent was pumped dry. Fmoc-AA-OH (1.2 equiv) and DIPEA (6.0 equiv) were then dissolved in DCM, the solution was clarified, and then added to the solid phase synthesis tube and mixed evenly with the resin. The reaction was performed under shaking at room temperature for 1.5 hours, and then the reaction solvent was pumped dry and the residue was washed twice with DMF and DCM respectively for the next reaction.

[0048] ii) Removal of Fmoc protecting group: 20% piperidine/DMF was added to the solid phase synthesis tube, shook for reaction for 10 minutes, and then the reaction solvent was pumped dry. The residue was washed twice with DMF and DCM respectively. The above operation was repeated to complete the removal of the Fmoc protecting group.

[0049] iii) Amino acid condensation: Fmoc-AA-OH (3.0 equiv) and ethyl cyanoglyoxylate-2-oxime (3.0 equiv) were dissolved in NMP to make a clarified solution, and then DIC (3.3 equiv) was added and reacted for 5 minutes in an ice-water bath. Subsequently, the reaction solution was added to the solid phase synthesis tube to react for 1.5 hours at room temperature. Then the reaction solvent was pumped dry and the residue was washed twice with DMF and DCM respectively for the following deprotection procedure.

[0050] iv) Condensation of directing group to N-terminus: Take 2-picolinic acid (PA-COOH) for an example, PA-COOH (3.0 equiv) and ethyl cyanoglyoxylate-2-oxime (3.0 equiv) were dissolved in NMP to make a clarified solution, and then DIC (3.3 equiv) was added therein and reacted for 5 minutes at room temperature. Subsequently, the reaction solution was added to the solid phase synthesis tube to react for 1.5 hours at room temperature. Then the reaction solvent was pumped dry and the residue was washed twice with DMF, DCM and Et.sub.2O respectively. The resin was air-dried at room temperature.

[0051] v) Cleavage from 2-Cl-trt resin: Trifluoroethanol, acetic acid and dichloromethane were mixed in a volume ratio of 1:1:3 to prepare a cleavage solution. The cleavage solution was then added into the solid phase synthesis tube to react for 1.0 hour, and the liquid phase was then separated and collected. Another cleavage solution was added into the solid phase synthesis tube to react for 1.0 hour, and then the liquid phase was collected again. The two liquid phases were combined and the solvent was evaporated and pumped dry to give a crude peptide with free carboxyl group at the C-terminus.

[0052] vi) Methyl esterification of C-terminus: The peptide with free carboxyl group at the C-terminus was dissolved in anhydrous methanol, and then thionyl chloride (5.0 equiv) was added therein slowly in an ice-water bath. The mixture was slowly warmed to room temperature and continuously reacted for 3 hours with the reaction monitored by LCMS during the process. After the reaction, the solvent was evaporated and the methyl esterification product was obtained, which was then extracted with ethyl acetate, washed twice with saturated sodium bicarbonate, then washed twice with saturated saline and dried over anhydrous sodium sulfate. After ethyl acetate was evaporated, the final product was obtained.

[0053] General preparation method 2: Preparation of the linear peptide with amide at C-terminus (Albericio, F. Angew. Chem., Int. Ed. 2017, 56, 314.)

##STR00010##

[0054] The steps of ii, iii and iv are the same as the above mentioned;

[0055] v) Cleavage from Rink-Amide-AM resin: A cleavage solution made of trifluoroacetic acid and water in a volume ratio of 95:5 was added to the solid phase synthesis tube to react for 2.0 hours at room temperature. Then the liquid phase was collected and the solvent was removed. Ether was added to the residue for precipitating the peptide, which was then centrifuged to give a crude peptide with amide at the C-terminus.

[0056] The crude peptide with amide at the C-terminus prepared by the above method has a high basic purity and can be used in the subsequent synthesis of cyclic peptide compounds. Purification can be made when necessary by the preparative HPLC method in the prior art.

[0057] II. The Cyclic Peptide Compounds of the Present Invention and the Preparation Method Thereof

Examples 1-9. Screening of Reaction Solvents

[0058] ##STR00011##

[0059] The linear peptide (serial No. S4) (43.4 mg, 0.05 mmol, 1.0 equiv), AgOAc (12.6 mg, 0.075 mmol, 1.5 equiv) and Pd(OAc).sub.2 (2.2 mg, 10 mol %) was weighed in an 8 mL reaction flask (sealed with a PTFE lid), then 2 mL solvent was added at room temperature and stirred for 5 minutes. The mixture was heated to 110° C. for 6 hours for reaction. The reaction solution was cooled to room temperature, diluted with 5 mL acetone, and filtered with diatomaceous earth. The filtrate obtained was evaporated to obtain an oily substance, which was purified by column chromatography to obtain the final white ring-closure product. The difference between Examples 1-9 only lies in the reaction solvent, as shown in Table 1 for detail.

[0060] It can be seen from the results of the examples 1-9 that when HFIP was chosen as the solvent, the yield was higher.

Examples 10-16: Screening of Divalent Palladium Metal Catalysts

[0061] ##STR00012##

[0062] The preparation methods of examples 10-16 were almost the same as that of example 6, only differing in the divalent palladium metal catalyst, as shown in Table 2 for detail.

[0063] It can be seen from the results of the examples 10-16 that when Pd(CH.sub.3CN).sub.4(BF.sub.4).sub.2 was chosen as the palladium metal catalyst, the yield was higher.

Examples 17-24: Screening of Silver Salts

[0064] ##STR00013##

[0065] The preparation methods of examples 17-24 were almost the same as that of example 14, only differing in the silver salts, as shown in Table 3 for detail.

TABLE-US-00001 TABLE 3 Screening of silver salts Example Silver salt Yield (%).sup.a 17 AgTFA  6 18 AgOTf  8 19 AgNO.sub.3 18 20 AgF  8 21 Ag.sub.2O 10 22 PhCOOAg 60 23 Ag.sub.2CO.sub.3 10 24 Ag.sub.3PO.sub.4 17 .sup.aLCMS Yield

[0066] It can be seen from the results of the examples 17-24 that when AgOAc in example 14 was chosen as the silver salt, the yield was higher.

Examples 25-29: Screening of Additives

[0067] ##STR00014##

[0068] The preparation methods of examples 25-29 were almost the same as that of example 14, only differing in the additives, as shown in Table 4 for detail.

TABLE-US-00002 TABLE 4 Screening of additives Example Additive Yield (%).sup.a 25 o-PBA 59 26 BP acid 20 27 1-Ad-COOH 56 28 PivOH 53 29 TsOH•H.sub.2O 55 .sup.aLCMS Yield

[0069] It can be seen from the results of the examples 25-29 that the yield of example 14, in which no additive was used, was higher.

Examples 30-33: Screening of the Concentration of Pd(CH.SUB.3.CN).SUB.4.(BF.SUB.4.).SUB.2 .Catalyst

[0070] ##STR00015##

[0071] The preparation methods of examples 30-33 were almost the same as that of example 14, only differing in that the concentration of Pd(CH.sub.3CN).sub.4(BF.sub.4).sub.2 chosen by examples 30-33 was different and the reaction time was extended to 12 hours, as shown in Table 5 for detail.

[0072] It can be seen from the results of the examples 30-33 that the yield of example 33, with the concentration of Pd(CH.sub.3CN).sub.4(BF.sub.4).sub.2 being 10 mol %, was higher.

Examples 34-37: Screening of Reactant Concentration

[0073] ##STR00016##

[0074] The preparation methods of examples 34-37 were almost the same as that of example 33, only differing in the reactant concentration, as shown in Table 6 for detail.

[0075] It can be seen from the results of the examples 34-37 that the yield of example 37, with 200 nM HFIP being added, was higher.

Examples 38-75

[0076] The compound of formula I (43.4 mg, 0.05 mmol, 1.0 equiv), AgOAc (12.6 mg, 0.075 mmol, 1.5 equiv) and Pd(CH.sub.3CN).sub.4(BF.sub.4).sub.2 (2.2 mg, 10 mol %) were weighed in 8 mL reaction flask (sealed with a PTFE lid), and then 2 mL solvent was added at room temperature, followed by stirring for 5 minutes. The mixture was then heated to 110-130° C. for 12-48 hours for reaction. The reaction solution was cooled to room temperature, diluted with 5 mL acetone, and filtered with diatomaceous earth. The filtrate obtained was evaporated to obtain an oily substance, which was purified by column chromatography to give the final ring-closure product. The specific choices of the compounds of formula I and the reaction conditions in examples 38-75 are shown in Table 7, wherein the compounds of formula I were showed in FIG. 1, the compounds of formula II were showed in FIG. 2, and the general equation for the reaction from compounds of formula I to compounds of formula II was showed in FIG. 4.

