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Cyclic peptide compounds

Imported: 13 Feb '17 | Published: 18 Jan '11

Masahiro Neya, Seiji Yoshimura, Kazunori Kamijyo, Takuya Makino, Minoru Yasuda, Toshio Yamanaka, Eisaku Tsujii, Yukiko Yamagishi

USPTO - Utility Patents

Abstract

The present invention relates to a new cyclic peptide compound or a salt thereof, which has anti-hepatitis C virus activities based on inhibitory activity against the RNA replication of hepatitis C virus replicon, to a process for preparation thereof comprising a rearrangement reaction under a mild acidic condition and the following amino acid changing reactions etc., to a pharmaceutical composition comprising the same, and to a method for prophylactic and/or therapeutic treatment of hepatitis C in a human being or an animal.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is an national phase application based on PCT/JP2006/321924, filed Oct. 26, 2006, and claims the benefit of U.S. Provisional Application Nos. 60/730,011, filed Oct. 26, 2005; and 60/751,204, filed Dec. 19, 2005, the contents of each of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a new cyclic peptide compound or a salt thereof having inhibitory activity against the RNA replication of hepatitis C virus (hereafter referred to as HCV) replicon. In particular, the present invention relates to a new cyclic peptide compound or a salt thereof, to a process for preparation thereof, to a pharmaceutical composition comprising the new cyclic peptide compound or a salt thereof, and to a method for the prophylactic and/or therapeutic treatment of hepatitis C in a human being or animal.

BACKGROUND ART

The estimated number of HCV carriers is about 170 million worldwide (about 3%) and about 1.5 million in Japan. Even in the combination therapy of using interferon (hereafter referred to as IFN) and ribavirin (Virazole), available as a first option for treatment, its effectiveness is 40% for all types of HCV. Furthermore, its effectiveness is only 15 to 20% for IFN-resistant virus (genotype 1b), particularly abundantly found in Japan. On the other hand, the combination therapy has side effects frequently. It is thus difficult to get rid of the virus completely by using currently available treatment methods. In the case when chronic hepatitis cannot be cured completely, the hepatitis will securely develop into cirrhosis hepatitis (30%) or hepatocellular carcinoma (25%). In Europe and the United States, hepatitis C has been a major indication for liver transplant. However, the redevelopment of HCV occurs frequently even in transplanted livers. For these reasons, the needs for new agents being improved in both effectiveness and safety, having higher antiviral effects and capable of inhibiting hepatitis C are very strong in society.

HCV is a virus having plus-strand RNA as a gene and is classified into Flaviviridae in accordance with the analysis of the base sequence of the gene. According to Fields Virology fourth edition, D. Knipe et al ed., Philadelphia, Lippincott Williams & Wilkins 2001, 1127-1161, although the existence of HCV was anticipated in 1970s, the discovery of HCV was very difficult. HCV was called non-A non-B hepatitis virus for many years. In 1989, according to Choo Q-L et al., Science 244, 359-362 (1989), part of the gene of this virus was cloned from the serum of an infected laboratory animal, and its cDNA sequence was identified and confirmed, whereby the virus was named “HCV.”

DISCLOSURE OF THE INVENTION

Cyclosporin A is used as an immunosuppressant for organ transplant. M. Thali et al., Nature 372, 363-365 (1994) reported that Cyclosporin A had anti-HIV activity by inhibiting the interaction between Cyclosporin A and the virus particle forming protein of Human Immunodeficiency Virus Type 1 (HIV-1). R. M. Wenger et al. reported in WO00/01715 that their novel cyclosporins has the anti-HIV activity. Furthermore, K. Inoue et al., 6th International Symposium on Hepatitis. C and Related Virus, 3-6. June (2000) Bethesda, Md., USA reported that Cyclosporin A had an anti-HCV activity, however, reports for supporting this finding are not presented by other groups up until now. And HIJIKATA et al. reported in WO2005/021028 that their modified cyclosporins have the anti-HCV activity.

M. Berenguer et al., J. Hepatol 32, 673-684 (2000) reported that the clinical use of Cyclosporin A serving as an immunosuppressant caused. HCV to multiply in transplant patients.

Hence, an anti-hepatitis C agent improved in the activity, transition in blood, selectivity and the side effects, for example, in comparison with Cyclosporin A, has been demanded because of the above-mentioned reasons.

Further, in order to convert the skeleton of the Cyclosporine compounds, it needs some severe conditions such as high temperature or high pressure. On the other hand, the conversion of the starting compound (FR901459 compound) to our compounds by a rearrangement reaction in the present invention needs the mild acidic condition because of the hydroxyl group on the 2-position of the starting compound.

The object cyclic peptide compound in the present invention is a new compound, and can be represented by the following general formula (I):

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wherein

X is

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    • in which
    • R1 is hydrogen or lower alkyl;
    • R2 is hydrogen, aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
      • hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, optionally substituted carbamoyloxy, and optionally substituted amino;
    • and

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is N-containing heterocyclic group;

Y is

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    • in which
    • R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
      • hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen-atom to which they attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
    • and
    • R4 and R5 are each independently hydrogen or lower alkyl;

and

custom character represents single bond or double bond;

or a salt thereof,

with proviso,

when R2 is hydrogen, R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, lower alkoxymethyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower)alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoky, optionally substituted amino and —OC(O)NR6R7 (wherein R6 and R7 are each as defined above).

Preferred embodiments of the object compound (I) are as follows.

1) The compound of the general formula (I),

wherein

    • X is

embedded image

      • in which
        • R1 is hydrogen or lower alkyl;
        • and
        • R2 is aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
          • hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
          •  lower alkyl, benzyloxycarbonyl and t-butoxycarbonyl;
    • and
    • Y is

embedded image

      • in which
        • R3 is cyclo(lower)alkyl, aryl, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of
          • hydroxy, lower alkoxy, and aryl(lower)alkoxy;
        • R4 is hydrogen;
        • and
        • R5 is lower alkyl;

or a salt thereof.

2) The compound of 1),

wherein

    • R1 is lower alkyl;
    • R2 is lower alkyl;
    • Y is

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      • in which
        • R3 is aryl or lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
        • R4 is hydrogen;
        • and
        • R5 is lower alkyl;
    • and
    • custom character moiety is double bond;

or a salt thereof.

3) The compound of 2),

wherein

    • R3 is lower alkyl which is optionally substituted by hydroxy or lower alkoxy;

or a salt thereof.

4) The compound of the general formula (I),

wherein

    • X is

embedded image

      • in which
        • R1 is lower alkyl;
        • and
        • R2 is hydrogen;
    • and
    • Y is

embedded image

      • in which
        • R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, (lower)alkoxy(lower)alkyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower)alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
          • hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
          •  lower alkyl and benzyloxycarbonyl;
        • and
        • R4 and R5 are each independently hydrogen or lower alkyl;

or a salt thereof.

5) The compound of 4),

wherein

    • Y is

embedded image

      • in which
        • R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, t-butyl, sec-butyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
          • hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
        • R4 is hydrogen
        • and
        • R5 is lower alkyl;
    • and
    • custom character moiety is double bond;

or a salt thereof.

6) The compound of the general formula (I),

wherein

    • X is

embedded image

    • and
    • Y is

embedded image

      • in which
        • R3 is lower alkyl;
        • and
        • R4 and R5 are each independently hydrogen or lower alkyl;

or a salt thereof.

7) The compound of 6),

wherein

    • X is

embedded image

    • R4 is hydrogen;
    • R5 is lower alkyl;
    • and
    • custom character moiety is double bond;

or a salt thereof.

The compound (I) or a salt thereof in the present invention can be prepared by the processes as illustrated in the following reaction schemes.

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The starting compounds or a salt thereof in the present invention can be prepared, for example, by the processes as illustrated in the following reaction schemes.

embedded image

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wherein
X and Y are as defined above,
L is a leaving group,
P is amino protective group,
R′ is methoxy or

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R″ is H or

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and
n in the “n times” is 2 or 3.

The processes for the preparation of the object compounds and the starting compounds are described below.

Process 1

The object compound (Ia) or a salt thereof can be prepared from the compound (IIa) or a salt thereof by the following processes.

a) Introduction of Protected Amino Acid

    • This reaction is the amidation of the compound (IIa) with the compound (V).
    • Usually, the compound (V) is carboxylic acid (L is OH) or the reactive derivative thereof (including an acyl halide (e.g., carbonyl chloride, carbonyl bromide, and the like), an acid anhydride, an activated ester (e.g., vinyl ester, propargyl ester, 2,4-dinitrophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, dimethyliminomethyl ester, p-nitrophenyl thioester, an activated ester with a N-hydroxy compound (such as N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like), and the like), or the like).
    • When the compound (V) is a free carboxylic acid compound, the reaction is preferably carried out in the presence of condensing agent (including carbodiimide (e.g., N,N-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, and the like), diphenylphosphinic azido, diphenylphosphonic chloride, or the like).
    • And this reaction in the present reaction is usually carried out in the presence of an additive such as N-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolydinyl)phosphinic chloride, and the like.
    • The reaction may be also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
    • The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol (e.g., methanol, ethanol, isopropyl alcohol, or the like), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction or the mixture thereof.
    • The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.

b) Deprotection

    • This reaction is elimination reaction of amino protective group of the compound (IIIa) or a salt thereof. And this reaction is also the reaction of methyl ester moiety of the compound (IIIa) or the salt thereof to carboxylic acid.
    • These two reactions are carried out at once (for example, referred to Preparation 68 or 161 described later) or in two divisional reactions (for example, referred to Preparations 7 and 171 or 153 and 169 described later) according to the reaction substrate or the reaction condition.

c) cyclization

    • This cyclization is carried out by the amidation of the compound (IVa), so this reaction can be carried out in the same manner as in the aforementioned Process 1-a), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1-a).
      Process 2

The object compound (Ib) or a salt thereof can be prepared from the compound (IIb) by a series of reaction that contains introduction of protected amino acid, deprotection and cyclization as illustrated aforementioned. And each reaction can be carried out in the same manner as in the aforementioned Process 1, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1.

Process 3

The object compound (Ic) or a salt thereof can be prepared from the compound (IIc) by a series of reaction that contains introductions of protected amino acid and deprotection reactions each twice, and cyclization as illustrated aforementioned. And each reaction can be carried out in the same manner as in the aforementioned Process 1, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1.

Process 4

The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) to catalytic hydrogenation.

Suitable catalysts to be used in the catalytic hydrogenation are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), and the like.

The hydrogenation is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process A

The compound (IX) or a salt thereof can be prepared from the compound (VII) or a salt thereof by the following processes.

a) Rearrangement

    • This reaction is the rearrangement of the compound (VII).
    • The reaction is usually carried out in the presence of acid (such as trifluoroacetic acid, sulfuric acid, methanesulfonic acid, or the like).
    • The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol (e.g., methanol, ethanol, isopropyl alcohol, or the like), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction or the mixture thereof.
    • The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.
    • This reaction of the present invention, because of and owing to the substrate, can be carried out under the mild condition such as mild acid (p-toluenesulfonic acid) and mild temperature (ambient temperature to warming) to give a compound selectively subjected the rearrangement reaction.

b) Amino Protection

    • This reaction is protection of amino moiety, which goes out by the rearrangement reaction.
    • The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, or the like), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction or the mixture thereof.
    • The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.
    • These series of reactions (a) rearrangement and b) amino protection) can be carried out by the method disclosed in Preparation 156 mentioned later or the similar manners thereto.

c) Hydrolysis

    • The compound (IX) or a salt thereof can be prepared, from the compound (VIII) or a salt thereof by hydrolysis.
    • The hydrolysis is preferably carried out in the presence of a base (including an inorganic base and organic base such as alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate of alkali metal or alkaline earth metal, trialkylamine (e.g., trimethylamine, etc.), hydrazine, picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like) or an acid (including an organic acid (e.g., formic acid, acetic acid, propanoic acid, trifluoroacetic acid, etc.), an inorganic acid (e.g., hydrobromic acid, sulfuric acid, hydrochloric acid, etc.) and Lewis acid (e.g., boron tribromide, aluminum chloride, titanium trichloride, etc.)).
    • The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvent which does not adversely affect the reaction or the mixture thereof.
    • A liquid base or acid can be also used as the solvent.
    • The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.
    • This reaction can be carried oUt by the method disclosed in Preparation 167 mentioned later or the similar manners thereto.
      Process B

The compound (II) or a salt thereof can be prepared from the compound (IX) or a salt thereof by the following processes.

a) Reaction with (X)

    • This reaction is the amidation of the compound (IX) with the compound (X), so this reaction can be carried out in the same manner as in the aforementioned Process 1-a), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1-a).
    • This reaction can be carried out by the method disclosed in Preparation 90 mentioned later or the similar manners thereto.

b) Deprotection

    • This reaction can be carried out in the same manner as in the aforementioned Process 1-b), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1-b).
    • This reaction can be carried out by the method disclosed in Preparation 152 mentioned later or the similar manners thereto.

c) Edman Degradation Method (n Times)

    • The reaction is usually carried out in a conventional solvent such as water, acetonitrile, acetone, alcohol (e.g., methanol, ethanol, isopropyl alcohol, or the like), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, ethyl acetate, N,N-dimethylformamide, or any other organic solvent which does not adversely affect the reaction or the mixture thereof.
    • The reaction temperature is not limited and the reaction is usually carried out under cooling to heating.
    • And the reaction is carried out repeatedly until the object compound can be obtained.
    • This reaction can be carried out by the method disclosed in Preparations 138, a series of 2 and 3, etc. mentioned later or the similar manners thereto (e.g., M. K. Eberle et al., J. Org. Chem. 59, 7249-7258 (1994) described about this type Edman degradation method).

The compound (VII) or a salt thereof (FR901459 compound) can be produced by fermentation of fungus (Stachybotrys chartarum No. 19392: deposit number FERM BP-3364) according to the method described in Japanese Laid-open Patent Application Hei 5-271267, for example.

More specifically, the object compound can be prepared by the processes described in Examples in the present application or similar processes.

The compounds obtained by the above-mentioned processes 1 to 4, and A and B can be isolated and purified by a conventional method, such as pulverization, recrystallization, column chromatography, high performance liquid chromatography, reprecipitation and demineralized resin column chromatography.

Suitable salts of the object compound (I) are conventional pharmaceutically acceptable and non-toxic salts, and may be a salt with a base or an acid addition salt, for example, a salt with an inorganic base (such as an alkali metal salt, e.g. sodium salt, potassium salt, etc., an alkaline earth metal salt, e.g. calcium salt, magnesium salt, etc., an ammonium salt), a salt with an organic base (such as an organic amine salt, e.g. triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N′N′-dibenzylethylenediamine salt, etc.), an inorganic acid addition salt (such as hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic carboxylic acid or sulfonic acid addition salt (such as formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), a salt with a basic or acidic amino acid (such as arginine, aspartic acid, glutamic acid, etc.) and the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions to be included within the scope of the invention are explained in detail as follows.

The term “lower” is intended a group having 1 to 6, preferably 1 to 4, unless otherwise indicated.

Suitable examples of “lower alkyl” and “lower alkyl” moiety may include a straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, and the like.

Suitable examples of “lower alkoxy” and “lower alkoxy” moiety may include a straight or branched one having 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and the like.

Suitable examples of “cyclo(lower)alkyl” may include cyclic alkyl having 3 to 6 carbon atom, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the like.

Suitable examples of “aryl” and “aryl” moiety may include phenyl which may be substituted with lower alkyl (e.g., phenyl, mesityl, tolyl, etc.), naphthyl, anthryl, tetrahydronaphthyl, indenyl, tetrahydroindenyl, and the like.

Suitable examples of “optionally substituted amino” may include amino which is optionally substituted by one or two suitable substitutent(s) such as lower alkyl, amino protective group (e.g., benzyloxycarbonyl, t-butoxycarbonyl(Boc) and the like) and the like.

Suitable examples of “optionally substituted carbamoyloxy” may include carbamoyloxy which is optionally substituted by one or two suitable substitutent(s) such as lower alkyl, amino protective group (e.g., benzyloxycarbonyl, t-butoxycarbonyl(Boc) and the like) and the like.

Suitable examples of “heterocyclic group” may include:

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), azepinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, aziridinyl, azetinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 2,5-methanopiperazinyl, hexahydroazepinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroindolyl, dihydroindazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s), and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s), for example, oxiranyl, 1,3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example benzothienyl, benzodithiinyl, etc.; and

unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc.; saturated condensed heteromonocyclic group containing 1 to 3 nitrogen atom(s), for example, tetrahydropyridopyrrolidinyl, etc.;

and the like.

Suitable “N-containing heterocyclic group” can be referred to the ones as mentioned above, wherein the heterocyclic group is containing at least one nitrogen atom such as pyrrolidinyl, piperidyl, morpholinyl, thiazolyl, oxazolyl, and the like.

Suitable “optionally substituted heterocyclic group” may include the heterocyclic group as mentioned above, which is optionally substituted by a suitable substituent such as lower alkyl, lower alkoxy, aryl, amino, lower alkoxycarbonyl, and the like.

The term “halogen” means fluorine, chlorine, bromine and iodine.

V. Lohmann et al., Science 285, 110-113 (1999) reported that they prepared human hepatoma cell lines (Huh-7) in which subgenomic HCV RNA molecules were introduced, and found that subgenomic HCV RNA was replicated in the cells at a high rate. It is thought that the replication mechanism of the subgenomic HCV RNA in these cell lines is extremely similar to the replication of full length HCV RNA genome in hepatic cells infected with HCV. Hence, the method for evaluating the activity of the compound (I) for inhibiting RNA replication in accordance with the present invention is based on the cellular assay method that uses Huh-7 cells in which subgenomic HCV RNA is introduced.

In order to show the usefulness of the compound (I) or a salt thereof in the present invention, a pharmacological test example of representative compounds in the present application is shown as follows.

TEST EXAMPLE

1. HCV Replicon Reporter Assay

The inhibitory activity of the test compounds against the replication of HCV replicon was evaluated by quantified the activity of luciferase, a reporter gene product encoded in the replicon system reported by Yokota et al., EMBO 4: 602-608 (2003). The enzyme assay was carried out according to the technical manual of the Steady-Glo® luciferase assay system (Promega). The replicon assay was carried out with the modified method reported by Lohmann et al., Science 285: 110 (1999). The details are described in the following.

1) Addition of Agent to Cells

6×103 HCV replicon cells in D-MEM medium containing 5% fetal bovine serum were seeded in each well of a 96-well microtiter plate (Corning Inc.). After the cells were incubated at 37° C. for 16 hours in 5% CO2, the test compound was added.

2) Luciferase Assay Procedure

After cultivation for two more days, the culture medium was removed and 25 μl of Glo Lysis buffer was added to each well and incubated for 5 minutes. Allowing lysis to occur, 25 μl of Steady-Glo® assay reagent was added to each well. After incubation for 5 minutes, the luminescence was measured with a luminometer, Mithras LB940 (BERTHOLD TECHNOLOGIES GmbH & Co. KG) following the manufacturer's instructions.

3) Test Result

The luciferase activities in replicon cells treated at each concentrations of the compound were employed for the calculation of EC50 value of the each compound, which gave the compound concentration indicating 50% enzyme activity level to the control (no drug group, containing only DMSO).

HCV replicon replication inhibitory activity: Test compound EC50 (μg/ml) Object compound of <0.5 Example 9 Object compound of <0.5 Example 12 Object compound of <0.5 Example 14 Object compound of <0.5 Example 15 Object compound of <0.5 Example 16 Object compound of <0.5 Example 25 Object compound of <0.5 Example 31 Object compound of <0.5 Example 32 Object compound of <0.5 Example 52

From the result of the above-mentioned test example, it is realized that the compound (I) or a salt thereof of the present invention possesses an anti-hepatitis C virus activity.

The anti-HCV agent in the present invention, containing the compound (I) or a salt thereof as an active ingredient, can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, in admixture with an organic or inorganic carrier or excipient suitable for oral; sublingual; buccal; nasal; respiratory; parenteral (intracutaneous, intraorgan, subcutaneous, intradermal, intramuscular, intra-articular, central-venous, hepatic-venous, peripheral-venous, lymphatic, cardiovascular, arterial, ocular including injection around eye or intravenous drip around eye); intravenous drip into eyeball, augen structure or augen layer; aural including auditory canal, papillary chamber, external and internal auditory canals, drum membrane, tympanum, internal-auditory including spiralis cochleae ganglion, labyrinth, etc.; intestinal; rectal; vaginal; ureteral; and vesical administration. With respect to intrauterine and perinatal adaptation diseases, parenteral administration is preferable since administration is carried out in maternal blood vessels, or in vacancies, such as maternal organs including uterus, uterine cervix and vagina; fetal embryo, fetus, neonate, and combination tissue; and amnion, umbilical cord, umbilical artery and vein; placenta, and the like. Use of these passages is changed depending on the condition of each patient.

The compound (I) or a salt thereof can be administered independently as a therapeutic agent or may be desired to be used as part of prescribed drugs. The “anti-HCV agent” in accordance with the present invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, in admixture with at least one or some suitable organic or inorganic carriers or excipients, or other pharmacological therapeutic agents. The active ingredient can be compounded with, for example, usual pharmacologically acceptable and non-toxic carriers in a solid form, such as granules, tablets, pellets, troches, capsules or suppositories; creams; ointments: aerosols; powders for insufflation; in a liquid form, such as solutions, emulsions or suspensions for injection; oral ingestion; eye drops; and any other forms suitable for use. And, if necessary, there may be included in the above preparations auxiliary substances, such as stabilizing, thickening, wetting, hardening and coloring agents; perfumes or buffers; or any other additives used commonly.

The compound (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired anti-hepatitis C effect upon the process or condition of diseases.

The combination use of IFN and/or ribavirin with the compound (I) or a salt thereof is effective against hepatitis C.

For applying the composition to humans, it is preferable to apply it by intravenous, intramuscular, pulmonary, oral administration, eye drop administration or insufflation. While the dosage of therapeutically effective amount of the compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-400 mg of the compound (I) per kg weight of human being in the case of intramuscular administration, a daily dose of 0.1-20 mg of the compound (I) per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the compound (I) per kg weight of human being is generally given for treating or preventing hepatitis C. However, these doses may be required to exceed the limit thereof to obtain therapeutic results.

The amount of the lipopeptide compound (I) or its pharmaceutically acceptable salt contained in the composition for a single unit dosage of the present invention is 0.1 to 400 mg, more preferably 1 to 200 mg, still more preferably 5, to 100 mg, specifically 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100 mg.

The present invention may include an article of manufacture, comprising packaging material and the compound (I) identified in the above contained within said packaging material, wherein said the compound (I) is therapeutically effective for preventing or treating hepatitis C, and wherein said packaging material comprises a label or a written material which indicates that said compound (I) can or should be used for preventing or treating hepatitis C.

The present invention may include a commercial package comprising the pharmaceutical composition-containing the compound (I) identified in the above and a written matter associated therewith, wherein the written matter states that the compound (I) can or should be used for preventing or treating hepatitis C.

It is to be noted that the compound (I) or a salt thereof may include one or more stereoisomer(s), such as optical isomer(s) and geometrical isomer(s), due to asymmetric carbon atom(s) and double bond(s), and that all such isomers and the mixture thereof are included within the scope of the present invention.

The compound (I) or a salt thereof may include solvated compound (e.g. hydrate, ethanolate, etc.).

The compound (I) or a salt thereof may include both the crystal form and non-crystal form.

The compound (I) or a salt thereof may include the prodrug form.

The patent specifications and publications cited herein are incorporated in this specification by reference.

The following Preparations and Examples are given for the purpose of illustrating the present invention. However, the present invention is not limited to these Preparations and Examples.

The Starting Compounds used and the Object Compounds obtained in the following Examples 1 to 83 are given as mentioned below.

The abbreviations, symbols and terms used in the Preparations, Examples, and Formulae in the above and subsequent descriptions of the present specification (including the tables) have the following meanings.

    • AcOEt Ethyl acetate
    • Bop-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
    • CHCl3 Chloroform
    • CH2Cl2 Dichloromethane
    • Et2O Diethyl ether
    • HCl Hydrochloric acid
    • HOAt 1-Hydroxy-7-azabenzotriazole
    • LiOH Lithium hydroxide
    • MeCN Acetonitrile
    • MeOH Methanol
    • MgSO4 Magnesium sulfate
    • NaHCO3 Sodium hydrogencarbonate
    • NaOH Sodium hydroxide
    • Na2SO4 Sodium sulfate
    • TFA Trifluoroacetic acid
    • WSCD 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
    • nBu n-Butyl
    • iBu Isobutyl
    • tBu tert-Butyl
    • Cy.Hex. Cyclohexyl
    • Et Ethyl
    • Me Methyl
    • Ph phenyl
    • iPr Isopropyl
    • Bn Benzyl
    • Boc tert-Butoxycarbonyl
    • Fmoc 9H-Fluoren-9-ylmethoxycarbonyl
    • Ex. Example number
    • Prep. Preparation number
    • MS Mass spectrometry data

Prep. 1

To a solution of the object compound of Prep. 158 below (crude 78 g, theoretical 76.9 g) in MeCN (555 ml) was added 1N HCl (555 ml) under ice bath cooling. The mixture was warmed to 30° C., and stirred at 30° C. for 3 hrs. The resulting mixture was neutralized with Na2CO3 solution (29.48 g in H2O 300 ml), and concentrated in vacuo. The pH value of residual solution was adjusted to 8 with saturated NaHCO3 aqueous solution, and the solution was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,6,9,18,21-pentaisobutyl-24-isopropyl-8,12,15,17,23,26-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-2,5,8,11,14,17,20,23,26,29-decaazahentriacontan-31-oate (crude 70 g, theoretical 65.5 g) as pale brown powder. Obtained crude product was used in next reaction without further purification.

Prep. 2

To a solution of the object compound of Prep. 1 (crude 70 g, theoretical 65.5 g) in AcOEt (660 ml) was added isothiocyanatobenzene (10 ml) at ambient temperature, and the pH value of the mixture was added to 7.5 with diisopropylethylamine. The reaction mixture was stirred at ambient temperature for 1.5 hrs. To the resulting solution was added N,N-dimethylpropanediamine (9.1 g) and stirred for 5 minutes. The reaction mixture was poured into 0.5N HCl (1 l) and extracted with AcOEt. The organic phase was washed with 0.5N HCl, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo and the residue was purified with Silica-gel column chromatography eluting with Hexane:AcOEt (2:1-1:1-1:2) to give-methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-1-anilino-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,6,9,18,21-pentaisobutyl-24-isopropyl-2,8,12,15,17,23,26-heptamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-1-thioxo-2,5,8,11,14,17,20,23,26,29-decaazahentriacontan-31-oate (44.3 g) as pale yellow powder.