TABLE-US-00003 TABLE 7 Reaction conditions of examples 38-75 compounds compounds of of formula I Reaction Reaction formula II Example (Serial No.) Solvent temperature/° C. time/h (Serial No.) Yield/% 38  S4 HFIP 110 12 4 76 39  S5 HFIP 130 48 5 61 40  S6 HFIP 110 12 6a + 6b 49 + 24 41  S7 HFIP 110 24 7 65 42  S8 HFIP 130 48 8 41 43  S9 HFIP 120 48 9 27 44 S10 HFIP 110 12 10 78 45 S11 HFIP 110 12 11 62 46 S12 HFIP 110 24 12 46 47 S13 DCE 110 12 13 61 48 S14 HFIP 110 12 14 80 49 S15 HFIP 110 12 15a + 15b 30 + 39 50 S16 HFIP 110 12 16 75 51 S17 HFIP 110 12 17 66 52 S18 HFIP 120 24 18 50 53 S19 HFIP 120 24 19 51 54 S20 HFIP 130 48 20 31 55 S21 HFIP 120 12 21 57 56 S22 HFIP 110 12 22 73 57 S23 HFIP 130 12 23 51 58 S24 H.sub.2O 110 12 25 65 59 S26 H.sub.2O 110 12 26 69 60 S27 H.sub.2O 110 12 27 41 61 S28 H.sub.2O/HFIP 110 12 28 66 62 S29 H.sub.2O/HFIP 110 12 29 47 63 S30 H.sub.2O 110 12 30 59 64 S31 H.sub.2O/HFIP 110 12 31 71 65 S32 H.sub.2O/HFIP 120 24 32 67 66 S33 H.sub.2O/HFIP 110 12 33 46 67 S34 H.sub.2O 110 12 34 72 68 S35 HFIP 110 12 37 55 69 S36 HFIP 120 12 38 47 70 S37 HFIP 110 12 39 37 71 S38 HFIP 110 12 40 15 72 S39 HFIP 110 12 41 16 73 S40 HFIP 110 12 42 19 74 S41 HFIP 110 12 43 76 75 S42 HFIP 110 12 44 78

[0077] The molar ratio of H.sub.2O to HFIP in the mixed solvent used in Examples 61 and 64 of the present invention is 9:1, and the molar ratio of H.sub.2O to HFIP in the mixed solvent used in Examples 62, 65, and 66 is 1:2.

[0078] The directing groups of the present invention have the same principle of action as PA, which is bidentate-directed intramolecular arylation, and all the directing groups can realize the construction of cyclic peptides. Among the directing groups of the present invention, PA has the best effect.

[0079] II. Removal of PA-Directing Group in the Product

Example 76

[0080] ##STR00017##

[0081] The product 10 (53.5 mg, 0.1 mmol, 1.0 equiv) was dissolved in THF/H.sub.2O (2:1, v/v) and stirred at room temperature, hydrochloric acid solution (1.5M, 1 mL) was slowly added therein, and then zinc powder (98.1 mg, 1.5 mmol, 15.0 equiv) was added. The mixture was stirred for 1.5 h at room temperature. After the completion of the reaction of the raw materials as monitored by TLC, NaHCO.sub.3 was added to adjust pH to 7-8, and then Fmoc-Cl (77.6 mg, 0.3 mmol, 3.0 equiv) was added, and reacted for 6 hours at room temperature. Then an appropriate amount of water was added to the system, which was then extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated saline, and dried over anhydrous sodium sulfate. After ethyl acetate was evaporated, the crude product was obtained, which was purified by column chromatography to obtain product 35 (58.7 mg, 90%).

Example 77

[0082] ##STR00018##

[0083] The method for removing PA in Example 77 was almost the same as that of example 76, differing in that after removal of the directing group PA, product 4 was subjected to a further condensation reaction with L-pyroglutamic acid so as to obtain product 36.

[0084] IV. Characterization of Product Structure

[0085] The test datas of products 4-42 are as follows:

[0086] Product 4

[0087] HRMS: Calcd for C.sub.41H.sub.50N.sub.6NaO.sub.7 [M+Na.sup.+]: 761.3633; found: 761.3633.

[0088] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (d, J=7.8 Hz, 1H), 8.60 (d, J=4.2 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.43 (d, J=5.6 Hz, 2H), 7.24-7.12 (m, 5H), 6.92-6.80 (m, 3H), 6.65 (d, J=5.2 Hz, 3H), 5.03 (t, J=8.4 Hz, 1H), 4.69 (s, 1H), 4.13-4.05 (m, 1H), 4.00 (t, J=9.2 Hz, 1H), 3.84 (d, J=6.2 Hz, 1H), 3.70 (s, 3H), 3.66-3.60 (m, 1H), 3.56 (d, J=13.6 Hz, 1H), 3.33 (dd, J=13.6, 5.2 Hz, 1H), 3.15-2.94 (m, 4H), 2.63 (d, J=13.8 Hz, 1H), 2.56-2.44 (m, 2H), 1.77 (s, 1H), 1.63-1.47 (m, 2H), 1.43-1.29 (m, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.70 (d, J=5.4, 6H), 0.64 (d, J=5.2, 6H).

[0089] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 173.2, 171.1, 170.5, 170.4, 169.6, 165.2, 148.8, 148.4, 137.6, 134.6, 134.5, 129.6, 128.9, 128.4, 127.1, 126.6, 122.2, 61.0, 54.8, 54.0, 52.9, 52.3, 52.2, 45.3, 39.8, 37.5, 37.2, 36.2, 35.3, 30.9, 29.7, 29.3, 24.9, 22.7, 21.7, 21.3, 15.7, 1.07.

[0090] Product 5

[0091] HRMS: Calcd for C.sub.40H.sub.49N.sub.6O.sub.7 [M+H.sup.+]: 725.3657; found: 725.3656.

[0092] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.63 (d, J=4.4 Hz, 1H), 8.54 (d, J=8.2 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.21 (d, J=4.6 Hz, 3H), 7.00 (d, J=7.4 Hz, 2H), 6.92 (s, 3H), 6.80 (d, J=6.4 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 4.96-4.85 (m, 2H), 4.12 (t, J=8.8 Hz, 1H), 4.05-3.98 (m, 1H), 3.82 (s, 3H), 3.68 (d, J=7.2 Hz, 1H), 3.65-3.57 (m, 2H), 3.41-3.30 (m, 2H), 3.21 (dd, J=14.0, 3.4 Hz, 1H), 3.05-2.99 (m, 1H), 2.95 (d, J=16.4 Hz, 1H), 2.77-2.67 (m, 1H), 2.47 (dd, J=11.4, 6.4 Hz, 1H), 2.30 (dd, J=14.4, 11.6 Hz, 1H), 1.99-1.76 (m, 4H), 1.68-1.59 (m, 1H), 1.41 (d, J=6.4 Hz, 4H), 0.79 (d, J=5.2 Hz, 3H), 0.72 (d, J=5.4 Hz, 3H).

[0093] .sup.14C NMR (100 MHz, CDCl.sub.3) δ 172.7, 171.5, 171.1, 170.6, 170.5, 165.7, 148.7, 148.6, 138.3, 137.6, 137.5, 134.9, 130.3, 129.0, 128.4, 126.9, 126.5, 122.4, 60.4, 55.0, 53.6, 53.2, 52.6, 49.0, 46.0, 39.9, 36.4, 34.7, 33.2, 30.7, 30.6, 24.9, 22.8, 21.9, 21.2.

[0094] Product 6a

[0095] HRMS: Calcd for C.sub.42H.sub.53N.sub.6O.sub.7 [M+H.sup.+]: 753.3970; found: 753.3975.

[0096] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.73 (d, J=8.0 Hz, 1H), 8.66 (d, J=4.2 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.22-7.14 (m, 6H), 7.05-6.97 (m, 4H), 6.69 (d, J=5.0 Hz, 1H), 5.04 (t, J=8.8 Hz, 1H), 4.81 (d, J=5.8 Hz, 1H), 4.46 (t, J=9.2 Hz, 1H), 4.19 (d, J=7.4 Hz, 1H), 4.13-4.03 (m, 1H), 3.73 (s, 3H), 3.62 (t, J=15.0 Hz, 2H), 3.47-3.38 (m, 1H), 3.26-3.12 (m, 3H), 2.89-2.80 (m, 1H), 2.35 (dd, J=12.0, 5.8 Hz, 1H), 2.30-2.22 (m, 1H), 1.96-1.84 (m, 1H), 1.83-1.73 (m, 2H), 1.37 (d, J=7.2 Hz, 3H), 1.25 (s, 2H), 0.88 (d, J=7.2 Hz, 3H), 0.79 (d, J=5.8 Hz, 3H), 0.70 (d, J=5.8 Hz, 3H).

[0097] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.4, 172 0, 171.8, 171.6, 171.1, 165.5, 148.8, 148.6, 141.8, 138.1, 137.6, 128.9, 128.8, 128.7, 128.3, 128.1, 127.0, 126.9, 126.4, 122.5, 61.1, 55.1, 54.4, 53.4, 53.0, 52.4, 46.4, 43.4, 40.2, 39.7, 37.2, 36.8, 31.0, 24.9, 22.6, 22.0, 21.5, 20.7, 11.3.

[0098] Product 6b

[0099] HRMS: Calcd for C.sub.42H.sub.53N.sub.6O.sub.7 [M+H.sup.+]: 753.3970. found: 753.3974.

[0100] The product 6b should be a conformational isomer, which has different ratios in different deuterated solvents.

[0101] .sup.1H NMR (400 MHz, CDCl3, ratio of isomer=2.5:1) δ 8.83 (d, J=8.6 Hz, 1H), 8.62 (dd, J=11.4, 4.4 Hz, 2H), 8.12 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.0 Hz, 1H), 7.53-7.43 (m, 3H), 7.30 (d, J=7.6 Hz, 2H), 7.18 (t, J=5.2 Hz, 5H), 7.08 (t, J=8.8 Hz, 2H), 6.97 (d, J=6.4 Hz, 3H), 6.23 (d, J=4.4 Hz, 1H), 5.35 (t, J=5.2 Hz, 1H), 5.04-4.96 (m, 1H), 4.92 (td, J=8.0, 3.6 Hz, 1H), 4.51 (d, J=8.4 Hz, 1H), 4.03-3.97 (m, 1H), 3.79 (s, 3H), 3.77 (s, 1H), 3.60 (s, 1H), 3.53 (dd, J=11.8, 6.4 Hz, 3H), 3.46 (d, J=7.8 Hz, 1H), 3.24 (dd, J=19.6, 10.6 Hz, 2H), 3.16 (s, 1H), 3.12-3.04 (m, 1H), 3.00 (d, J=14.6 Hz, 2H), 2.36-2.26 (m, 1H), 2.22 (t, J=7.6 Hz, 1H), 2.10 (t, J=14.0 Hz, 2H), 2.02 (s, 1H), 1.89 (d, J=7.8 Hz, 3H), 1.79-1.70 (m, 2H), 1.63 (s, 7H), 1.18 (t, J=7.2 Hz, 5H), 0.89 (t, J=11.2 Hz, 5H), 0.82 (d, J=5.8 Hz, 4H).