Prep. 3

To a solution of the object compound of Prep. 2 (44.3 g) in MeCN (337 ml) was added 1N HCl (337 ml) and the mixture was stirred at 30° C. for 2 hrs. The resulting mixture was neutralized with Na2CO3 solution (58.8 g in H2O 300 ml), and concentrated in vacuo. The pH value of residual solution was adjusted 8 with saturated NaHCO3 aqueous solution, and the solution was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 and brine, and dried over Na2SO4. Solvent was removed in vacuo and the residue was purified with Silica-gel column chromatography eluting CHCl3:MeOH (100:0-97:3) to give methyl (2S,5S,8S,11S,14S,17R,20S,23S,26S)-26-amino-2-[(1R)-1-hydroxyethyl-]-5-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-11,14,23-triisobutyl-8-isopropyl-6,9,15,17,20,24,28-heptamethyl-4,7,10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21,24-octaazanonacosan-1-oate (29.1 g) as pale yellow form.

1H-NMR (chloroform-d, δ ppm): 10.27 (0.5H, d, J=9.0 Hz), 7.38 (0.5H, d, J=8.5 Hz), 7.00 (0.5H, d, J=8.5 Hz), 6.93 (0.5H, d, J=8.5 Hz), 6.89 (1H, d, J=8.5 Hz), 6.84 (0.5H, d, J=8.0 Hz), 6.80 (0.5H, d, J=8.0 Hz), 5.14-5.51 (5H, m), 4.86-5.04 (1H, m), 4.66-4.81 (2H, m), 4.55 (2H, m), 4.31 (1H, m), 4.00 (1H, m), 3.77 (1H, m), 3.76 (1.5H, s), 3.75 (1.5H, s), 3.25 (1.5H, s), 3.14 (1.5H, s), 3.06 (1.5H, s), 3.02 (1.5H, s), 3.01 (1.5H, s), 3.00 (3H, s), 2.71 (1.5H, s), 2.35 (2H, m), 2.03-1.24 (61H, m)

Prep. 4

To a solution of the object compound of Prep. 59 below (3.2 g) in CH2Cl2 (38.5 ml) was added TFA (9.6 ml) under ice bath cooling, and the mixture was stirred for 2 hrs under ice bath cooling. To the mixture was added TFA (7 ml) and the mixture was additionally stirred for 1 hour under ice bath cooling. Resulting mixture was neutralized with Na2CO3 aqueous solution (6.6 g in 100 ml H2O) under ice bath cooling, and concentrated in vacuo. To the residual solution was added saturated NaHCO3 aqueous solution to adjust pH=8, and the mixture was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, and dried over NaSO4. Solvent was removed in vacuo to give methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-3-sec-butyl-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-24-isopropyl-8,12,15,17,23,26-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-2,5,8,11,14,17,20,23,26,29-decaazahentriacontan-31-oate (3.0 g) as colorless solid.

The compounds of Prep. 5-19 were obtained in a similar manner to that of Prep. 4.

Prep. 20

To a solution of the object compound of Prep. 208 below (1.20 g) in dioxane (10 ml) was added 1N LiOH (3.1 ml) under ice-bath cooling. After being stirred for 3 hrs at the same temperature, the solution was acidified with 5% citric acid to be pH 5, concentrated in vacuo to remove dioxane, and extracted with AcOEt (50 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (3R,16S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-(1-tert-butoxyethyl)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-3,5,11,15,18,20,26,29-octamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (790 mg) as a solid.

The compounds of Prep. 21-24 were obtained in a similar manner to that of Prep. 20.

Prep. 25

To a solution of the object compound of Prep. 4 (81 mg) was added (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}propanoic acid (33.5 mg), Bop-Cl (26.2 mg), and diisopropylethylamine (36 μl) under ice bath cooling. The mixture was stirred for 13 hrs at ambient temperature, and extracted with AcOEt. The organic phase was washed with 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=90:10) to give methyl-(5R,8S,11S,14S,17S,20R,23S,26S,29S,32S,35S)-8-sec-butyl-1-(9H-fluoren-9-yl)-35-[(1R)-1-hydroxyethyl]-32-[(1R,2R,4E)-1-30-hydroxy-2-methyl-4-hexen-1-yl]-11,14,23,26-tetraisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-2-oxa-4,7,10,13,16,19,22,25,28,31,34-undecaazahexatriacontan-36-oate (74 mg) as colorless solid.

The compounds of Prep. 26-40 were obtained in a similar manner to that of Prep. 25.

Prep. 41

To a solution of the object compound of Prep. 25 (73 mg) in dioxane (1.9 ml) was added 1N NaOH (0.49 ml) at ambient temperature and the mixture was stirred for 2 hrs. To the reaction mixture was added 10% citric acid aqueous solution to adjust pH=4, and the solution was extracted with AcOEt. The organic phase was washed with brine, and was dried over Na2SO4. Solvent was removed in vacuo and the residue was triturated with Et2O to give (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-sec-butyl-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-3,5,11,15,18,20,26,29-octamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (56 mg) as colorless powder.

The compounds of Prep. 42-56 were obtained in a similar manner to that of Prep. 41.

Prep. 57

To a solution of the object compound of Prep. 93 below (1.60 g) in N,N-dimethylformamide (16 ml) was added piperidine (1.1 ml) at room temperature. After being stirred at the same temperature for 2 hrs, the reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt (60 ml) and the solution was washed with 5% citric acid aqueous solution, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by Silica-gel column (eluent 2% MeOH in CHCl3) to give methyl (2S,5S,8S,11S,14S,17R,20S,23S,26S,29S)-2-[(1R)-1-hydroxyethyl]-5-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-11,14,23,26-tetraisobutyl-8-isopropyl-6,9,15,17,20,24,30,32,32-nonamethyl-29-(methylamino)-4,7,10,13,16,19,22,25,28-nonaoxo-31-oxa-3,6,9,12,15,18,21,24,27-nonaazatritriacontan-1-oate (1.34 g) as a powder.

The compound of Prep. 58 was obtained in a similar manner to that of Prep. 57.

Prep. 59

To a solution of the object compound of Prep. 3 (3.0 g) in CH2Cl2 (60 ml) was added (2S,3S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylpentanoic acid (839 mg) and HOAt (466 mg), and WSCD (531 mg) under ice bath cooling, and the mixture was stirred for 1.5 hrs under ice bath cooling. The resulting mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-sec-butyl-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-2,2,5,11,15,18,20,26,29-nonamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32-decaazatetratriacontan-34-oate (3.22 g) as pale yellow powder. Obtained product was used in next reaction without further purification.

The compounds of Prep. 60-67 were obtained in a similar manner to that of Prep. 59.

Prep. 68

Methyl-(6R,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-sec-butyl-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-2,2,11,15,18,20,26,29,35-nonamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oate (80 mg) was dissolved in 20% TFA/CH2Cl2 (2 ml) under ice-bath cooling. After being stirred at the same temperature for 4 hrs, to the solution was added saturated NaHCO3 aqueous solution to be pH 8. The mixture was extracted with CHCl3 (20 ml) and the organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was dissolved in MeOH (4 ml). To the solution was added 1N LiOH (0.60 ml) under ice-bath cooling. After being stirred for 1 hr at the same temperature, the solution was acidified with 5% citric acid aqueous solution to be pH5, concentrated in vacuo to remove MeOH, and extracted with CHCl3 (20 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (5S,8S,11S,14S,17S,20R,23S,26S,29S,32R)-32-amino-5-[(1R)-1-hydroxyethyl]-8-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-14,17,26,29-tetraisobutyl-11-isopropyl-3,9,12,18,20,23,27,33-octamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-3,6,9,12,15,18,21,24,27,30-decaazapentatriacontan-1-oic acid (45 mg) as a solid.

The compounds of Prep. 69-74 were obtained in a similar manner to that of Prep. 68.

Prep. 75

To a solution of the object compound of Prep. 193 below (53 mg) in dioxane (0.64 ml) was added 1N NaOH (0.16 ml) at ambient temperature and the mixture was stirred for 2 hrs. To the reaction mixture was added 10% citric acid aqueous solution to adjust pH=4, and the solution was extracted with AcOEt. The organic phase was washed with brine, and was dried over Na2SO4. Solvent was removed in vacuo and the residue was triturated with Et2O to give (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,6,9,12,21,24-hexaisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (18 mg) as colorless powder.

The compounds of Prep. 76-89 were obtained in a similar manner to that of Prep. 75.

Prep. 90

To a solution of the object compound of Prep. 167 below (5.40 g), methyl {[(2S,3R)-2-amino-3-hydroxybutanoyl](methyl)amino}acetate hydrochloride (1.46 g) and HOAt (0.550 g) in CH2Cl2 (8.0 ml) was added a solution of WSCD (0.627 g) in CH2Cl2 (4 ml) under ice-bath cooling. After being stirred at the same temperature for 3 hrs, the reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the solution was washed with 0.5N HCl, 1M NaHCO3, and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give methyl (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S,39S)-6,39-bis[(1R)-1-hydroxyethyl]-36-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35,41-undecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40-tridecaoxo-3-oxa-5,8,11,14,11,20,23,26,29,32,35,38,41-tridecaazatritetracontan-43-oate (6.00 g) as a powder.

Prep. 91

To a solution of the object compound of Prep. 3 (120 mg), (2S)-2-[{(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoyl}(ethyl)amino]-3-methylpentanoic acid (59 mg), and HOAt (19 mg) in CH2Cl2 (6 ml) was added a solution of WSCD (0.21 mg) in CH2Cl2 (1 ml) under ice-bath cooling. After being stirred at the same temperature for 1 hr and at room temperature for 5 hrs, the reaction solution was concentrated in vacuo. The residue was dissolved in AcOEt (20 ml) and the solution was washed with 0.5N HCl, 1M NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give methyl (6R,9S,12S,15S,18S,21R,24S,27S,30S,33S,36S)-9-sec-butyl-8-ethyl-36-[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,24,27-tetraisobutyl-30-isopropyl-2,2,5,6,14,18,21,23,29,32-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oate (155 mg) as an amorphous powder.

The compound of Prep. 92 was obtained in a similar manner to that of Prep. 91.

Prep. 93

To a solution of the object compound of Prep. 3 (1.20 g), (2S,3R)-3-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}butanoic acid (516 mg), and HOAt (171 mg) in CH2Cl2 (20 ml) was added a solution of WSCD (195 mg) in CH2Cl2 (1 ml) under ice-bath cooling. After being stirred at the same temperature for 1 hr and at room temperature for 4 hrs, the reaction solution was concentrated in vacuo. The residue was dissolved in AcOEt (50 ml) and the solution was washed with 0.5N HCl, 1M NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo. to give methyl (5S,8S,11S,14S,17R,20S,23S,26S,29S,32S)-5-(1-tert-butoxyethyl)-1-(9H-fluoren-9-yl)-32-[(1R)-1-hydroxyethyl]-29-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-8,11,20,23-tetraisobutyl-26-isopropyl-4,10,14,17,19,25,28-heptamethyl-3,6,9,12,15,18,21,24,27,30-decaoxo-2-oxa-4,7,10,13,16,19,22,25,28,31-decaazatritriacontan-33-oate (1.6 g) as an amorphous powder.

The compound of Prep. 94 was obtained in a similar manner to that of Prep. 93.

Prep. 95

To a solution of the object compound of Prep. 166 below (1.20 g), (2S,3R)-3-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}butanoic acid (527 mg), and HOAt (174 mg) in CH2Cl2 (20 ml) was added a solution of WSCD (199 mg) in CH2Cl2 (1 ml) under ice-bath cooling. After being stirred at the same temperature for 1 hr and at room temperature for 4 hrs, the reaction solution was concentrated in vacuo. The residue was dissolved in AcOEt (50 ml) and the solution was washed with 0.5N HCl, 1M NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by Silica-gel column (eluent: 2% MeOH in CHCl3) to give methyl (5S,8S,11S,14S,17R,20S,23S,26S,29S,32S)-5-(1-tert-butoxyethyl)-1-(9H-fluoren-9-yl)-32-[(1R)-1-hydroxyethyl]-29-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-8,11,20,23-tetraisobutyl-26-isopropyl-4,10,14,17,19,25,28,34-octamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-2-oxa-4,7,10,13,16,19,22,25,28,31,34-undecaazahexatriacontan-36-oate (1.58 g) as an amorphous powder.

The compounds of Prep. 96-109 and 111-116 were obtained in a similar manner to that of Prep. 95.

Prep 110

To a solution of the object compound of Ex. 25 below (190 mg) in pyridine (1.2 ml) were added acetic anhydride (280 μl). After the mixture was stirred overnight, the mixture was diluted with AcOEt, washed with 1N aqueous hydrochloric acid and aqueous NaHCO3, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt=1/4 and then CH2Cl2/MeOH=9/1) to give (1R)-1-{(2S,5R,8S,11S,14S,17S,20R,23S,26S,29S,32S)-8-(1-tert-butoxyethyl)-32-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-11,14,23,26-tetraisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl}ethyl acetate (193 mg).

Prep. 117

To a solution of the object compound of Prep. 154 below (crude 84 g, theoretical 82.5 g) in MeCN (1 l) was added 1N HCl (1.11 l) under ice bath cooling. The mixture was warmed to 30° C., and stirred at 30° C. for 4 hrs. The resulting mixture was neutralized with Na2CO3 solution (58.8 g in H2O 300 ml), and concentrated in vacuo. The pH value of residual solution was adjusted 8 with saturated NaHCO3 aqueous solution, and the solution was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,12,21,24-pentaisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (crude 78 g, theoretical 69.4 g) as pale brown powder. Obtained crude product was used in next reaction without further purification.

Prep. 118

To a solution of the object compound of Prep. 4 (100 mg) was added (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid (27.6 mg), Bop-Cl (43.2 mg), and diisopropylethylamine (59 μl) under ice bath cooling. The mixture was stirred for 13 hrs at ambient temperature, and extracted with AcOEt. The organic phase was washed with 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=90:10) to give methyl (6R,9S,12S,15S,18S,21R,24S,27S,30S,33S,36S)-9-sec-butyl-6-ethyl-36-(1-hydroxyethyl)-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,24,27-tetraisobutyl-30-isopropyl-2,2,5,8,14,18,21,23,29,32-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oate (64.8 mg) as colorless solid.

The compounds of Prep. 119-127 were obtained in a similar manner to that of Prep. 118.

Prep. 128

To a solution of the object compound of Prep. 118 (64.8 mg) in CH2Cl2 (1.2 ml) was added TFA (0.36 ml) under ice bath cooling, and the mixture was stirred for 2 hrs under ice bath cooling. To the resulting solution was added saturated NaHCO3 aqueous solution to adjust pH=8. The mixture was extracted with AcOEt, and the organic phase was washed with saturated NaHCO3 aqueous solution and brine. Solvent was removed in vacuo to give methyl (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-sec-butyl-3-ethyl-33-(1-hydroxyethyl)-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (58.6 mg). Obtained product was used in next reaction without further purification.

The compounds of Prep. 129-137 were obtained in a similar manner to that of Prep. 128.

Preparation 138

To a solution of the object compound of Prep. 168 below (3.70 g) in AcOEt (40 ml) was added a solution of isothiocyanatobenzene (757 mg) in AcOEt (10 ml) at room temperature. After being stirred for 30 minutes at the same temperature, N,N-dimethylaminopropylamine (752 mg) was added to the solution. The solution was stirred for 15 minutes, washed with 0.2N HCl, NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a powder. The resulting powder was dissolved in MeCN (100 ml) and 1N HCl (60 ml) was added under ice-bath cooling. After being stirred at room temperature for 6 hrs, the solution was neutralized with 1N Na2CO3 (50 ml), concentrated in vacuo to remove MeCN, and extracted with AcOEt (200 ml). The organic layer was washed with NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by Silica-gel column (eluent:2% MeOH in CHCl3) to give methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,6,9,18,21-pentaisobutyl-24-isopropyl-8,12,15,17,23,26,32-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (3.19 g) as a powder.

Prep. 139

To a solution of the object compound of Prep. 128 (58.6 mg) in MeOH (1.2 ml) was added 1N NaOH (0.23 ml) at ambient temperature and the mixture was stirred for 2 hrs. To the reaction mixture was added 10% citric acid aqueous solution to adjust pH=4, and the solution was extracted with AcOEt. The organic phase was washed with brine, and was dried over Na2SO4. Solvent was removed in vacuo and the residue was triturated with Et2O to give (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-6-sec-butyl-3-ethyl-33-(1-hydroxyethyl)-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (58.6 mg) as colorless powder.

The compounds of Prep. 140-148 were obtained in a similar manner to that of Prep. 139.

Prep. 149

Methyl (6R,9S,12S,15S,18S,21R,24S,27S,30S,33S,36S)-9-(1-tert-butoxyethyl)-6-ethyl-36-[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,24,27-tetraisobutyl-30-isopropyl-2,2,5,8,14,18,21,23,29,32-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oate (110 mg) was dissolved in 20% TFA/CH2Cl2 (3 ml) under ice-bath cooling. After being stirred at the same temperature for 4 hrs, to the solution was added saturated NaHCO3 aqueous solution to be pH 8. The mixture was extracted with CHCl3 (20 ml) and the organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was dissolved in MeOH (4 ml). To the solution was added 1N LiOH (0.77 ml) under ice-bath cooling. After being stirred for 1 hr at the same temperature, the solution was acidified with 5% citric acid aqueous solution to be pH 5, concentrated in vacuo to remove MeOH, and extracted with AcOEt (20 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-3-ethyl-33-[(1R)-1-hydroxyethyl]-6-(1-hydroxyethyl)-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24-tetraisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (70 mg) as a solid.

The compounds of Prep. 150 and 151 were obtained in a similar manner to that of Prep. 149.

Prep. 152

The object compound of Prep. 90 (6.00 g) was dissolved in 20% TFA in CH2Cl2 (80 ml) under ice-bath cooling and the mixture was stirred at the same temperature for 4 hrs. To the solution was added saturated NaHCO3 aqueous solution to be pH 0.8 and the mixture was extracted with CHCl3 (200 ml). The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl (5S,8S,11S,14S,17S,20R,23S,26S,29S,32S,38S,39R)-38-amino-39-hydroxy-5-[(1R)-1-hydroxyethyl]-8-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-14,17,26,29,32-pentaisobutyl-11-isopropyl-3,9,12,18,20,23,27,33,36-nonamethyl-4,7,10,13,16,19,22,25,28,31,34,37-dodecaoxo-3,6,9,12,15,18,21,24,27,30,33,36-dodecaazatetracontan-1-oate (5.70 g) as an amorphous powder.

The compound of Prep. 153 was obtained in a similar manner to that of Prep. 152.

Preparation 154

To a solution of the object compound of Prep. 155 below (crude 75.0 g, theoretical 71.8 g) in a mixed solvent (AcOEt 750 ml and pyridine 67.5 ml) was added isothiocyanatobenzene (19.8 ml), and the mixture was stirred for 13 hrs. To the mixture was added pyridine (67.5 ml) and diisopropylethylamine, and the pH value of the mixture was adjusted to 8. The mixture was stirred for 3 hrs. To the resulting solution was added N,N-dimethylpropanediamine (19.8 g) and stirred for 5 minutes. The reaction mixture was poured into 0.5N HCl (1 l) and extracted with AcOEt. The organic phase was washed with 0.5N HCl, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (3S,9S,12S,15S,18S,21R,24S,27S,30S,33S,36S)-1-anilino-3,36-bis[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,15,24,27-pentaisobutyl-30-isopropyl-5,8,14,18,21,23,29,32-octamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-1-thioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaazaheptatriacontan-37-oate (crude 84 g, theoretical 82.5 g) as brown form. Obtained crude product was used in next reaction without further purification.

Prep. 155

To a solution of the object compound of Prep. 157 below (crude 80.2 g theoretical 77.1 g) in CH2Cl2 was added TFA (205 ml) under ice bath cooling. The mixture was stirred for 2 hrs under ice bath cooling. The pH value of the solution was adjusted with a solution of Na2CO3 (147 g/500 ml H2O) and saturated NaHCO3 aqueous solution under ice bath cooling. The resulting solution was extracted with CHCl3. The organic phase was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (2S,5S,8S,11S,14S,17R,20S,23S,26S,29S,35S,36R)-35-amino-36-hydroxy-2-[(1R)-1-hydroxyethyl]-5-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-11,14,23,26,29-pentaisobutyl-8-isopropyl-6,9,15,17,20,24,30,33-octamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3,6,9,12,15,18,21,24,27,30,33-undecaazaheptatriacontan-1-oate (75 g, crude) as brown powder. Obtained crude product was used in next reaction without further purification.

Prep. 156

To a solution of (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21,24-pentaisobutyl-3-isopropyl-1,4,10,12,15,19,25,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (100 g) in tetrahydrofuran (1 l) was added 4-methylbenzenesulfonic acid (70.6 g) and the mixture was stirred at 50° C. for 14 hrs. To the mixture was added 1N NaOH and neutralized under ice bath cooling, and was added Boc2O (17.9 g). The pH value of the mixture was adjusted to 8 with 1N NaOH under ice bath cooling. The mixture was stirred at ambient temperature for 2.5 hrs. Resulting mixture was concentrated in vacuo and extracted with AcOEt. The organic phase was washed with saturated Na2CO3 aqueous solution, 0.1N HCl, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give tert-butyl {(3S,6S,9S,12S,15R,18S,21S,24S,27S,33S,34R)-3-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-9,12,21,24,27-pentaisobutyl-6-isopropyl-4,7,13,15,18,22,28,31,34-nonamethyl-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-1-oxa-4,7,10,13,16,19,22,25,28,31-decaazacyclotetratriacontan-33-yl}carbamate (167.2 g) as brown form. Obtained crude product was used in next reaction without further purification.

Prep. 157

To a solution of the object compound of Prep. 167 below (71.0 g) in CH2Cl2 (1 l) was added methyl (2S,3R)-2-amino-37-hydroxybutanoate hydrochloride (10.8 g) and HOAt (10.8 g) at ambient temperature. To the mixture was added WSCD (9.9 g) under ice bath cooling. The mixture was stirred for 1.5 hrs at ambient temperature. The resulting mixture was concentrated in vacuo and extracted with AcOEt. The organic phase was washed with 0.5N HCl, saturated NaHCO3, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S,39S)-6,39-bis[(1R)-1-hydroxyethyl]-36-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34,37-dodecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35,38-dodecaazatetracontan-40-oate (80.2 g, crude) as brown form. Obtained-crude product was used in next reaction without further purification.

Prep. 158

To a solution of the object compound of Prep. 117 (crude 78 g, theoretical 69.4 g) in AcOEt (690 ml) was added isothiocyanatobenzene (11.3 g) at ambient temperature, and the mixture was stirred for 1 hr. To the solution was added diisopropylethylamine (5 ml), and the mixture was additionally stirred for 1.5 hrs. To the resulting solution was added N,N-dimethylpropanediamine (9.1 g) and stirred for 5 minutes. The reaction mixture was poured into 0.5N HCl (1 l) and extracted with AcOEt. The organic phase was washed with 0.5N HCl, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-1-anilino-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,12,21,24-pentaisobutyl-27-isopropyl-2,5,11,15,18,20,26,29-octamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-1-thioxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (crude 78 g, theoretical 76.9 g) as brown form. Obtained crude product was used in next reaction without further purification.

Prep. 159

To a solution of the object compound of Prep. 1 (87 mg) was added (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}propanoic acid (36 mg), Bop-Cl (28.2 mg), and diisopropylethylamine (39 μl) under ice bath cooling. The mixture was stirred for 13 hrs at ambient temperature, and extracted with AcOEt. The organic phase was washed with 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=90′ 10) to give methyl (5R,8S,11S,14S,17S,20R,23S,26S,29S,32S,35S)-1-(9H-fluoren-9-yl)-35-[(1R)-1-hydroxyethyl]-32-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-8,11,14,23,26-pentaisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-2-oxa-4,7,10,13,16,19,22,25,28,31,34-undecaazahexatriacontan-36-oate (110 mg) as colorless solid.

The compound of Prep. 160 was obtained in a similar manner to that of Prep. 159.

Prep. 161

To a solution of the object compound of Prep. 95 (1.55 g) in dioxane (30 ml) was added 1N LiOH (10 ml) under ice-bath cooling. After being stirred for 3 hrs at the same temperature, the solution was acidified with 5% citric acid to be pH 5, concentrated in vacuo to remove dioxane, and extracted with AcOEt (50 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (5S,8S,11S,14S,17S,20R,23S,26S,29S,32S)-5-[(1R)-1-hydroxyethyl]-8-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-14,17,26,29-tetraisobutyl-11-isopropyl-3,9,12,18,20,23,27,33,35,35-decamethyl-32-(methylamino)-4,1,10,13,16,19,22,25,28,31-decaoxo-34-oxa-3,6,9,12,15,18,21,24,27,30-decaazahexatriacontan-1-oic acid as a solid.

The compounds of Prep. 162-165 were obtained in a similar manner to that of Prep. 161.

Prep. 166

To a solution of the object compound of Prep. 138 (3.15 g) in AcOEt (40 ml) was added a solution of isothiocyanatobenzene (511 mg) in AcOEt (10 ml) at room temperature. After being stirred for 30 minutes at the same temperature, N,N-dimethylaminopropylamine (527 mg) was added to the solution. The solution was stirred for 15 minutes, washed with 0.2N HCl, NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a powder. The resulting powder was dissolved in MeCN (100 ml) and 1N HCl (50 ml) was added under ice-bath cooling. After being stirred at room temperature for 6 hrs, the solution was neutralized with 1N Na2CO3 (25 ml), concentrated in vacuo to remove MeCN, and extracted with AcOEt (150 ml). The organic layer was washed with NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by Silica-gel column (eluent:2% MeOH in CHCl3) to give methyl (5S,8S,11S,14S,17S,20R,23S,26S,29S)-29-amino-5-[(1R)-1-hydroxyethyl]-8-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-14,17,26-triisobutyl-11-isopropyl-3,9,12,18,20,23,27,31-octamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3,6,9,12,15,18,21,24,27-nonaazadotriacontan-1-oate (2.72 g) as a powder.