[0102] .sup.1H NMR (400 MHz, Acetone, ratio of isomer 1.3:1) δ 8.77 (d, J=9.4 Hz, 1H), 8.71 (dd, J=9.8, 4.7 Hz, 2H), 8.16 (d, J=7.8 Hz, 1H), 8.06 (t, J=8.6 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.95 (dt, J=7.8, 3.8 Hr, 1H), 7.64 (dd, J=11.2, 6.4 Hz, 2H), 7.50-7.46 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.33 (d, J=7.2 Hz, 2H), 7.31-7.26 (m, 3H), 7.23 (d, J=6.8 Hz, 4H), 7.21-7.14 (m, 10H), 7.13 (s, 1H), 7.12-7.07 (m, 2H), 6.99 (d, J=7.6 Hz, 1H), 5.35 (t, J=4.8 Hz, 1H), 4.83 (d, J=10.8 Hz, 1H), 4.78 (d, J=11.4 Hz, 2H), 4.73 (d, J=9.4 Hz, 2H), 4.66 (d, J=4.2 Hz, 1H), 4.15-4.06 (m, 1H), 3.07 (dt, J=10.2, 6.2 Hz, 2H), 3.75 (s, 1H), 3.72 (s, 3H), 3.71 (s, 2H), 3.63 (s, 1H), 3.57-3.50 (m, 2H), 3.50-3.42 (m, 2H), 3.23 (dd, J=19.6, 10.8 Hz, 2H), 3.16 (d, J=4.2 Hz, 2H), 3.13-3.02 (m, 4H), 2.93 (s, 3H), 282 (s, 5H), 2.41-2.29 (m, 1H), 2.14 (t, J=7.4 Hz, 1H), 1.85 (d, J=5.8 Hz, 4H), 1.72-1.50 (m, 5H), 1.48-1.39 (m, 4H), 1.12 (t, J=7.4 Hz, 4H), 1.06-0.97 (m, 4H), 0.88 (t, J=6.6 Hz, 4H), 0.84 (d, J=6.6 Hz, 3H), 0.78 (d, J=2.2 Hz, 3H), 0.76 (d, J=2.4 Hz, 3H), 0.71 (d, J=6.4 Hz, 3H)

[0103] Product 7

[0104] HRMS: Calcd for C.sub.27H.sub.49N.sub.6O.sub.7 [M+H.sup.+]: 689.3657; found: 689.3661.

[0105] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (d, J=8.3 Hz, 1H), 8.57 (d, J=4.6 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.42 (dd, J=7.4, 4.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.18 (d, J=5.8 Hz, 2H), 7.09 (s, 1H), 7.07-7.00 (m, 3H), 6.39 (d, J=7.8 Hz, 1H), 4.74-467 (m, 1H), 4.53 (t, J=8.5 Hz, 1H), 4.46 (dd, J=8.2, 2.8 Hz, 1H), 4.42-4.33 (m, 2H), 4.10-4.05 (m, 1H), 3.79 (s, 3H), 3.70-3.64 (m, 1H), 3.47 (dd, J=17.2, 3.8 Hz, 1H), 3.24 (dd, J=13.6, 2.6 Hz, 1H), 3.04 (dd, J=13.6, 10.2 Hz, 1H), 2.86 (dd, J=13.8, 6.6 Hz, 1H), 2.60 (dd, J=13.8, 9.2 Hz, 1H), 2.32-2.21 (m, 1H), 2.20-2.14 (m, 3H), 2.05-0.99 (m, 1H), 1.76-1.56 (m, 9H), 1.44-1.33 (m, 1H), 1.18 (d, J=14.2 Hz, 2H), 1.09 (dd, J=21.0, 8.6 Hz, 3H), 0.99 (t, J=7.4 Hz, 3H).

[0106] .sup.13C NMR (100 MHz, CDCl.sub.2) δ 172.5, 171.7, 170.8, 170.5, 160 3, 64.1, 149.6, 148.4, 140.3, 137.3, 131.2, 129.2, 127.5, 127.2, 126.4, 122.2, 100.4, 60.9, 56.0, 54.1, 53.8, 52.6, 48.2, 45.0, 42.7, 40.3, 36.6, 36.3, 29.7, 29.5, 29.1, 26.2, 25.8, 25.7, 24.8, 22.7, 12.6

[0107] Product 8

[0108] Product 8 is a mixture of diastereomers in a ratio of 2:1.

[0109] HRMS: Calcd for C.sub.42H.sub.57N.sub.6O.sub.8 [M+H.sup.+]: 769.3919; found: 769.3922.

[0110] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.16 (d, J=9.4 Hz, 1H), 8.69-8.52 (m, 2H), 8.18 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.57-7.51 (m, 1H), 7.50-7.41 (m, 2H), 7.24 (d, J=7.4 Hz, 2H), 7.21-7.16 (m, 3H), 7.13 (d, J=7.6 Hz, 3H), 7.11-7.05 (m, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.84 (d, J=74 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.72 (t, J=6.8 Hz, 2H), 6.56 (d, J=8.2 Hz, 1H), 5.12 (d, J=9.4 Hz, 1H), 4.87 (ddd, J=17.4, 8.0, 4.4 Hz, 2H), 4.73-4.52 (m, 2H), 4.48 (d, J=7.4 Hz, 1H), 4.29 (dd, J=15.4, 9.4 Hz, 2H), 4.15 (dd, J=13.8, 7.0 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 1H), 3.70 (s, 3H), 3.68 (s, 1H), 3.53-3.45 (m, 1H), 3.30 (ddd, J=20.4, 14.4, 5.4 Hz, 1H), 3.18 (dd, J=14.0, 3.6 Hz, 1H), 3.09 (d, J=2.8 Hz, 1H), 2.99 (d, J=4.8 Hz, 1H), 2.47-2.94 (m, 1H), 2.02 (d, J=8.2 Hz, 1H), 2.87 (dd, J=8.4, 5.8 Hz, 1H), 2.80 (dd, J=15.8, 7.6 Hz, 1H), 2.74 (s, 1H), 2.62 (s, 1H), 2.43 (dd, J=11.0, 6.4 Hz, 1H), 2.21 (d, J=8.8 Hz, 1H), 2.16 (d, J=2.6 Hz, 1H), 2.01-1.88 (m, 4H), 1.87-1.77 (m, 1H), 1.74-1.62 (m, 1H), 1.59-1.45 (m, 3H), 1.41-1.29 (m, 3H), 1.08-0.09 (m, 6H), 0.91-0.78 (m, 10H), 0.74 (d, J=6.2 Hz, 1H).

[0111] Product 9

[0112] HRMS: Calcd for C.sub.31H.sub.39N.sub.6O.sub.7 [M+H.sup.+]: 607.2875; found: 607.2878.

[0113] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.92 (d, J=7.8 Hz, 1H), 8.66 (d, J=4.6 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.5-7.50 (m, 1H), 6.99 (d, J=7.8 Hz, 2H), 6.94 (d, J=7.8 Hz, 2H), 6.75 (d, J=6.6 Hz, 1H), 4.88 (d, J=3.4 Hz, 1H), 4.26-4.20 (m, 2H), 4.05 (dd, J=15.6, 5.4 Hz, 1H), 3.90 (d, J=6.6 Hz, 1H), 3.87 (s, 2H), 3.79 (s, 3H), 3.65 (s, 1H), 3.62 (d, J=6.0 Hz, 1H), 3.36 (dd, J=14.0, 5.6 Hz, 1H), 3.15 (dd, J=14.0, 3.2 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 2.53 (d, J=13.8 Hz, 1H), 2.45 (d, J=5.8 Hz, 1H), 2.22 (t, J=12.2 Hz, 1H), 2.00 (s, 1H), 1.89 (s, 1H), 1.72 (s, 1H), 1.42 (s, 3H), 1.03 (s, 3H).

[0114] Product 10

[0115] HRMS: Calcd for C.sub.28H.sub.34N.sub.5O.sub.6, [M+H.sup.+]: 536.2504; found: 536.2508.

[0116] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (d, J=4.6 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.85 (td, J=7.8, 1.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.13 (d, J=8.0 Hz, 2H), 6.87 (s, 2H), 6.67 (d, J=8.6 Hz, 1H), 6.52 (dd, J=8.6, 4.0 Hz, 1H), 4.97 (dd, J=7.2, 4.6 Hz, 1H), 4.75 (d, J=8.8 Hz, 1H), 4.44 (dd, J=17.4, 9.0 Hz, 1H), 3.86 (t, J=7.6 Hz, 1H), 3.75 (d, J=4.6 Hz, 3H), 3.71-3.61 (m, 2H), 3.40 (dd, J=17.4, 4.2 Hz, 1H), 3.22 (dd, J=13.4, 22 Hz, 1H), 3.02 (dd, J=13.4, 5.6 Hz, 1H), 2.81 (dd, J=14.2, 3.8 Hz, 1H), 2.68 (dd, J=11.6, 5.0 Hz, 1H), 2.46-2.34 (m, 1H), 2.13 (dd, J=11.0, 4.8 Hz, 1H), 2.03 (dd, J=11.8, 5.2 Hz, 1H), 1.94-1.83 (m, 1H), 1.79 (dd, J=19.4, 8.2 Hz, 1H), 1.39 (d, J=7.0 Hz, 3H).