Prep. 167

To a solution of the object compound of Prep. 156 (crude 167 g, theoretical 108 g) in MeOH (1 l) was added 1N NaOH (819 ml) under ice bath cooling. The mixture was stirred at ambient temperature for 8 hrs. To the mixture was added 1N NaOH (82 ml) and the mixture was stirred for 2 hrs. The resulting mixture was neutralized with 1N HCl and concentrated in vacuo. The residual solution was acidified (pH=3) with 1N HCl and extracted with AcOEt. The organic phase was washed with 0.1N HCl and brine, and dried over MgSO4. The solvent was removed in vacuo. The resulting oil was triturated with AcOEt:hexane=450 ml: 1500 ml to give (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-6-[(1R)-1-hydroxyethyl]-36-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oic acid (80.4 g).

Prep. 168

To a solution of the object compound of Prep. 152 (5.70 g) in AcOEt (100 ml) was added a solution of isothiocyanatobenzene (1.08 g) in AcOEt (10 ml) at room temperature. After being stirred for 2 hrs at the same temperature, N,N-dimethylaminopropylamine (820 mg) was added to the solution. The solution was stirred for 15 minutes, washed with 0.2N HCl, NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a powder. The resulting powder was dissolved in MeCN (100 ml) and 1N HCl (100 ml) was added under ice-bath cooling. After being stirred at room temperature for 6 hrs, the solution was neutralized with 1N Na2CO3 (50 ml), concentrated in vacuo to remove MeCN, and extracted with AcOEt (200 ml). The organic layer was washed with NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by Silica-gel column (eluent:2% MeOH in CHCl3) to give methyl (6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,12,21,24-pentaisobutyl-27-isopropyl-5,11,15,18,20,26,29,35-octamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaazaheptatriacontan-37-oate (3.77 g) as a powder.

Prep. 169

To a solution of methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-3-sec-butyl-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-24-isopropyl-8,12,15,17,23,26,32-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (230 mg) in MeOH (4 ml) was added 1N LiOH (1.84 ml) under ice-bath cooling. After being stirred for 1 hr at the same temperature, the solution was acidified with 5% citric acid to be pH 5, concentrated in vacuo to remove MeOH, and extracted with AcOEt (20 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-3-sec-butyl-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-24-isopropyl-8,12,15,17,23,26,32-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (188 mg) as a solid.

The compounds of Prep. 170-177 were obtained in a similar manner to that of Prep. 169.

Prep. 178

To a solution of the object compound of Prep. 1 (66 mg) in CH2Cl2 (2.5 ml) was added (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid (16.5 mg) and HOAt (9.1 mg), and WSCD (10.4 mg) under ice bath cooling, and the mixture was stirred for 1.5 hrs under ice bath cooling. The resulting mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution, and brine, and dried over Na2SO4. Solvent was removed in vacuo to give methyl (6R,9S,12S,15S,18S,21R,24S,27S,30S,33S,36S)-36-[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,12,15,24,27-hexaisobutyl-30-isopropyl-2,2,5,8,14,18,21,23,29,32-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oate (57 mg) as pale yellow powder. Obtained product was used in next reaction without further purification.

The compounds of Prep. 179-192 were obtained in a similar manner to that of Prep. 178

Prep. 193

To a solution of the object compound of Prep. 178 (57 mg) in CH2Cl2 (1.2 ml) was added TFA (0.3 ml) under ice bath cooling, and the mixture was stirred for 2 hrs under ice bath cooling. Resulting mixture was neutralized with NaHCO3 aqueous solution (430 mg in 20 ml H2O) under ice bath cooling, and concentrated in vacuo. To the residual solution was added saturated NaHCO3 aqueous solution to adjust pH=8, and the mixture was extracted with AcOEt. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, and dried over NaSO4. Solvent was removed in vacuo to give methyl (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,6,9,12,21,24-hexaisobutyl-27-isopropyl-5,11,15,18,20,26,29-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (53 mg) as colorless solid.

The compounds of Prep. 194-207 were obtained in a similar manner to that of Prep. 193.

Prep. 208

To a solution of the object compound of Prep. 57 (1.00 g), (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}propanoic acid (399 mg), and Bop-Cl (416 mg) in CH2Cl2 (20 ml) was added N-ethyl-N-isopropyl-2-propanamine (422 mg) under ice-bath cooling. After being stirred at room temperature over night, the reaction solution was concentrated in vacuo. The residue was dissolved in AcOEt (50 ml) and the solution was washed with 0.5N HCl, 1M NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by Silica-gel column (eluent:2% MeOH in CHCl3) to give methyl (5R,8S,11S,14S,17S,20R,23S,26S,29S,32S,35S)-8-(1-tert-butoxyethyl)-1-(9H-fluoren-9-yl)-35-[(1R)-1-hydroxyethyl]-32-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-11,14,23,26-tetraisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-2-oxa-4,7,10,13,16,19,22,25,28,31,34-undecaazahexatriacontan-36-oate (1.25 g) as an amorphous powder.

The compounds of Prep. 209-212 were obtained in a similar manner to that of Prep. 208.

Prep. 213

To a solution of the object compound of Prep. 159 (110 mg) in dioxane (2.4 ml) was added 1N NaOH (0.6 ml) at ambient temperature and the mixture was stirred for 2-hrs. To the reaction mixture was added 10% citric acid aqueous solution to adjust pH=4, and the solution was extracted with AcOEt. The organic phase was washed with brine, and was dried over Na2SO4. Solvent was removed in vacuo and the residue was triturated with Et2O to give (3R,6S,9S,12S,15S,18R,21S,24S,27S,30S,33S)-33-[(1R)-1-hydroxyethyl]-30-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,12,21,24-pentaisobutyl-27-isopropyl-3,5,11,15,18,20,26,29-octamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (79 mg) as colorless powder.

The compound of Prep. 214 was obtained in a similar manner to that of Prep. 213.

Prep. 215

To a solution of the object compound of Prep. 110 (193 mg) was dissolved in 10% TFA in CH2Cl2 (6 ml) under ice-bath cooling. After being stirred at the same temperature for 2 hrs, to the reaction solution was added 1M NaHCO3 aqueous solution to be pH=8. The reaction mixture was extracted with CHCl3 (50 ml) and the organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by Silica-gel column (eluent: 2% MeOH in CHCl3) to give (1R)-1-{(2S,5R,8S,11S,14S,17S,20R,23S,26S,29S,32S)-8-(1-hydroxyethyl)-32-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-11,14,23,26-tetraisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl}ethyl acetate (183 mg) as an amorphous powder.

Prep. 216

To a solution of the object-compound of Prep. 215 (187 mg) in CH2Cl2 (1.2 ml) were added 4-nitrophenyl chloroformate (54 mg) and N-methylmorpholine (29 μl). After the mixture was stirred overnight, three further portions of 4-nitrophenyl chloroformate (54 mg) and N-methylmorpholine (29 μl) were added at intervals of 1 hour. After the starting compound was consumed, the mixture was diluted with AcOEt, washed with 1 N aqueous hydrochloric acid and aqueous NaHCO3, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt=1/4 and then CH2Cl2/MeOH=9/1) to give (1R)-1-[(2S,5R,8S,11S,14S,17S,20R,23S,26S,29S,32S)-32-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-11,14,23,26-tetraisobutyl-29-isopropyl-4,5,7,13,17,20,22,28,31-nonamethyl-8-(1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl]ethyl acetate (87 mg).

Prep. 217

To a solution of the object compound of Prep. 216 (27 mg) in tetrahydrofuran (1 ml) was added morpholine (4.9 μl), and the mixture was stirred at room temperature overnight. The residue was chromatographed on silica gel (CH2Cl2/MeOH=97/3 to 90/10) to give 1-{(2S,5S,8S,11S,14R,17S,20S,23S,26S,29S,32R)-29-[(1R)-1-acetoxyethyl]-26-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-5,8,17,20-tetraisobutyl-23-isopropyl-1,7,11,14,16,22,25,31,32-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl}ethyl morpholine-4-carboxylate (22 mg).

The compounds of Prep. 218-220 were obtained in a similar manner to that of Prep. 217, and the compound of Ex. 1 was obtained in a similar manner to that of Prep. 4.

Ex. 2

To a solution of the object compound of Prep. 139 (42.7 mg) in CH2Cl2 (43 ml) was added HOAt (5.5 mg) and WSCD (6.3 mg) under ice bath cooling, and the mixture was stirred at 5° C. for 13 hrs. The reaction mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with H2O, 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and was dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=95:5) to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-33-sec-butyl-3-ethyl-6-(1-hydroxyethyl)-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (29 mg) as colorless powder.

The compounds of Ex. 3-11 were obtained in a similar manner to that of Ex. 2.

Ex. 12

The object compound of Ex. 25 below (1.00 g) was dissolved in 10% TFA in CH2Cl2 (10 ml) under ice-bath cooling. After being stirred at the same temperature for 2 hrs, to the reaction solution was added 1M NaHCO3 aqueous solution to be pH 8. The reaction mixture was extracted with CHCl3 (50 ml) and the organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by Silica-gel column (eluent:2% MeOH in CHCl3) to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-33-(1-hydroxyethyl)-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (62.5 mg) as an amorphous powder.

The compound of Ex. 13 was obtained in a similar manner to that of Ex. 12.

Ex. 14

To a solution of the object compound of Prep. 41 (42.7 mg) in CH2Cl2 (48 ml) was added HOAt (7.3 mg) and WSCD (8.3 mg) under ice bath cooling, and the mixture was stirred at 5° C. for 13 hrs. The reaction mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with H2O, 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and was dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=95:5) to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-33-sec-butyl-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (29 mg) as colorless powder.

The compounds of Ex. 15-24 were obtained in a similar manner to that of Ex. 14.

Example 25

To a solution of the object compound of Prep. 20 (785 mg) and HOAt (99 mg) in CH2Cl2 (785 ml) was added a solution of WSCD (113 mg) in CH2Cl2 (10 ml) for 3 hrs under ice-bath cooling. After being stirred at 5° C. overnight, the solution was concentrated in vacuo. The residue was dissolved in AcOEt (40 ml)-H2O (40 ml), the solution was washed with 0.2N HCl, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a powder. The crude powder was purified by Silica-gel column chromatography (eluent Hexane:Acetone, 2:1) to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-33-(1-tert-butoxyethyl)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (365 mg) as an amorphous powder.

The compounds of Ex. 26-35 were obtained in a similar manner to that of Ex. 25.

Ex. 36

To a solution of the object compound of Prep. 75 (48 mg) in CH2Cl2 (37 ml) was added HOAt (6.0 mg) and WSCD (6.9 mg) under ice bath cooling, and the mixture was stirred at 5° C. for 13 hrs. The reaction mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with H2O, 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and was dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=95:5) to give, (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-3,15,18,27,30,33-hexa-isobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (34 mg) as colorless powder.

The compounds of Ex. 37-51 were obtained in a similar manner to that of Ex. 36

Ex. 52

To a solution of the object compound of Prep. 161 (920 mg) and HOAt (489 mg) in CH2Cl2 (1000 ml) was added a solution of WSCD (558 mg) in CH2Cl2 (10 ml) and the mixture was stirred under ice-bath cooling. After being stirred at 5° C. overnight, the solution was concentrated in vacuo. The residue was dissolved in AcOEt (100 ml)-H2O (100 ml), the solution was washed with 0.2N HCl, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a powder. The crude powder was purified by Silica-gel column chromatography (eluent: 4% MeOH in CHCl3) to give (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-24-(1-tert-butoxyethyl)-30-[(1R)-1-hydroxyethyl]-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-3-isopropyl-1,4,10,12,15,19,25,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (448 mg) as an amorphous powder.

The compounds of Ex. 53-73 were obtained in a similar manner to that of Ex. 52.

Ex. 74

To a solution of the object compound of Prep. 213 (79 mg) in CH2Cl2 (63 ml) was added HOAt (10.3 mg) and WSCD (11.7 mg) under ice bath cooling, and the mixture was stirred at 5° C. for 13 hrs. The reaction mixture was concentrated in vacuo and the residue was extracted with AcOEt. The organic phase was washed with H2O, 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution, and brine, and was dried over Na2SO4. Solvent was removed in vacuo, and the residue was purified by preparative thin layer chromatography (CHCl3:MeOH=95:5) to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30,33-pentaisobutyl-12-isopropyl-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (43 mg) as colorless powder.

Ex. 75

(3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-3-[(Benzyloxy)methyl]-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30,33-pentaisobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (22 mg) are dissolved in MeOH (1 ml) and hydrogenated at room temperature and atmospheric pressure over 5% Pd on charcoal. After 2 hrs, the catalyst was filtered off and the filtrate was concentrated in vacuo under reduced pressure. The residue was purified by silica-gel column chromatography (hexane-acetone, 1:1) to yield (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxymethyl)-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30,33-pentaisobutyl-12-isopropyl-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (18 mg).