[0117] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.0, 170.8, 170.2, 168.7, 164.4, 149.9, 148.2, 137.9, 137.4, 132.2, 130.3, 129.3, 128.0, 126.3, 122.5, 77.4, 77.1, 76.8, 61.2, 55.3, 53.0, 52.1, 48.0, 43.0, 39.2, 37.6, 37.1, 29.7, 25.8, 23.1.

[0118] Product 11

[0119] HRMS: Calcd for C.sub.38H.sub.47N.sub.6O.sub.5 [M+H.sup.+]: 667.3602; found: 667.3607.

[0120] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.74 (d, J=8.4 Hz, 1H), 8.66 (d, J=4.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.80 (td, J=7.8, 1.4 Hz, 1H), 7.50 (dd, J=7.4, 4.8 Hz, 1H), 7.28 (t, J=5.4 Hz, 3H), 7.24 (d, J=7.8 Hz, 1H), 7.19 (t, J=6.8 Hz, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.04-7.00 (m, 2H), 6.40 (d, J=3.8 Hz, 1H), 5.23 (dd, J=15.8, 9.8 Hz, 1H), 5.19-5.11 (m, 1H), 4.75-4.69 (m, 1H), 3.99-3.87 (m, 2H), 3.79 (dd, J=14.8, 3.4 Hz, 1H), 3.60 (d, J=8.0 Hz, 1H), 3.57-3.46 (m, 2H), 2.99 (t, J=13.6 Hz, 2H), 2.73 (dd, J=13.8, 4.8 Hz, 1H), 2.47-2.37 (s, 1H), 2.09 (dd, J=12.6, 6.2 Hz, 1H), 1.92-186 (m, 1H), 1.84-1.72 (m, 1H), 1.70-1.57 (m, 2H), 1.34-1.28 (m, 3H), 0.84 (d, J=5.8 Hz, 3H), 0.80 (d, J=7.2 Hz, 3H), 0.74 (d, J=5.8 Hz, 3H).

[0121] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.9, 172.0, 171.9, 171.5, 148.8, 148.5, 138.6, 137.7, 136.5, 129.9, 129.0, 128.3, 128.2, 127.1, 126.8, 126.6, 126.4, 122.5, 61.2, 55.9, 52.7, 52.1, 46.6, 42.6, 40.4, 38.7, 37.5, 37.4, 36.3, 32.0, 25.0, 22.5, 22.1, 21.7, 14.9.

[0122] Product 12

[0123] HRMS: Calcd for C.sub.50H.sub.69N.sub.10O.sub.31S [M+H.sup.+]: 1017.4863; found: 1017.4863.

[0124] .sup.1H NMR (400 MHz, DMSO) δ 9.02 (d, J=8.8 Hz, 1H), 8.68 (d, J=4.6 Hz, 1H), 8.32 (d, J=5.4 Hz, 1H), 8.20 (d, J=4.4 Hz, 1H), 8.05-7.99 (m, 2H), 7.94 (t, J=5.4 Hz, 3H), 7.83 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.64 (dd, J=7.8, 3.6 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 7.02 (s, 1H), 6.96 (t, J=6.8 Hz, 2H), 6.69 (s, 1H), 6.39 (s, 1H), 4.64-4.54 (m, 1H), 4.46 (t, J=8.2 Hz, 1H), 4.05 (t, J=7.0 Hz, 1H), 3.99-3.91 (m, 11H), 3.85 (dd, J=16.8, 7.2 Hz, 1H), 3.70 (s, 3H), 3.65 (d, J=5.4 Hz, 2H), 3.39 (dd, J=16.6, 4.2 Hz, 1H), 3.21-3.14 (m, 1H), 3.03 (s, 2H), 2.95 (s, 2H), 2.87 (dd, J=13.8, 9.4 Hz, 3H), 2.78 (d, J=10.8 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.0-2.01 (m, 1H), 1.99 (m, 3H), 1.64 (m, 1H), 1.55 (s, 1H), 1.43 (m, 1H), 1.40 (s, 8H), 1.30 (m, 2H), 1.23 (m, 1H), 1.16 (dd, J=14.0, 6.6 Hz, 1H), 0.83 (m, 9H)

[0125] Product 13

[0126] HRMS: Calcd for C.sub.49H.sub.26N.sub.9O.sub.12 [M+H.sup.+]: 976.5138; found: 976.5141.

[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.59 (dd, J=14.0, 6.2 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.91-7.78 (m, 2H), 7.67 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.52-7.45 (m, 1H), 7.23 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.06 (d, J=9.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 2H), 5.06 (t, J=8.8 Hz, 1H), 4.93 (dd, J=15.2, 7.2 Hz, 1H), 4.72 (t, J=8.4 Hz, 1H), 4.59 (dd, J=13.2, 6.6 Hz, 3H), 4.55-4.42 (m, 2H), 4.02 (m, 2H), 3.90-3.82 (m, 1H), 3.77 (s, 3H), 3.72-3.68 (m, 1H), 3.65 (d, J=5.6 Hz, 1H), 3.55 (dd, J=16.8, 4.8 Hz, 1H), 3.05 (dd, J=24.8, 10.4 Hz, 2H), 2.92-2.84 (n, 1H), 2.73 (s, 3H, 2.45-2.38 (m, 1H), 2.31 (d, J=6.8 Hz, 1H), 2.22 (d, J=5.8 Hz, 2H), 2.04 (dd, J=12.8, 5.6 Hz, 2H), 1.83 (dd, J=12.4, 7.8 Hz, 1H), 1.75-1.69 (m, 3H), 1.59 (d, J=10.4 Hz, 1H), 1.49 (s, 9H), 1.44 (d, J=7.8 Hz, 3H), 1.26 (s, 2H), 0.85 (t, J=66 Hz, 6H), 0.78 (d, J=6.4 Hz, 3H)

[0128] Product 14

[0129] HRMS: Calcd for C.sub.27H.sub.35N.sub.4O.sub.5, [M+H.sup.+]: 495.2602; found 495.2602.

[0130] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.88 (d, J=9.2 Hz, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 6.94 (d, J=76 Hz, 1H), 6.89 (s, 3H), 6.23 (d, J=8.6 Hz, 1H), 6.12 (d, J=10.0 Hz, 1H), 4.83-4.73 (m, 2H), 4.09 (d, J=10.0 Hz, 1H), 3.85 (s, 3H), 3.35 (dd, J=13.6, 48 Hz, 1H), 2.87-2.75 (m, 2H), 2.54 (dd, J=14.6, 3.4 Hz, 1H), 2.40 (d, J=3.6 Hz, 1H), 3.32 (d, J=7.0 Hz, 4H), 0.92 (s, 4H).

[0131] .sup.13C NMR (1001 MHz, CDCl.sub.3) δ 172.1, 170.7, 169.8, 164.8, 149.8, 148.5, 141.2, 137.3, 136.1, 129.6, 129.2, 127.5, 126.7, 126.4, 122.5, 60.9, 56.0, 52.5, 39.9, 38.2, 37.6, 33.8, 26.3, 21.3

[0132] Product 15a

[0133] HRMS: Calcd for C.sub.27H.sub.34N.sub.5O.sub.4 [M+H.sup.+]: 492.2605; found: 492.2608.

[0134] .sup.1H NMR (400 MHz, CDCl.sub.3), diastereomer, d.r.=3:1) δ 8.70 (t, J=5.6 Hz, 1H), 8.65 (d, J=4.2 Hz, 2H), 8.53 (s, 1H), 8.26 (d, J=4.2 Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.89 (t, J=7.8 Hz, 11H), 7.72 (t, J=7.6 Hz, 1H), 7.57 (d, J=10.6 Hz, 1H), 7.55-7.49 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.14 (t, J=7.4 Hz, 3H), 7.05 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 6.35 (d, J=5.6 Hz, 1H), 5.03 (dd, J=10.2, 4.8 Hz, 1H), 4.64 (dd, J=17.4, 9.4 Hz, 1H), 4.16 (dd, J=16.0, 6.8 Hz, 1H), 4.06 (dd, J=10.6, 7.2 Hz, 2H), 3.90 (t, J=8.6 Hz, 1H), 3.82 (dd, J=13.0, 6.0 Hz, 1H), 3.74-3.69 (m, 2H), 3.67 (d, J=5.6 Hz, 1H), 3.59 (dd, J=20.4, 9.2 Hz, 1H), 3.55-3.48 (m, 1H), 3.46-3.29 (m, 31H), 3.18 (s, 1H), 3.06 (d, J=13.8 Hz, 1H), 2.93 (d, J=14.8 Hz, 1H), 2.62-2.45 (m, 2H), 2.35-2.20 (m, 2H), 2.14 (d, J=11.2 Hz, 1H), 1.98 (s, 1H), 1.85 (s, 1H), 1.77-1.58 (m, 2H), 1.43 (d, J=7.2 Hz, 3H), 1.32 (d, J=7.2 Hz, 1H), 1.28 (d, J=7.2 Hz, 1H), 0.90 (d, J=7.2 Hz, 3H).

[0135] Product 15b

[0136] HRMS: Calcd for C.sub.27H.sub.34N.sub.5O.sub.4 [M+H.sup.+]: 492.2605; found 492.2607.

[0137] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (d, J=7.8 Hz, 1H), 8.66 (d, J=4.4 Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.67 (s, 1H), 7.54-7.48 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.13 (t, J=7.4 Hz, 2H), 6.91 (s, 1H), 6.76 (s, 1H), 4.36 (d, J=7.6 Hz, 1H), 4.00 (dd, J=15.8, 6.2 Hz, 1H), 3.74-3.57 (m, 3H), 3.56-3.46 (m, 3H), 3.10 (dd, J=13.4, 2.8 Hz, 1H), 3.07-2.96 (m, 1H), 2.77-2.66 (m, 1H), 2.40 (dd, J=16.4, 8.8 Hz, 2H), 2.09 (dd, J=13.4, 5.6 Hz, 2H), 1.92-1.81 (m, 2H), 1.69-1.58 (m, 2H), 1.55-1.45 (m, 1H), 1.17 (t, J=7.4 Hz, 3H).

[0138] .sup.13C NMR (100 MHz, CDCl.sub.3)) δ 170.3, 148 6, 137.5, 130.4, 129.7, 128.1, 126.3, 122.7, 60.0, 51.8, 46.6, 45.4, 38.1, 36.6, 33.6, 30.9, 21.8, 21.5, 12.6.

[0139] The product 16 is the two diastereomers separated, designated as 16-1 and 16-2.

[0140] Product 16-1

[0141] HRMS: Calcd for C.sub.41H.sub.49N.sub.6O.sub.7 [M+H.sup.+]: 737.3657; found: 737.3661.

[0142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.62 (d, J=4.8 Hz, 1H), 8.57 (d, J=5.2 Hz, 1H), 7.69-7.62 (m, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.42 (t, J=6.4 Hz, 1H), 7.15 (d, J=7.6 Hz, 6H), 7.02 (d, J=3.2 Hz, 2H), 6.95 (d, J=7.6 Hz, 2H), 6.06 (d, J=7.4 Hz, 1H), 4.63 (dd, J=14.8, 7.6 Hz, 1H), 4.48 (dt, J=11.6, 5.8 Hz, 1H), 4.33 (t, J=8.0 Hz, 1H), 4.18 (d, J=7.2 Hz, 1N), 3.79-3.72 (m, 1H), 3.69 (s, 3H), 3.57 (dd, J=10.0, 5.4 Hz, 1H), 3.48-3.40 (m, 11H), 3.14 (dd, J=13.6, 4.0 Hz, 1H), 3.02 (dd, J=14.2, 6.2 Hz, 1H), 2.86 (dd, J=14.4, 8.0 Hz, 1H), 2.73 (d, J=13.6, 8.0 Hz, 1H), 2.64-2.50 (m, 2H), 1.98 (dd, J=16.8, 9.4 Hz, 2H), 1.78-1.61 (m, 3H), 1.49 (s, 2H), 1.19 (dd, J=14.8, 8.6 Hz, 1H), 0.96 (dd, J=11.6, 5.8 Hz, 1H), 0.87 (d, J=5.6 Hz, 3H), 0.82 (d, J=5.2 Hz, 3H).

[0143] Product 16-2

[0144] HRMS: Calcd for C.sub.41H.sub.49N.sub.6O.sub.7 [M+H.sup.+]: 737.3657; found: 737.3658.

[0145] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (d, J=6.0 Hz, 1H), 8.66 (s, 1H), 7.96 (s, 1H), 7.84-7.71 (m, 3H), 7.48 (s, 1H), 7.32 (s, 1H), 7.22 (t, J=7.6 Hz, 4H), 7.16-7.10 (m, 2H), 7.07 (d, J=6.4 Hz, 1H), 6.45 (s, 1H), 6.24 (d, J=9.0 Hz, 1H), 5.01 (s, 1H), 4.91 (d, J=5.8 Hz, 1H), 3.96-3.85 (m, 2H), 3.79 (s, 3H), 3.65 (d, J=11.2 Hz, 1H), 3.42-3.13 (m, 5H), 2.72 (d, J=5.6 Hz, 1H), 2.41 (dd, J=15.2, 7.8 Hz, 1H), 2.23 (s, 1H), 1.84 (s, 1H), 1.77-1.62 (m, 3H), 1.51 (d, J=6.4 Hz, 4H), 1.37-1.28 (m, 2H), 1.15 (d, J=5.8 Hz, 1H), 0.84 (d, J=4.8 Hz, 3H), 0.74 (d, J=5.2 Hz, 3H).

[0146] Product 17

[0147] HRMS: Calcd for C.sub.29H.sub.35N.sub.5O.sub.6 [M+H.sup.+]: 550.2660; found: 550.2662.

[0148] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.27 (d, J=4.6 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.40-7.32 (m, 1H), 7.21 (d, J=9.8 Hz, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 6.89-6.81 (m, 2H), 6.73 (d, J=6.2 Hz, 1H), 5.45 (d, J=7.6 Hz, 1H), 5.21 (s, 1H), 4.58 (dd, J=17.4, 8.4 Hz, 1H), 3.85 (d, J=4.0 Hz, 1H), 3.64 (s, 3H), 3.59 (s, 1H), 3.54 (d, J=4.0 Hz, 1H), 3.16 (dd, J=14.2, 5.2 Hz, 1H), 3.05 (d, J=12.2 Hz, 1H), 2.26 (dd, J=16.0, 8.4 Hz, 1H, 1.24 (d, J=7.6 Hz, 1H), 1.05 (s, 10H), 0.99 (d, J=6.4 Hz, 2H), 0.94 (s, 1H).

[0149] .sup.13C NMR 4100 MHz, CDCl.sub.3) δ 171.4, 109.3, 164 2, 149.2, 147.9, 137.2, 136.9, 135.7, 133 0, 128.2, 127.0, 126.4, 122.4, 63.9, 53.2, 52.1, 50.6, 43.0, 32.6, 26.7, 21.4, 19.8, 4.8

[0150] Product 18

[0151] HRMS: Calcd for C.sub.31H.sub.38N.sub.5O.sub.6 [M+H.sup.+]: 576.2817; found: 576.2816.

[0152] .sup.1H NMR (404 MHz, CDCl.sub.3) δ 8.62 (d, J=4.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.86 (t, J=7.0 Hz, 1H), 7.49-7.41 (m, 1H), 7.18-7.12 (m, 2H), 6.94 (dd, J=28.4, 7.2 Hz, 2H), 6.82 (d, J=8.6 Hz, 1H), 6.10 (s, 1H), 5.06 (s, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.62 (dd, J=17.8, 9.6 Hz, 1H), 3.86 (t, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.72-3.63 (m, 2H), 3.47 (dd, J=17.6, 4.0 Hz, 1H), 3.28 (d, J=11.6 Hz, 1H), 3.05 (dd, J=13.2, 5.4 Hz, 1H), 2.40 (t, J=10.0 Hz, 1H), 2.19 (dd, J=21.4, 13.4 Hz, 3H), 2.04 (d, J=16.8 Hz, 3H), 1.92-1.84 (m, 3H), 1.79-1.69 (m, 2H), 1.47 (dd, J=23.6, 13.8 Hz, 2H).

[0153] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.1, 170.7, 170.3, 168.4, 164.3, 150.0, 148.2, 143 5, 137.3, 132.8, 132.2, 129.2, 128 4, 127.2, 126.3, 122.6, 61.8, 58.6, 56.3, 53.2, 52.2, 48.1, 46.8, 46.1, 42.9, 37.1, 36.2, 34.9, 29.8, 29.4, 26.8, 26.2, 25.9, 18.5

[0154] The product 19 is the two diastereomers separated, designated as 19-1 and 19-2.

[0155] Product 19-1

[0156] HRMS: Calcd for C.sub.30H.sub.36N.sub.5O.sub.6 [M+H.sup.+]: 562.2660; found: 562.2657.

[0157] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.21 (s, 1H), 8.59 (d, J=4.4 Hz, 1H), 8.24 (d, J=4.0 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.0 Hz, H), 7.46 (dd, J=6.8, 5.0 Hz, 1H), 7.15 (s, 2H), 7.01 (d, J=9.8 Hz, 3H), 4.84-4.71 (m, 1H), 4.27 (dd, J=14.6, 7.0 Hz, 1H), 4.13 (d, J=7.4 Hz, 1H), 3.76 (s, 3H), 3.62-3.53 (m, 2H), 3.46-3.35 (m, 3H), 2.95 (dd, J=10.4, 4.6 Hz, 1H), 2.73 (dd, J=14.2, 12.6 Hz, 1H), 2.61 (dd, J=11.2, 6.4 Hz, 1H), 2.51 (dd, J=14.4, 9.6 Hz, 1H), 2.44-2.33 (m, 1H), 2.14-2.01 (m, 2H), 1.94-1.82 (m, 2H), 1.80-1.60 (m, 3H), 1.58-1.44 (m, 1H).

[0158] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.2, 171.7, 170.5, 169.8, 164.4, 148.5, 148.2, 142.3, 137.4, 135.2, 130.4, 127.1, 126.6, 125.6, 122.7, 61.1, 52.8, 52.4, 52.1, 49.3, 46.5, 45.3, 45.2, 36.5, 31.0, 30.6, 26.9, 24.5, 22.1

[0159] Product 19-2

[0160] HRMS: Calcd for C.sub.30H.sub.36N.sub.5O.sub.6 [M+H.sup.+]: 1562.2660; found: 562.2659.

[0161] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.65 (d, J=8.8 Hz, 1H), 8.61 (d, J=4.4 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.51-7.43 (m, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.00 (s, 1H), 6.91 (s, 2H), 6.54 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 5.04 (d, J=9.0 Hz, 1H), 4.98 (s, 1H), 4.50 (dd, J=17.4, 8.8 Hz, 1H), 4.22 (dd, J=14.0, 7.0 Hz, 1H), 4.14 (s, 1H), 4.06-3.94 (m, 1H), 3.79 (s, 3H), 3.70 (dd, J=12.2, 6.6 Hz, 2H), 3.46 (dd, J=17.4, 3.8 Hz, 1H), 3.23 (d, J=11.4 Hz, 1H), 3.07 (dd, J=13.4, 5.6 Hz, 1H), 2.81-2.70 (m, 1H), 2.46 (dd, J=18.8, 10.8 Hz, 1H), 2.21-2.11 (m, 2H), 2.04 (d, J=7.6 Hz, 2H), 1.90 (dd, J=16.6, 6.21 Hz, 2H), 1.79-1.67 (m, 3H).