Ex. 76

(3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)7-3-[(Benzyloxy)methyl]-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (20 mg) are dissolved in MeOH (2 ml) and hydrogenated at room temperature and atmospheric pressure over Pd on charcoal. After 40 minutes, the catalyst was filtered off and the filtrate was concentrated in vacuo under reduced pressure. The residue was purified by silica-gel preparative thin layer chromatography (CHCl3:MeOH=95:5) to yield (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxymethyl)-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,4,10,13,19,21,24,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (12 mg) as colorless powder.

Ex. 77

To a solution of the object compound of Prep. 217 (11.5 mg) in tetrahydrofuran (1 ml) was added sodium methanolate (25 mmol) in MeOH (1 ml), and the mixture was stirred at room temperature overnight. The mixture was submitted by ODS purification to give 1-{(2S,5S,8S,11S,14R,17S,20S,23S,26S,29S,32R)-29-[(1R)-1-hydroxyethyl]-2,6-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-5,8,17,20-tetraisobutyl-23-isopropyl-1,7,11,14,16,22,25,31,32-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl}ethyl morpholine-4-carboxylate (9 mg).

The compounds of Ex. 78-80 were obtained in a similar manner to that of Ex. 77.

Ex. 81

A solution of (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (60 mg) in MeOH (6.0 ml) was hydrogenated over 20% Pd/C (50% wet; 30 mg) at room temperature for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was evaporated to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (56 mg).

The compounds of Ex. 82 and 83 were obtained in a similar manner to that of Ex. 81.

The structure and the mass spectrometry data (ESI-MS [(M+H)+] unless otherwise-indicated) for the compounds of Examples and Preparations are shown in Table 1˜42, and the peak δ ppm of 1H-NMR data (chloroform-d, TMS internal standard) for the compounds of Examples are shown in Table 43.

Table 1˜11: Example Compounds represented by following formula

embedded image

TABLE 1 embedded image Ex. R2 MS 1 —CH2NHMe 1263.5 6 —CH2OC(O)NMe2 1321.4 9 —CH2OMe 1264.5 11 —CH2OBn 1340.7 16 Et 1249.1 18 —CH2NMeBoc 1363.5 32 Me 1234.7 34 Bn 1310.5 69 H 1220.7 76 —CH2OH 1252.6

TABLE 2 embedded image Ex. R2 MS 5 —CH2OMe 1282.9 15 Me 1253.4 19 iBu 1294.5 63 H 1239

TABLE 3 embedded image Ex. R2 R5 MS 2 Et Me 1246.6 3 nBu 1292.5 4 —(CH2)3NMeCO2Bn 1424.1 7 —(CH2)4NMeCO2Bn 1437.1 8 —CH2OC(O)NMe2 1319.7 10 —CH2OMe 1262.7 14 Me 1232.7 21 iBu 1274.8 23 —CH2OtBu 1304.8 62 H 1219 27 Me Et Negative (ESI): 1246 [M − H]

TABLE 4 embedded image Ex. R2 MS 12 Me 1221 26 Et 1256 71 H 1206.6

TABLE 5 embedded image Ex. R3 MS 59 tBuOCH2 1249 60 Cy. Hex.-CH2 1259 73 Bn 1252

TABLE 6 embedded image Ex. R2 R3 R5 MS 13 31 Me embedded image Et Me 1233 1218.6 17 24 65 —CH2-Cy. Hex. Me H embedded image 1314.69 1232.7 1218.6 20 30 64 iBu Me H embedded image 1301.0 1259 1245 25 29 35 52 Me iPr Et H embedded image 1277 1305 1291 1263 28 57 Me H embedded image 1310.5 1297 33 Me embedded image 1248.3 53 H embedded image 1353.7 54 H embedded image H 1205

TABLE 7 embedded image Ex. Y MS 22 embedded image 1190.8 72 embedded image 1188.6

TABLE 8 embedded image Ex. R3 MS 55 embedded image 1318 61 embedded image 1219 66 embedded image 1247

TABLE 9 embedded image Ex. Ra R2 MS 56 EtHN(O)C— H 1277.2 58 embedded image 1297 67 Et 1235 68 MeO(CH2)2 1264.6 70 Me2N(O)C— 1277.7 77 embedded image Me 1333.70 78 Me2N(O)C— 1291.66 79 EtHN(O)C— 1291.66 80 embedded image 1346.73

TABLE 10 embedded image Ex. X MS 38 embedded image 1244.7 40 embedded image 1244.7 48 embedded image 1306.8

TABLE 11 embedded image Ex. R1 R2 MS 36 Me embedded image 1274.4 37 embedded image 1308.5 41 embedded image 1274.5 42 embedded image 1437.6 47 embedded image 1274.8 51 embedded image 1340.8 74 embedded image 1232.5 75 embedded image 1250.7 39 H embedded image 1409.3 43 embedded image 1376.1 44 embedded image 1261.9 45 embedded image 1260.7 46 embedded image 1324.6 49 embedded image 1280.7 50 Et H 1232.7

TABLE 12 Example Compounds represented by following formula embedded image Ex. Ra MS 81 Me 1237.48 82 tBu 1278.99 83 H 1223.53
  • Table 13˜22 Preparation Compounds represented by following formula Type 1

embedded image

TABLE 13 (Type 1 - 1) embedded image Prep. R3 R4 MS 1 embedded image H 1179.6 4 embedded image 1179.7 5 embedded image 1181 10 embedded image 1179 13 embedded image 1165 14 embedded image 1206 15 embedded image 1195 16 embedded image 1199.6 57 embedded image 1224 58 embedded image 1257.7 6 Me Me 1151

TABLE 14 (Type 1 - 2) embedded image Prep. R2 R3 MS 25 33 34 Me iBu —CH2OtBu embedded image   1486.9 1529 1559 26 28 31 38 Me —CH2NMeBoc Et Bn embedded image 1488 1618 1502 1565 27 32 35 Me H —CH2-Cy.Hex. embedded image 1487 1472 1569 36 Me embedded image 1472 37 embedded image 1502 159  embedded image   1486.9 211  embedded image   1564.4 212  embedded image 1513 39 40 Me iBu embedded image   1506.7   1548.5 208  209  210  Me iPr Et embedded image 1531 1560 1560

TABLE 15 (Type 1 - 3) embedded image Prep. R1 R2 R3 R4 MS 29 Me iBu Cy.Hex. H 1555.1 30 H Me Me 1444 160 H —(CH2)4NHBoc iBu H 1630

TABLE 16 (Type 1 - 4) embedded image Prep. Rb R2 R3 MS 117 Me H embedded image 1250.7 128 129 130 132 135 136 Et nBu —(CH2)3NMeCO2Bn —(CH2)4NMeCO2Bn —CH2OC(O)NMe2 —CH2OMe embedded image 1278.7 1306.5 1455.7 1470   1351   1294   131 133 137 —CH2OMe —CH2OC(O)NMe2 —CH2OBn embedded image 1296   1253   1372.8 134 —CH2OMe embedded image 1314.5 193 200 197 203 199 202 207 Me H H Me Me H Et iBu   —CH2OBn   —(CH2)4NMeCO2Bn —(CH2)4NHCO2Bn H embedded image 1306.8 1292   1356.8 1370.8 1469.9 1441.9 1264.7

TABLE 17 (Type 1 - 5) embedded image Prep. Rc Rd R2 MS 158 Me —C(O)NHPh H 1385.6 194 Me H embedded image 1340.8 198 Me embedded image 1306   201 204 H Me embedded image 1292   1306.8 206 H embedded image 1312.7

TABLE 18 (Type 1 - 6) embedded image Prep. Re R3 R4 MS 2 —C(S)NHPh embedded image H 1314.5 59 Boc embedded image 1279.6 60 embedded image 1299.4 61 embedded image 1281 62 embedded image 1295 65 embedded image 1279 66 embedded image 1265 67 embedded image 1306 63 Me Me 1251 93 Fmoc embedded image H 1446 94 embedded image 1479.9

TABLE 19 (Type 1 - 7) embedded image Prep. R1 R2 R3 R5 MS  64 Me Et embedded image Me 1439   118 119 121 123 124 125 Et —(CH2)4NMeCO2Bn —(CH2)3NMeCO2Bn nBu —CH2OMe —CH2OC(O)NMe2 embedded image 1379.5 1570   1556.6 1406.7 1394   1451   120 126 127 —CH2OMe —CH2OC(O)NMe2 —CH2OBn embedded image 1396   1453   1472.8 122 —CH2OMe embedded image 1414.1  91 Me embedded image Et 1379    92 embedded image 1365   179 192 178 185 182 184 191 H Me Me H H Me Et —CH2OBn   iBu   —(CH2)4NHCO2Bn —(CH2)4NMeCO2Bn H embedded image Me 1456.9 1470.9 1406.9 1392   1542   1570.0 1364.8

TABLE 20 (Type 1 - 8) embedded image Prep. R1 R2 MS 186 188 H Me embedded image 1392   1406.9 180 Me embedded image 1406.9 187 Me embedded image 1440.9 190 H embedded image 1412.8

TABLE 21 (Type 1 - 9) embedded image Prep. Y MS 181 embedded image 1376.7 183 embedded image 1377.6 189 embedded image 1438.9 195 embedded image 1276.8 196 embedded image 1277.1 205 embedded image 1324.7

TABLE 22 (Type 1 - 10) embedded image Prep. Rf MS 154 —C(S)NHPh 1486.5 155 H 1351.6 157 Boc 1451.6
  • Table 23˜31: Preparation Compounds represented by following formula Type 2

embedded image

TABLE 23 (Type 2 - 1) embedded image Prep. Rg MS 7 embedded image 1351 8 —C(O)NMe2 1309 11 —C(O)NHEt 1309 12 Me 1252 17 —(CH2)2OMe 1296 18 H 1238.6

TABLE 24 (Type 2 - 2) embedded image Prep. R3 MS 9 embedded image 1385 138 embedded image 1251 153 embedded image 1251

TABLE 25 (Type 2 - 3) embedded image Prep. R3 MS 95 embedded image 1517 97 embedded image 1501 102 embedded image 1503 103 embedded image 1501 109 embedded image 1551

TABLE 26 (Type 2 - 4) embedded image Prep. R3 MS 96 —(CH2)2NMeCO2Bn 1485 98 Bn 1385 105 —CH2-Cy.Hex. 1391 108 Ph 1371 111 Cy.Hex. 1377

TABLE 27 (Type 2 - 5) embedded image Prep. Rh MS 99 —(CH2)2OMe 1396 101 embedded image 1451 107 Me 1352 112 —C(O)NHEt 1409 113 —C(O)NMe2 1409 116 H 1338.7

TABLE 28 (Type 2-6) embedded image Prep. R3 R5 MS 104 embedded image Me 1351 106 embedded image 1351 114 embedded image 1367 100 embedded image H 1336

TABLE 29 (Type 2-7) embedded image Prep. Ri MS 19 H 1220.6 115 Boc 1320.7

TABLE 30 (Type 2-8) embedded image Prep. Rj MS 90 Boc 1545 152 H 1423

TABLE 31 (Type 2-9) Prep. R MS 168 embedded image 1322
  • Table 32˜36: Preparation Compounds represented by following formula Type 3

embedded image

TABLE 32 (Type 3-1) embedded image Prep. R1 R2 R3 MS  55  79  86 Me H Me embedded image Cy. Hex. iBu 1318.9 1278 1292.7  76 embedded image 1326.7  84 embedded image 1292  85 H embedded image 1298.7 214 embedded image 1393

TABLE 33 (Type 3-2) embedded image Prep. R1 R2 R3 R4 R5 MS  43 Me H Me Me Me 1208  77  81  83 H —(CH2)4NHCO2Bn —CH2OBn iBu embedded image H 1427.9 1342.7 1278  88 Et H 1250.7 150 Me Me embedded image H Et 1265 151 embedded image Negative (ESI): 1249 [M − H]

TABLE 34 (Type 3-3) embedded image Prep. R2 R3 MS 22 Me Cy. Hex. 1277 44 H tBu 1236 46 Me 1250 47 —CH2-Cy. Hex. 1332 48 Me iPr 1236 53 Me Ph 1270.6 54 iBu 1313.1 144 CH2OMe 1300.8 75 iBu iBu 1292.7 80 —(CH2)4NMeCO2Bn 1455.9 89 —CH2OBn 1356.8 213 Me 1250.7

TABLE 35 (Type 3-4) embedded image Prep. R2 R3 MS  20  21  24 Me Et iPr embedded image 1295 1309 1323  23 Me embedded image 1328.9  41  45  56 139 140 141 145 146 147 Me —CH2OtBu iBu Et —CH2OC(O)NMe2 —(CH2)3NMeCO2Bn nBu —CH2OMe —(CH2)4NMeCO2Bn embedded image 1232.7 1322 1292 1264.7 1337 1442.1 1292.5 1280 1455  42  49  50  52 142 143 148 Bn Et Me —CH2NMeBoc —CH2OC(O)NMe2 —CH2OMe —CH2OBn embedded image 1328 1266 1252 1381 1339 1282 1358.7 51 Me embedded image 1266 149 Et embedded image 1253

TABLE 36 (Type 3-5) embedded image Prep. X MS 78 embedded image 1262.5 82 embedded image 1262.5 87 embedded image 1324.7
  • Table 37˜40: Preparation Compounds represented by following formula Type 4

embedded image

TABLE 37 (Type 4-1) embedded image Prep. R3 MS 69 Bn 1272 71 Ph 1257 72 Cy. Hex. 1263 73 —CH2-Cy. Hex. 1277 163 —CH2OtBu 1267 170 —(CH2)2NMeCO2Bn 1371