[0162] .sup.13C NMR (100 MHz, CDCl.sub.2) δ 172.2, 171.0, 170.2, 168.5, 164.3, 149.9, 148.3, 141.8, 137.4, 132.7, 126.1, 122.5, 60.7, 53.2, 51.3, 50.4, 47.8, 43.1, 37.1, 35.2, 32.0, 29.6, 25.5, 22.3.

[0163] Product 20

[0164] HRMS: Calcd for C.sub.26H.sub.31N.sub.3O.sub.4 [M+H.sup.+]: 478.2444; found: 478.2448.

[0165] .sup.1H NMR (400 MHz, Acetone) δ 8.79 (d, J=8.8 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.40 (d, J=4.4 Hz, 2H), 8.27 (s, 2H), 8.18 (d, J=7.7 Hz, 1H), 8.05 (dd, J=13.6, 6.0 Hz, 3H), 7.96 (d, J=7.6 Hz, 2H), 7.89 (t, J=7.2 Hz, 3H), 7.67-7.61 (m, 1H), 7.60-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.35-7.26 (m, 2H), 7.16 (s, 3H), 7.00 (d, J=6.8 Hz, 1H), 6.91 (d, J=7.6 Hz, 3H), 6.77 (d, J=7.2 Hz, 2H), 6.65 (t, J=7.6 Hz, 2H), 4.93-4.86 (m, 2H), 4.38 (d, J=8.4 Hz, 1H), 4.32 (dd, J=16.5, 8.8 Hz, 3H), 4.24-4.17 (m, 1H), 4.01 (dd, J=13.2, 6.6 Hz, 4H), 3.81-3.72 (m, 2H), 3.72-3.66 (m, 2H), 3.61-3.51 (m, 2H), 3.50-3.47 (m, 2H), 3.45-3.42 (m, 1H), 3.38 (dd, J=9.2, 4.9 Hz, 2H), 3.17-3.08 (m, 2H), 3.02-2.94 (m, 1H), 2.94-2.84 (m, 4H), 2.83 (s, 5H), 2.80 (s, 4H), 2.76-2.70 (m, 31H), 2.51 (d, J=5.2 Hz, 1H), 2.47 (d, J=4.8 Hz, 1H), 2.45-2.41 (m, 2H), 2.39 (d, J=2.2 Hz, 1H), 2.36 (d, J=2.2 Hz, 1H), 2.33-2.27 (m, 2H), 2.25-2.19 (m, 2.16-2.09 (m, 2H), 2.01-1.94 (m, 4H), 1.78 (t, J=12.9 Hz, 2H), 1.56 (dd, J=17.2, 10.3 Hz, 1H), 1.36 (d, J=7.2 Hz, 3H), 1.21 (d, J=6.8 Hz, 7H).

[0166] Product 21

[0167] HRMS: Calcd for C.sub.27H.sub.33N.sub.4O.sub.7 [M+H.sup.+]: 525.2344; found 525.2347.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 848 (d, J=8.8 Hz, 1H), 8.43 (s, 1H), 8.01 (d, J=7.4 Hz, 1H), 7.66 (t, J=7.6 Hz, 3H), 7.57 (d, J=6.8 Hz, 1H), 7.26-7.20 (m, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.04 (s, 1H), 7.02 (s, 1H), 7.01-6.99 (m, 1H), 6.67 (d, J=9.0 Hz, 1H), 6.57 (d, J=8.6 Hz, 1H), 5.11 (s, 1H), 4.96 (d, J=11.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.41 (s, 1H), 3.88 (t, J=10.0 Hz, 1H), 3.55 (s, 3H), 2.77 (d, J=12.8 Hz, 1H), 2.03 (dd, J=28.6, 16.0 Hz, 2H), 1.87 (d, J=6.4 Hz, 1H), 0.95 (d, J=5.6 Hz, 3H), 0.77 (dd, J=14.2, 6.0 Hz, 6H).

[0169] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 171.0, 164.7, 148.4, 141.4, 137.2, 133.9, 130.8, 129.9, 128.6, 127.3, 126.3, 122.3, 109.9, 77.3, 77.0, 76.7, 58.4, 56.6, 53.0, 50.8, 42.1, 37.6, 32.3, 19.1, 18.3, 18.2.

[0170] Product 22

[0171] HRMS: Calcd for C.sub.34H.sub.40N.sub.5O.sub.6 [M+H.sup.+]: 614.2973; found: 614.2977.

[0172] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.78 (d, J=6.8 Hz, 1H), 8.64-8.51 (m, 3H), 8.09 it, J=6.8 Hz, 2H), 7.91-7.79 (m, 4H), 7.76 (s, 1H), 7.61 (s, 1H), 7.49 (s, 2H), 7.47-7.41 (m, 2H), 7.38 (d, J=3.4 Hz, 2H), 7.19 (dd, J=19.0, 6.6 Hz, 6H), 7.11 (d, J=5.4 Hz, 4H), 6.72 (d, J=6.0 Hz, 1H), 6.47 (s, 1H), 6.15 (s, 1H), 6.06 (s, 1H), 4.70 (d, J=5.2 Hz, 1H), 4.64 (s, 3H), 4.50 (s, 1H), 4.36 (s, 1H), 3.72 (s, 3H), 3.71 (s, 2H), 3.41 (d, J=9.2 Hz, 1H), 3.17 (d, J=13.8 Hz, 4H), 2.96 (ddd, J=21.6, 20.8, 14.0 Hz, 4H), 2.82 (dd, J=13.6, 7.6 Hz, 1H), 2.64 (d, J=11.4 Hz, 3H), 2.42 (s, 1H), 2.02 (s 3H), 1.88 (s, 1H), 1.45 (d, J=12.8 Hz, 8H), 1.04 (d, J=6.2 Hz, 3H), 0.44 (d, J=5.6 Hz, 2H).

[0173] Product 23

[0174] HRMS: Calcd for C.sub.44H.sub.50N.sub.5O.sub.9 [M+H.sup.+]: 792.3603; found: 792.3604.

[0175] .sup.1H NMR (410 MHz, DMSO) δ 8.73-8.66 (m, 2H), 8.57 (t, J=9.6 Hz, 2H), 8.09-8.01 (m, 2H), 7.68-7.62 (m, 1H), 7.42-7.25 (m, 1H), 7.19 (t, J=7.6 Hz, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 5.35 (d, J=13.6 Hz, 1H), 5.20-5.11 (m, 2H), 4.97 (s, 2H), 4.88 (t, J=10.9 Hz, 2H), 4.67-4.59 (m, 2H), 2.97-2.86 (m, 2H), 2.74 (d, J=10.4 Hz, 1H), 2.61-2.53 (m, 2H), 2.29-2.17 (m, 1H), 2.13 (s, 1H), 2.11-1.94 (m, 1H), 1.84-1.73 (m, 1H), 1.62 (d, J=7.6 Hz, 1H), 1.48 (dd, J=13.6, 7.2 Hz, 1H), 1.35-1.26 (m, 4H), 0.85 (d, J=56 Hz, 3H),

[0176] .sup.13C NMR (101 MHz, DMSO) δ 172.0, 171.8, 171.5, 170.6, 163.3, 156.1, 149.2, 148.7, 140.9, 138.2, 137.3, 136.6, 135.9, 128.7, 128.5, 128.4, 128.2, 128.0, 127.8, 127.0, 126.0, 124.2, 121.9, 66.3, 65.1, 64.6, 55.8, 51.8, 50.0, 41.1, 36.4, 33.2, 31.4, 29.4, 29.2, 29.1, 28.8, 26.1, 22.5, 16.7.

[0177] Product 25

[0178] HRMS: Calcd for C.sub.31H.sub.42N.sub.7O.sub.5 [M+H.sup.+]: 592.3242; found: 592.3242.

[0179] .sup.1H NMR 6M MHz, CDCOOD) δ 8.62 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.87 (dd, J=15.0, 7.4 Hz, 1H), 7.50 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.99 (s, 2H), 6.83 (d, J=7.6 Hz, 1H), 4.96 (d, J=9.2 Hz, 1H), 4.80 (d, J=9.2 Hz, 1H), 4.28 (s, 1H), 4.19 (s, 1H), 4.10 (s, 1H), 3.63 (d, J=24.6 Hz, 1H), 3.59-3.52 (m, 1H), 3.48 (s, 1H), 3.29 (d, J=12.0 Hz, 1H), 3.04 (d, J=10.2 Hz, 1H), 2.94 (s, 3H), 2.72 (t, J=12.4 Hz, 2H), 2.63-2.56 (m, 1H), 2.50-2.38 (m, 1H), 2.27-2.17 (m, 1H), 2.08 (dd, J=18.8, 4.8 Hz, 1H), 1.62 (s, 4H), 1.48 (s, 3H), 1.27 (d, J=6.4 Hz, 3H), 1.09 (d, J=8.0 Hz, 3H).

[0180] Product 26

[0181] HRMS: Calcd for C.sub.30H.sub.38N.sub.7O.sub.6 [M+H.sup.+]: 592.2878; found: 592.2879.

[0182] .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.78 (d, J=4.0 Hz, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 8.02 (d, J=4.0 Hz, 2H), 7.64 (s, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.24 (d, J=6.6 Hz, 2H), 7.15 (d, J=7.6 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.0 Hz, 2H), 6.97 (d, J=72 Hz, 1H), 4.84 (s, 1H), 4.76-4.70 (m, 1H), 4.37 (s, 1H), 4.23-4.19 (m, 1H), 4.05 (d, J=6.2 Hz, 1H), 3.96 (s, 1H), 3.76 (dd, J=17.2, 7.2 Hz, 2H), 3.57 (dd, J=19.2, 11.4 Hz, 1H), 3.41-3.35 (m, 2H), 3.20-3.15 (m, 2H), 3.08 (dd, J=1.6, 6.2 Hz, 2H), 2.85 (d, J=17.6 Hz, 2H), 2.79 (t, J=13.6 Hz, 1H), 2.71 (s, 2H), 2.60 (s, 3H), 2.35-2.15 (m, 11H), 2.10-2.00 (m, 3H), 1.93 (d, J=5.6 Hz, 2H), 1.41 (d, J=6.8 Hz, 3H), 1.21 (d, J=7.2 Hz, 3H)

[0183] Product 27

[0184] HRMS: Calcd for C.sub.29H.sub.37N.sub.6O.sub.6, [M+H.sup.+]: 565.2769; found: 565.2772.

[0185] .sup.1H NMR (400 MHz, DMSO) δ 8.75 (d, J=4.4 Hz, 1H), 8.67 (d, J=8.8 Hz, 1H), 8.07 (t, J=9.4 Hz, 2H), 7.67 (s, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 6.98 (s, 4H), 6.29 (s, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.77 (d, J=8.8 Hz, 1H), 4.41-4.21 (m, 2H), 4.09 (s, 2H), 3.65 (s, 2H), 3.00 (d, J=9.6 Hz, 1H), 2.89 (s, 1H), 2.59 (d, J=10.6 Hz, 1H), 2.34 (d, J=9.6 Hz, 1H), 2.00 (s, 4H), 1.87 (s, 1H), 1.78 (s, 1H), 1.33 (d, J=6.8 Hz, 3H), 0.85 (d, J=48 Hz, 3H)

[0186] Product 28

[0187] HRMS: Calcd for C.sub.31H.sub.42N.sub.9O.sub.3 [M+H.sup.+]: 620.3303; found: 620.3307.

[0188] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.74 (d, J=7.6 Hz, 2H), 8.54 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 8.02-7.96 (m, 2H), 7.66-7.57 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.22-7.02 (m, 6H), 6.95 (d, J=76 Hz, 1H), 4.82 (s, 1H), 4.72 (d, J=4.8 Hz, 1H), 4.34 (t, J=72 Hz, 1H), 4.25 (s, 1H), 4.05 (d, J=6.8 Hz, 1H), 3.92 (s, 1H), 3.74 (s, 2H), 3.61-3.53 (m, 1H), 3.40-3.33 (m, 1H), 3.24-3.08 (m, 7H), 2.90-2.90 (m, 1H), 2.84 (d, J=14.0 Hz, 1H), 2.80-2.65 (m, 3H), 2.60-2.52 (m, 3H), 2.10-1.99 (m, 4H), 1.98-1.89 (m, 4H), 1.86 (d, J=5.6 Hz, 2H), 1.61-1.47 (m, 5H), 1.39 (d, J=6.4 Hz, 3H), 1.20 (d, J=72 Hz, 3H).

[0189] Product 29

[0190] HRMS: Calcd for CH.sub.34H.sub.45N.sub.8O.sub.7 [M+H.sup.+]: 677.3406; found: 677.3406.

[0191] .sup.1H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.77 (d, J=4.6 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.98-7.91 (m, 2H), 7.69-7.64 (m, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 7.14-7.07 (m, 1H), 7.04 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 4.21-4.12 (m, 1H), 3.95 (d, J=8.4 Hz, 1H), 3.77 (d, J=5.4 Hz, 1H), 3.37 (d, J=6.4 Hz, 1H), 2.96 (d, J=11.0 Hz, 3H), 2.62 (t, J=12.6 Hz, 1H), 2.41 (t, J=6.4 Hz, 2H), 2.34 (dd, J=14.8, 7.6 Hz, 1H), 2.01 (s, 3H), 1.88-1.75 (m, 2H), 1.35 (d, J=6.6 Hz, 1H), 1.07 (dd, J=13.8, 8.4 Hz, 1H), 0.95 (m, 1H), 0.88 (s, 9H)

[0192] Product 30

[0193] HRMS: Calcd for C.sub.54H.sub.80N.sub.17O.sub.13 [M+H.sup.+]: 1174.6116; found: 1174.6118.

[0194] .sup.1H NMR (60 MHz, CD.sub.3OD, 6:1 mixture of diastereoisomers) δ 8.68-8.65 (m, 1H), 8.51 (s, 2H), 8.14-8.09 (m, 1H), 8.02-7.98 (m, 1H), 7.61 (dd, J=7.2, 5.2 Hz, 1H), 7.19 (s, 3H), 7.17 (d, J=4.8 Hz, 1H), 5.35 (dd, J=12.4, 7.6 Hz, 1H), 5.01 (d, J=4.8 Hz, 1H), 4.62 (dd, J=8.4, 4.0 Hz, 1H), 4.55-4.52 (m, 1H), 4.47-4.39 (m, 3H), 4.38-4.31 (m, 2H), 4.10 (t, J=13.2 Hz, 1H), 4.03-3.90 (m, 4H), 3.86-3.82 (m, 2H), 3.78-3.71 (m, 2H), 3.70-3.58 (m, 3H), 3.35 (s, 2H), 3.24-3.19 (m, 2H), 3.14-3.11 (m, 2H), 3.02-2.94 (m, 2H), 2.94-2.89 (m, 3H), 2.40-2.28 (m, 5H), 2.21 (m, 4H), 2.16-2.07 (m, 3H), 2.02 (m, 5H), 1.96-1.82 (m, 5H), 1.77 (dd, J=13.6, 5.6 Hz, 1H), 1.70 (dd, J=14.8, 8.0 Hz, 4H), 1.67-1.59 (m, 3H), 1.42 (dd, J=27.6, 4.4 Hz, 2H), 1.36-1.31 (m, 2H), 0.91 (d, J=7.2 Hz, 3H).

[0195] Product 31

[0196] HRMS: Calcd for C.sub.27H.sub.30N.sub.5O.sub.6 [M+H.sup.+]: 520.2202; found: 520.2200.

[0197] .sup.1H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.01 (t, J=7.2 Hz, 1H), 7.67-7.58 (m, 1H), 7.25-7.04 (m, 3H), 6.77 (s, 1H), 4.78 (d, J=5.6 Hz, 2H), 4.28 (dd, J=17.2, 2.4 Hz, 1H), 4.17 (d, J=6.4 Hz, 1H), 3.72 (s, 2H), 3.49 (d, J=17.2 Hz, 1H), 3.35 (s, 3H), 3.25 (d, J=13.2 Hz, 1H), 3.03 (dd, J=13.2, 5.2 Hz, 1H), 2.78 (dd, J=23.6, 10.4 Hz, 2H), 2.46-2.34 (m, 1H), 2.21-2.16 (m, 2H), 2.06-1.92 (n, 2H), 1.91-1.82 (m, 1H), 1.36 (d, J=5.2 Hz, 3H)

[0198] Product 32

[0199] HRMS: Calcd for C.sub.31H.sub.44N.sub.9O.sub.5 [M+H.sup.+]: 622.3460. found 622.3458.

[0200] .sup.1H NMR (400 MHz, DMSO) δ 8.72 (d, J=4.4 Hz, 1H), 8.67-8.59 (m, 2H), 8.56 (d, J=8.0 Hz, 1H), 8.06 (q, J=7.6 Hz, 2H), 7.71-7.64 (m, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.12 (t, J=7.6 Hz, 2H), 7.00 (s, 1H), 6.99-6.93 (m, 2H), 6.92 (s, 1H), 4.81 (d, J=9.2 Hz, 1H), 4.54 (t, J=6.4 Hz, 1H), 4.45 (dd, J=14.0, 7.2 Hz, 1H), 4.26-4.17 (m, 1H), 3.12 (d, J=6.4 Hz, 2H), 2.96 (d, J=8.8 Hz, 2H), 2.65 (d, J=12.0 Hz, 1H), 2.28 (m, 1H), 2.16-1.99 (m, 2H), 1.61 (s, 2H), 1.52-1.39 (m, 2H), 0.88 (s, 3H), 0.87 (s, 3H), 0.82 (d, J=64 Hz, 3H).

[0201] Product 33

[0202] HRMS: Calcd for C.sub.37H.sub.50N.sub.11O.sub.9 [M+H.sup.+]: 792.3787; found: 792.3787.

[0203] .sup.1H NMR (600 MHz, DMSO,) δ 8.70 (dd, J=9.2, 7.8 Hz, 2H), 8.13 (s, 3H), 8.08 (d, J=7.8 Hz, 2H), 8.06-4.01 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.65 (dd, J=9.0, 3.0 Hz, 1H), 7.58 (s 1H), 7.42 (s, 1H), 7.26 (s, 1H), 7.13 (d, J=7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.84 (s, 1H), 4.88 (d, J=10.8 Hz, 1H), 4.62 (dd, J=14.4, 7.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.39 (d, J=9.6, 3.6 Hz, 1H), 4.08 (q, J=66 Hz, 1H), 3.93 (dd, J=17.4, 6.0 Hz, 1H), 3.15-3.07 (m, 4H), 2.99 (t, J=11.4 Hz, 2H), 2.77 (dd, J=14.4, 9.6 Hz, 1H), 2.58-2.53 (m, 1H), 2.34-2.25 (m, 2H), 2.13 (s, 2H), 1.94 (t, J=11.4 Hz, 1H), 1.88-1.82 (m, 4H), 1.69-1.67 (m, 1H), 1.60-1.58 (m, 3H), 1.49-1.45 (m, 1H), 0.89 (d, J=6.6 Hz, 3H).

[0204] Product 34

[0205] HRMS: Calcd for C.sub.37H.sub.41N.sub.14O.sub.11 [M+H.sup.+]: 1161.7143; found: 1161.7143. The product 34 is unseparated diastereomers in a ratio of 2:1.