TABLE 38 (type 4-2) embedded image Prep. Rk MS 171 embedded image 1337 172 Me 1238 173 —C(O)NMe2 1295 174 —C(O)NHEt 1295 175 —(CH2)2OMe 1282 176 H 1224.6

TABLE 39 (Type 4-3) embedded image Prep. R3 R5 MS 68 embedded image H 1223 70 embedded image Me 1237 74 embedded image 1253 161 embedded image 1281 162 embedded image 1315 164 embedded image 1265 165 embedded image 1336 169 embedded image 1237

TABLE 40 (Type 4-4) Prep. R MS 177 embedded image 1206.6

TABLE 41 Preparation Compounds of the Other Type represented by following formula embedded image Prep. Rn Rp MS 3 embedded image H 1052.6 166 embedded image 1123 167 OH embedded image 1336.6 156 embedded image 1818.7

TABLE 42 Preparation Compounds of the Another Type represented by following formula embedded image Prep. Ra MS 110 But- 1318.73 215 HO— 1262.73 216 embedded image 1427.72 217 embedded image 1375.60 218 Me2N(O)C— 1330.70 219 EtHN(O)C— 1375.77 220 embedded image 1430.73

TABLE 43 Ex. NMR Data 1 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 7.20 (1H, d, J = 9 Hz), 7.0 (1H, d, J = 8 Hz), 6.58 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.35-5.25 (2H, m), 5.12 (1H, m), 4.85-4.77 (2H, m), 4.75-7.60 (3H, m), 4.65-4.52 (2H, m), 4.31-4.10 (3H, m), 4.0-3.8 (2H, m), 3.72 (1H, brs), 3.45 (3H, s), 3.39 (3H, s), 3.20 (6H, s), 3.13 (6H, s), 3.10 (3H, s), 3.02 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 2 8.30 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 9.0 Hz), 6.95 (1H, d, J = 9.0 Hz), 6.68 (1H, d, J = 9.5 Hz), 6.57 (1H, d, J = 9.5 Hz), 5.65 (1H, d, J = 3.0 Hz), 5.37-5.56 (3H, m), 5.30 (1H, m), 5.13 (1H, m), 4.97 (2H, m), 4.86 (2H, m), 4.70 (2H, m), 4.53 (1H, m), 4.22 (1H, m), 3.99 (1H, s), 3.42 (1H, s), 3.13 (3H, s), 3.42 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.97 (3H, s), 2.93 (3H, s), 2.57 (1H, d, J = 4.5 Hz), 2.33 (2H, m), 2.15-0.75 (64H, m), 1.65 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 6.0 Hz), 0.75 (3H, d, J = 6.5 Hz) 3 8.35 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.9 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.57 (1H, d, J = 8.9 Hz), 5.64 (1H, d, J = 3 Hz), 5.38-5.52 (3H, m), 5.30 (1H, m), 5.13 (1H, m), 4.95 (2H, m), 4.87 (2H, m), 4.70 (2H, m), 4.53 (1H, m), 4.23 (1H, m), 3.95 (1H, s), 3.41 (1H, s), 3.13 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.97 (3H, s), 2.93 (3H, s), 2.56 (1H, d, J = 5.5 Hz), 2.34 (2H, m), 0.75-2.15 (68H, m), 1.66 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6.5 Hz) 4 8.14 (1H, d, J = 8.5 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.34 (5H, m), 6.94 (1H, d, J = 8.5 Hz), 6.89 (1H, d, J = 8.5 Hz), 6.53 (1H, d, J = 8.5 Hz), 5.62 (1H, d, J = 2.5 Hz), 5.41 (3H, m), 5.26 (1H, m), 5.11 (2H, s), 5.11 (1H, m), 4.91 (2H, m), 4.86 (2H, m), 4.69 (2H, m), 4.52 (1H, m), 4.22 (1H, m), 3.97 (1H, m), 3.45 (1H, s), 3.20-3.41 (2H, m), 3.12 (3H, s), 3.09 (3H, s), 3.04 (3H, s), 3.02 (3H, s), 2.93 (3H, s), 2.91 (3H, s), 2.88 (3H, s), 2.70 (1H, s), 2.35 (2H, m), 0.75-21.15 (63H, m), 1.66 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6.5 Hz) 5 9.24 (0.5H, d, J = 9.0 Hz), 8.89 (0.5H, d, J = 9.0 Hz), 8.33 (0.5H, d, J = 9.0 Hz), 7.55 (0.5H, d, J = 9.0 Hz), 7.06-7.42 (5H, m), 7.17 (1H, d, J = 9.0 Hz), 7.05 (0.5H, d, J = 9.0 Hz), 6.98 (0.5H, d, J = 9.0 Hz), 6.87 (1H, d, J = 9.0 Hz), 6.42 (0.5H, s), 6.14 (0.5H, s), 5.67 (1H, s), 5.29-5.49 (3H, m), 5.06 (1H, m), 4.89 (3H, m), 4.71 (1H, m), 4.57 (1H, m), 4.28 (2H, m), 3.48-3.81 (3H, m), 3.36 (1.5H, s), 3.33 (1.5H, s), 3.23 (1.5H, s), 3.20 (1.5H, s), 3.13 (3H, s), 3.08 (3H, s), 2.98 (1.5H, s), 2.96 (1.5H, s), 2.94 (1.5H, s), 2.90 (1.5H, s), 2.75 (1.5H, s), 2.69 (1.5H, s), 2.62 (0.5H, d, J = 5.5 Hz), 2.52 (0.5H, d, J = 5.5 Hz), 2.36 (2H, m), 0.60-2.10 (61H, m) 6 8.20 (1H, brd, J = 9 Hz), 7.70 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.55 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.35-5.25 (2H, m), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.75 (5H, m), 4.75-4.65 (2H, m), 4.65-4.55 (2H, m), 4.31-4.10 (3H, m), 3.72 (1H, brs), 3.17 (3H, s), 3.12 (6H, s), 3.08 (3H, s), 3.05 (3H, s), 2.93 (6H, s), 2.89 (3H, s), 2.85 (3H, s), 2.55 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 7.5 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 7 7.75 (1H, brd, J = 9 Hz), 7.55 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.80-6.70 (5H, m), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.30-5.25 (2H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.23 (1H, m), 4.21 (1H, m), 3.88 (1H, brs), 3.50-3.41 (2H, m), 3.17 (3H, s), 3.13 (3H, s), 3.05 (3H, s), 3.02 (3H, s), 2.98 (3H, s), 2.96 (3H, s), 2.90 (3H, s), 2.38 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-0.80 (51H, m), 1.62 (3H, d, 6 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 8 8.98 (1H, brd, J = 9 Hz), 7.58 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.80 (1H, d, J = 8 Hz), 6.72 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.55 (3H, m), 4.45-4.40 (1H, m), 4.38-4.25 (2H, m), 4.25-4.05 (1H, m), 3.73 (1H, brs), 3.39 (3H, s), 3.30 (3H, s), 3.18 (3H, s), 3.14 (3H, s), 3.06 (3H, s), 2.90 (6H, s), 2.85 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (11H, m), 1.64 (3H, d, J = 6 Hz), 1.36 (3H, d, J = 7.5 Hz), 1.31 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.10-0.70 (34H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 9 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.4-5.2 (2H, m), 5.10-5.0 (2H, m), 5.0-4.60 (5H, m), 4.65-4.55 (1H, m), 4.31-4.10 (2H, m), 4.05-3.98 (1H, m), 3.85-3.50 (2H, m), 3.72 (1H, brs), 3.38 (3H, s), 3.33 (3H, s), 3.28 (3H, s), 3.20 (3H, s), 3.19 (3H, s), 3.05 (6H, s), 2.90 (3H, s), 2.54 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 0.97 (3H, d, J = 7 Hz), 0.90 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 10 8.45 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.27 (1H, m), 4.21 (1H, m), 3.88 (1H, brs), 3.75-3.70 (1H, m), 3.65-3.60 (1H, m), 3.37 (3H, s), 3.14 (3H, s), 3.12 (3H, s), 3.05 (3H, s), 3.02 (3H, s), 2.92 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (11H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.0-0.8 (34H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 12 8.71 (1H, d, J = 9 Hz), 7.67 (1H, d, J = 9 Hz), 6.97 (1H, d, J = 9 Hz), 6.92 (1H, d, J = 8 Hz), 6.86 (1H, d, J = 7 Hz), 5.66 (1H, d, J = 3 Hz), 5.56-4.78 (11H, m), 4.32-4.15 (3H, m), 3.69 (1H, brs), 3.28 (3H, s), 3.19 (3H, s), 3.08 (3H, s), 3.06 (6H, s), 2.99 (1H, d, J = 5 Hz), 2.91 (3H, s), 2.51 (1H, brd, J = 6 Hz), 2.45-2.25 (2H, m), 2.20-1.50 (11H, m), 1.66 (3H, d, J = 6 Hz), 1.48-1.16 (9H, m), 1.45 (3H, d, J = 6 Hz), 1.14 (3H, d, J = 6 Hz), 1.10 (3H, d, J = 6 Hz), 1.05-0.80 (26H, m), 0.82 (3H, d, J = 6 Hz), 0.72 (3H, d, J = 7 Hz) 14 8.45 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.27 (1H, m), 4.21 (1H, m), 3.88 (1H, brs), 3.13 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 3.01 (3H, s), 2.98 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (11H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (34H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 15 9.28 (1H, d, J = 8.5 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.15-7.43 (5H, m), 7.12 (1H, d, J = 9.0 Hz), 6.97 (1H, d, J = 8.5 Hz), 6.86 (1H, d, J = 8.0 Hz), 6.42 (1H, s), 5.69 (1H, d, J = 2.5 Hz), 5.21-5.57 (4H, m), 5.08 (1H, m), 4.88 (4H, m), 4.72 (1H, m), 4.56 (1H, m), 4.27 (2H, m), 3.70 (1H, m), 3.24 (3H, s), 3.13 (3H, s), 3.09 (3H, s), 3.07 (3H, s), 2.92 (3H, s), 2.73 (3H, s), 2.52 (1H, d, J = 5.0 Hz), 2.36 (2H, m), 0.68-2.04 (62H, m) 16 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.35-5.25 (2H, m), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (3H, m), 4.75-4.65 (2H, m), 4.73 (1H, m), 4.53 (1H, m), 4.31-4.10 (3H, m), 3.72 (1H, brs), 3.31 (3H, s), 3.22 (3H, s), 3.18 (3H, s), 3.06 (6H, s), 3.02 (3H, s), 2.90 (3H, s), 2.19 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (12H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (33H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 17 8.95 (1H, brd, J = 9 Hz), 7.72 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.93 (1H, d, J = 9 Hz), 6.55 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.35 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.25 (1H, m), 4.22 (1H, m), 3.88 (1H, brs), 3.15 (3H, s), 3.12 (3H, s), 3.06 (3H, s), 3.03 (6H, s), 2.92 (3H, s), 2.48 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-0.8 (63H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) 18 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 7.20 (1H, d, J = 9 Hz), 7.00 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.35-5.25 (2H, m), 5.12 (1H, m), 4.9-4.8 (5H m), 4.65-4.52 (2H, m), 4.31-4.10 (3H, m), 4.0-3.8 (2H, m), 3.72 (1H, brs), 3.55 (3H, s), 3.39 (3H, s), 3.24 (3H, s), 3.13 (6H s), 3.10 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.46 (9H, s), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 19 9.20 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 9.0 Hz), 7.07-7.40 (5H, m), 7.14, 6.49 (1H, brd, J = 7.0 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.43 (1H, s), 5.66 (1H, d, J = 3.0 Hz), 5.30-5.50 (3H, m), 5.25 (1H, m), 5.10 (1H, m), 4.93 (2H, m), 4.84 (3H, m), 4.70 (1H, m), 4.54 (1H, m), 4.27 (1H, m), 4.27 (1H, m), 3.77 (1H, s), 3.21 (3H, s), 3.09 (3H, s), 3.06 (3H, s), 3.03 (3H, s), 2.91 (3H, s), 2.65 (3H, s), 2.51 (1H, d, J = 5.0 Hz), 2.36 (2H, m), 0.75-2.15 (65H, m), 0.75 (3H, d, J = 6.5 Hz) 20 8.34 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 8.5 Hz), 6.95 (1H, d, J = 8.5 Hz), 6.87 (1H, d, J = 8.0 Hz), 6.55 (1H, d, J = 8.5 Hz), 5.65 (1H, d, J = 3.0 Hz), 5.40-5.56 (3H, m), 5.31 (1H, m), 5.06 (3H, m), 4.87 (2H, m), 4.71 (2H, m), 4.52 (1H, m), 4.27 (1H, m), 3.96 (1H, s), 3.48 (1H, d, J = 5.0 Hz), 3.12 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.95 (3H, s), 2.93 (3H, s), 2.55 (1H, d), 2.34 (2H, m), 0.80-2.15 (67H, m), 1.66 