[0206] Product 35

[0207] HRMS: Calcd for C.sub.37H.sub.41N.sub.4O.sub.7 [M+H.sup.+]: 653.2970; found: 653.2969.

[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.83-7.77 (m, 2H), 7.68-7.62 (m, 2H), 7.40 (ddd, J=24.4, 15.2, 7.2 Hz, 5H), 7.06 (d, J=6.8 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 6.75 (d, J=6.0 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.18 (dd, J=9.2, 3.6 Hz, 1H), 5.17 (d, J=80 Hz, 1H), 4.99 (dd, J=7.2, 4.8 Hz, 1H), 4.65 (dd, J=10.8, 6.4 Hz, 1H), 4.57 (dd, J=17.6, 9.2 Hz, 1H), 4.37 (dd, J=10.8, 6.0 Hz, 1H), 4.22 (dd, J=13.6, 7.2 Hz, 2H), 3.87 (t, J=7.6 Hz, 1H), 3.60 (s, 3H), 3.57-3.52 (m, 1H), 3.47 (dd, J=17.6, 4.0 Hz, 1H), 3.20 (dd, J=13.4, 2.2 Hz, 1H), 3.03 (dd, J=13.2, 5.6 Hz, 1H), 2.73 (dd, J=14.2, 4.0 Hz, 1H), 2.58-2.46 (m, 1H), 2.23-2.04 (m, 3H), 2.00-1.91 (m, 1H), 1.84 (dd, J=18.4, 7.6 Hz, 1H), 1.31 (d, J=7.6 Hz, 3H).

[0209] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.0, 170.8, 170.2, 168.7, 164.4, 149.9, 148.2, 137.9, 137.4, 132.2, 130.3, 129.3, 128.0, 127.8, 126.3, 125.1, 124.8, 120.1, 77.4, 77.1, 76.8, 61.2, 55.3, 53.0, 52.1, 48.0, 43.0, 39.2, 37.6, 37.1, 29.7, 25.8, 23.1.

[0210] Product 36

[0211] HRMS: Calcd for C.sub.40H.sub.53N.sub.6O.sub.8 [M+H.sup.+]: 745.3919; found 745.3919.

[0212] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.13 (d, J=6.4 Hz, 1H), 8.13 (s, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.28 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.20 (dd, J=11.6, 6.6 Hz, 2H), 6.93 (d, J=6.8 Hz, 2H), 6.85 (d, J=7.2 Hz, 3H), 6.63 (d, J=5.6 Hz, 1H), 4.88 (dd, J=13.8, 5.8 Hz, 1H), 1.75 (d, J=4.0 Hz, 1H), 4.32-4.23 (m, 1H), 4.11-4.04 (m, 1H), 3.94-3.88 (m, 2H), 3.75 (s, 3H), 3.60 (dd, J=22.0, 10.0 Hz, 2H), 3.45 (dd, J=13.6, 4.8 Hz, 1H), 3.08 (dd, J=23.6, 9.2 Hz, 3H), 2.85 (dd, J=14.0, 1.12 Hz, 1H), 2.77-2.62 (m, 3H), 2.59-2.45 (m, 4H), 1.82 (s, 1H), 1.68-1.60 (m, 2H), 1.38-1.19 (m, 4H), 0.92 (d, J=7.2 Hz, 3H), 0.79 (d, J=5.6 Hz, 3H), 0.69 (d, J=5.6 Hz, 3H).

[0213] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 180.0, 174.6, 173.0, 172.6, 170.7, 170.5, 169.1, 137.9, 134.8, 129.6, 129.3, 128.4, 126.8, 77.4, 77.1, 76.8, 61.3, 58.6, 54.8, 54.3, 53.9, 52.9, 52.4, 45.6, 40.0, 38.0, 37.8, 35.6, 35.1, 29.5, 25.3, 25.1, 22.8, 21.7, 16.1

[0214] Product 37.

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (d, J=7.7 Hz, 1H), 8.59 (d, J=4.7 Hz, 1H), 7.66 (t, J=7.0 Hz, 11H), 7.49 (d, J=7.7 Hz, 1H), 7.47-7.38 (m, 1H), 7.25 (s, 1H), 7.21-7.12 (m, 5H), 7.06 (d, J=4.5 Hz, 1H), 6.96 (d, J=7.6 Hz, 2H), 6.71 (d, J=6.7 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 5.47 (s, 1H), 5.24 (s, 1H), 4.97-4.85 (m, 2H), 4.51 (dd, J=14.7, 7.7 Hz, 1H), 4.06-3.97 (m, 1H), 3.68 (d, J=7.8 Hz, 1H), 3.66-3.58 (m, 1H), 3.46 (dd, J=15.2, 3.2 Hz, 1H), 3.34-3.22 (m, 3H), 3.04 (dd, J=15.9, 10.0 Hz, 3H), 2.38 (dd, J=12.1, 5.9 Hz, 1H), 2.00 (s, 1H), 1.86 (s, 2H), 1.80-1.66 (m, 2H), 1.59 (s, 2H), 1.35 (d, J=7.5 Hz, 2H), 1.33 (s, 1H), 0.85 (d, J=7.0 Hz, 1H), 0.72 (d, J=6.1 Hz, 3H), 0.67 (d, J=6.2 Hz, 3H).

[0216] Product 38.

[0217] .sup.1H NMR (400 MHz, Acetone) δ 8.6-8.54 (m, 2H), 8.10-8.02 (m, 2H), 7.97 (id, J=7.6, 1.6 Hz, 1H), 7.85-7.78 (m, 1H), 7.61-7.57 (m, 1H), 7.57-7.54 (m, 1H), 7.50 (td, J=7.2, 1.6 Hz, 2H), 7.38 (dd, J=7.2, 1.6 Hz, 1H), 7.21 (s, 4H), 6.97 (d, J=7.2 Hz, 1H), 5.69-5.64 (m, 1H), 4.60-4.55 (m, 1H), 4.45-4.33 (m, 2H), 4.03 (d, J=8.4 Hz, 1H), 3.74 (s, 3H), 3.72-3.65 (m, 1H), 3.54-3.45 (m, 3H), 3.24 (dd, J=13.6, 5.2 Hz, 1H), 3.07-3.02 (m, 1H), 1.96-1.71 (m, 4H).

[0218] Product 39: HRMS: Calcd C.sub.27H.sub.34N.sub.5O.sub.7 [M+H.sup.+]: 540.2453; found: 540.2455.

[0219] Product 40 HRMS: Calcd for C.sub.27H.sub.33N.sub.6O.sub.5 [M+H.sup.+]: 537.2456; found: 53.72459.

[0220] Product 41 HRMS: Calcd for C.sub.22H.sub.33N.sub.6O.sub.8 [M+H.sup.+]: 581.2354; found: 581.2353.

[0221] Product 42: HRMS: Calcd for C.sub.25H.sub.34N.sub.5O.sub.7 [M+H.sup.+]: 516.2453; found 516.2457.

[0222] Product 43

[0223] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (d, J=7.6 Hz, 1H), 8.62 (d, J=4.4 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.44 (dd, J=12.8, 6.6 Hz, 2H), 7.37 (d, J=7.4 Hz, 1H), 7.25 (s, 2H), 7.22 (d, J=3.4 Hz, 2H), 7.02 (t, J=10.0 Hz, 4H), 6.83 (s, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.22 (s, 1H), 5.55 (s, 1H), 4.90 (s, 1H), 4.78 (d, J=7.8 Hz, 1H) 4.08 (t, J=8.4 Hz, 1H), 3.04 (s, 1H), 3.88 (d, J=7.6 Hz, 1H), 3.64 (dd, J=20.6, 9.8 Hz, 1H), 3.55 (d, J=13.2 Hz, 1H), 3.46 (d, J=13.4 Hz, 1H), 3.33 (t, J=10.0 Hz, 2H), 3.26-3.09 (m, 3H), 3.04 (dd, J=13.6, 5.8 Hz, 1H), 2.68 (dd, J=14.2, 3.8 Hz, 1H), 2.55 (s, 1H), 2.30 (dd, J=11.8, 6.4 Hz, 1H), 2.23 (t, J=7.2 Hz, 2H, 1.90 (dd, J=12.4, 6.6 Hz, 1H), 1.86-1.74 (m, 1H), 1.61 (d, J=14.4 Hz, 3H), 1.59-1.48 (m, 3H), 1.48-1.40 (m, 3H), 1.36 (s, 3H), 1.10 (d, J=7.0 Hz, 3H), 0.81 (d, J=5.8 Hz, 3H), 0.73 (d, J=5.8 Hz, 3H).

[0224] Product 44

[0225] .sup.1H NMR (40) MHz, CDCl.sub.3) δ 8.60 (d, J=4.4 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.83 (dd, J=8.4, 7.2 Hz, 1H), 7.44 (dd, J=6.8, 5.2 Hz, 1H), 7.17 (dd, J=16.0, 7.2 Hz, 2H), 7.05 (s, 2H), 6.91 (d, J=7.8 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 5.07-5.00 (m, 1H), 3.89 (s, 3H), 3.87-3.81 (m, 2H), 3.80-3.71 (m, 1H), 3.64-3.46 (m, 2H), 3.37 (dd, J=14.3, 4.3 Hz, 1H), 3.19 (t, J=13.6 Hz, 1H), 3.13-3.01 (m, 2H), 2.81-2.71 (m, 1H), 2.67 (dd, J=20.0, 8.7 Hz 2H), 2.30 (d, J=13.1 Hz, 1H), 2.08 (s, 1H), 2.02-1.92 (m, 1H), 1.87-1.79 (m, 2H), 1.12 (d, J=68 Hz, 3H).

[0226] The above are only the preferred embodiments of the present invention. It should be noted that improvements and modifications can be made by those of ordinary skill in the art without departing from the principle of the present invention, which should also be regarded as falling within the protection scope of the present invention.