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 7.5 Hz), 0.80 (3H, d, J = 6.5 Hz), 0.74 (3H, d, J = 6.5 Hz) 21 8.45 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.0-4.8 (5H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.27 (1H, m), 4.21 (1H, m), 3.88 (1H, brs), 3.13 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 3.01 (3H, s), 2.98 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (14H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.0-0.8 (40H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 22 8.06 (1H, d, J = 9 Hz), 7.75 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 7.06 (1H, d, J = 9 Hz), 6.71 (1H, d, J = 8 Hz), 5.53-5.41 (4H, m), 5.32-5.30 (1H, m), 5.18-5.12 (1H, m), 4.96-4.85 (3H, m), 4.72-4.68 (1H, m), 4.68-4.55 (2H, m), 4.22-4.12 (2H, m), 3.71 (1H, brd, J = 5 Hz), 3.38 (1H, m), 3.25 (3H, s), 3.16 (3H, s), 3.06 (3H, s), 3.25-2.93 (2H, m), 3.02 (3H, s), 3.00 (3H, s), 2.98 (3H, m), 2.45-2.26 (2H, m), 2.13-1.97 (4H, m), 1.86-1.62 (3H, m), 1.63 (3H, brd, J = 6 Hz), 1.57-1.0 (6H, m), 1.49 (3H, s), 1.48 (3H, s), 1.33 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 23 8.58 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.90 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.25 (1H, m), 4.22 (1H, m), 4.0-3.8 (1H, m), 3.83 (1H, brs), 3.75-3.70 (1H, m), 3.65-3.60 (1H, m), 3.14 (3H, s), 3.12 (3H, s), 3.09 (3H, s), 3.06 (3H, s), 3.03 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (11H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.0-0.8 (42H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 24 9.00 (1H, brd, J = 9 Hz), 7.72 (1H, brd, J = 9 Hz), 6.95 (2H, d, J = 9 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.35 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.25 (1H, m), 4.22 (1H, m), 3.88 (1H, brs), 3.18 (3H, s), 3.15 (3H, s), 3.06 (3H, s), 3.05 (6H, s), 2.91 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 1.0-0.8 (35H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 25 9.38 (1H, brd, J = 9 Hz), 7.52 (1H, brd, J = 9 Hz), 6.97 (1H, d, J = 9 Hz), 6.87 (1H, d, J = 8 Hz), 6.68 (1H, d, J = 9 Hz), 5.66 (1H, d, J = 3 Hz), 5.6-5.2 (4H, m), 5.04 (1H, m), 5.0-4.8 (5H, m), 4.71 (1H, m), 4.6-4.5 (2H, m), 4.3-4.2 (2H, m), 3.74 (1H, brs), 3.30 (3H, s), 3.21 (3H, s), 3.06 (3H, s), 3.05 (3H, s), 3.03 (3H, s), 2.89 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.45-2.25 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.41 (3H, d, J = 7 Hz), 1.33 (3H, d, J = 7 Hz), 1.19 (9H, s), 1.12 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 7 Hz), 1.04-0.85 (27H, m), 0.82 (3H, d, J = 6 Hz), 0.72 (3H, d, J = 7 Hz) (for a major conformer) 26 8.85 (1H, brd, J = 9 Hz), 7.75 (1H, brd, J = 9 Hz), 6.98 (1H, brd, J = 9 Hz), 6.88 (2H, brs), 5.64 (1H, brs), 5.55-4.49 (13H, m), 4.32-4.17 (2H, m), 3.72 (1H, brs), 3.30 (3H, s), 3.19 (3H, s), 3.08 (6H, s), 3.05 (3H, s), 2.92 (3H, s), 2.51 (1H, brs), 2.42-0.65 (69H, m) 27 8.42 (1H, brd, J = 9 Hz), 7.85 (1H, brd, J = 8 Hz), 6.96 (1H, d, J = 8 Hz), 6.76 (1H, d, J = 9 Hz), 6.76 (1H, d, J = 9 Hz), 5.65 (1H, d, J = 3 Hz), 5.54-5.10 (5H, m), 5.05-4.78 (4H, m), 4.75-4.60 (2H, m), 4.57-4.45 (1H, m), 4.32-4.28 (2H, m), 3.86 (1H, brs), 3.25-3.05 (2H, m), 3.14 (3H, s), 3.13 (3H, s), 3.05 (3H, s), 3.00 (3H, s), 2.94 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.43-2.23 (2H, m), 2.20-0.80 (56H, m), 1.66 (3H, d, J = 6 Hz), 1.42 (3H, d, J = 6 Hz), 1.33 (3H, d, J = 6 Hz), 1.14 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 7 Hz), 0.76 (3H, d, J = 7 Hz) 28 9.21 (1H, d, J = 9.0 Hz), 7.57 (1H, d, J = 9.0 Hz), 7.29 (5H, m), 6.97 (1H, d, J = 8.5 Hz), 6.87 (1H, d, J = 8.0 Hz), 6.80 (1H, d, J = 6.8 Hz), 5.66 (1H, d, J = 2.9 Hz), 5.29-5.53 (4H, m), 5.06 (1H, m), 4.81-4.98 (4H, m), 4.72 (1H, m), 4.57 (4H, m), 4.45 (1H, m), 4.24 (2H, m), 3.72 (1H, s), 2.90 (3H, s), 3.02 (3H, s), 3.07 (6H, s), 3.22 (3H, s), 3.23 (3H, s), 2.50 (1H, d, J = 3.0 Hz), 2.35 (2H, m), 0.75-2.10 (59H, m), 1.66 (3H, d, J = 6.5 Hz), 0.72 (3H, d, J = 7.0 Hz) 29 8.48 (1H, d, J = 9 Hz), 8.20 (1H, d, J = 9 Hz), 7.67 (1H, d, J = 9 Hz), 7.37 (1H, d, J = 9 Hz), 7.12 (1H, d, J = 8 Hz), 6.60 (1H, brs), 5.60-3.85 (14H, m), 3.8-3.6 (1H, m), 3.19 (3H, s), 3.15 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 3.00 (3H, s), 2.92 (3H, s), 2.55-1.90 (6H, m), 1.88-0.74 (58H, m), 1.37 (3H, d, J = 7 Hz), 1.30 (3H, d, J = 7 Hz), 1.07 (9H, s), 0.74 (3H, J = 7 Hz) 30 8.54 (1H, brd, J = 9 Hz), 7.76 (1H, d, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.88 (1H, d, J = 8 Hz), 6.61 (1H, d, J = 9 Hz), 5.66 (1H, d, J = 3 Hz), 5.56-5.18 (4H, m), 5.15-5.05 (1H, m), 5.03-4.80 (4H, m), 4.76-4.64 (2H, m), 4.58-4.45 (1H, m), 4.30-4.15 (2H, m), 3.86 (1H, brs), 3.12 (3H, s), 3.09 (3H, s), 3.04 (3H, s), 3.02 (3H, s), 2.97 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.42-2.25 (2H, m), 2.20-0.85 (52H, m), 1.62 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 8 Hz), 1.32 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 7 Hz), 0.80 (3H, d, J = 7 Hz), 0.73 (3H, d, J = 7 Hz) 31 7.85 (1H, brd, J = 9 Hz), 7.48 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.55-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.55 (3H, m), 4.27-4.10 (2H, m), 3.88 (1H, brs), 3.13 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 3.02 (3H, s), 2.98 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (33H, m), 0.74 (3H, d, J = 7 Hz) 32 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.35-5.25 (2H, m), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (3H, m), 4.75-4.65 (2H, m), 4.73 (1H, m), 4.53 (1H, m), 4.31-4.10 (3H, m), 3.72 (1H, brs), 3.32 (3H, s), 3.22 (3H, s), 3.20 (3H, s), 3.05 (6H, s), 3.03 (3H, s), 2.90 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.35 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m) 0.74 (3H, d, J = 7 Hz) (for a major conformer) 33 9.10 (1H, brd, J = 9 Hz), 7.60 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.35-5.25 (2H, m), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (3H, m), 4.75-4.65 (2H, m), 4.73 (1H, m), 4.53 (1H, m), 4.31-4.10 (3H, m), 3.72 (1H, brs), 3.60 (1H, m), 3.45 (1H, m), 3.29 (3H, s), 3.24 (3H, s), 3.06 (6H, s), 3.03 (3H, s), 2.90 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.35 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (33H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 34 8.80 (1H, brd, J = 9 Hz), 7.45-7.25 (5H, m), 7.60 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.2 (4H, m), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.65 (5H, m), 4.58 (1H, m), 4.45 (1H, m), 4.31-4.10 (3H, m), 3.9-3.8 (2H, m), 3.55 (1H, brs), 3.32 (3H, s), 3.22 (3H, s), 3.05 (6H, s), 3.02 (3H, s), 2.90 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 35 9.16 (1H, brd, J = 9 Hz), 7.61 (1H, brd, J = 9 Hz), 6.95 (1H, brd, J = 8 Hz), 6.85 (1H, brd, J = 8 Hz), 6.62 (1H, brd, J = 8 Hz), 5.64 (1H, d, J = 3 Hz), 5.52-4.44 (13H, m), 4.33-4.09 (2H, m), 3.74 (1H, brs), 3.32 (3H, s), 3.20 (3H, s), 3.07 (6H, s), 3.02 (3H, s), 2.92 (3H, s), 2.49 (1H, brs), 2.43-0.77 (57H, m), 1.68 (3H, d, J = 6 Hz), 1.62 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 6 Hz), 1.18 (9H, s), 0.74 (3H, d, J = 7 Hz) 36 8.45 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (3H, m), 5.31 (1H, dd, J = 12 and 4 Hz), 5.12 (1H, dd, J = 10 and 4 Hz), 5.0-4.8 (4H, m), 4.75-4.65 (2H, m), 4.53 (1H, m), 4.27 (1H, m), 4.21 (1H, m), 3.88 (1H, brs), 3.13 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 3.01 (3H, s), 2.98 (3H, s), 2.92 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.9 (5H, m), 1.9-1.1 (11H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.13 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (34H, m), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 37 7.83 (1H, brd, J = 9 Hz), 7.55 (1H, brd, J = 9 Hz), 7.32-7.20 (5H, m), 7.05 (1H, d, J = 9 Hz), 7.02 (1H, d, J = 9 Hz), 6.70 (1H, d, J = 8 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.39-5.32 (2H, m), 5.15-5.05 (2H, m), 4.95-4.90 (1H, m), 4.83-4.7 (4H, m), 4.63 (1H, m), 4.37-4.32 (4H, m), 3.65 (1H, brs), 3.38 (3H, s), 3.33 (3H, s), 3.05 (3H, s), 3.02 (3H, s), 3.00 (3H, s), 2.62 (3H, s), 2.49 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.8 (4H, m), 1.9-0.8 (46H, m), 1.66 (3H, d, J = 6 Hz), 1.33 (3H, d, J = 6 Hz), 1.14 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 38 9.18 (1H, d, J = 8.5 Hz), 7.45 (1H, d, J = 9.0 Hz), 7.06 (1H, d, J = 9.0 Hz), 6.99 (1H, d, J = 9.0 Hz), 6.85 (1H, d, J = 7.5 Hz), 5.70 (1H, d, J = 3.5 Hz), 5.27 (4H, m), 5.17 (1H, m), 4.94 (3H, m), 4.69 (3H, m), 4.54 (1H, m), 4.29 (2H, m), 3.71 (1H, m), 3.60 (1H, m), 3.46 (1H, m), 3.21 (3H, s), 3.09 (3H, s), 3.07 (3H, s), 3.02 (3H, s), 2.89 (3H, s), 2.50 (1H, d, J = 5.0 Hz), 2.35 (2H, m), 0.80-2.20 (69H, m), 0.72 (3H, d, J = 7.0 Hz) 39 7.72 (1H, brd, J = 9 Hz), 7.45-7.40 (5H, m), 7.30 (1H, d, J = 9 Hz), 7.15 (1H, d, J = 9 Hz), 7.05 (1H, d, J = 9 Hz), 6.90 (1H, d, J = 8 Hz), 6.70 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.56-5.4 (2H, m), 5.39-5.32 (2H, m), 5.15-5.05 (2H, m), 5.11-5.10 (2H, m), 4.95-4.90 (2H, m), 4.9-4.5 (3H, m), 4.4-4.3 (2H, m), 4.19-4.15 (1H, m), 4.00-3.95 (2H, m), 3.55 (1H, brs), 3.36 (3H, s), 3.25 (3H, s), 3.20 (3H, s), 3.05 (3H, s), 2.94 (3H, s), 2.50 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.8 (4H, m), 1.9-0.8 (53H, m), 1.66 (3H, d, J = 6 Hz), 1.50 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 6.5 Hz), 1.25 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 40 8.34 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 7.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 6.97 (1H, d, J = 7.0 Hz), 5.80 (1H, d, J = 9.0 Hz), 5.25-5.54 (5H, m), 4.95 (3H, m), 4.53-4.75 (4H, m), 4.14 (1H, m), 4.05 (1H, m), 3.92 (1H, m), 3.78 (1H, m), 3.59 (1H, m), 3.44 (3H, s), 3.16 (3H, s), 3.06 (6H, s), 2.70 (3H, s), 2.29 (3H, m), 0.75-2.15 (72H, m) 41 8.00 (1H, brd, J = 9 Hz), 7.67 (1H, brd, J = 9 Hz), 7.18 (1H, d, J = 9 Hz), 6.90 (1H, d, J = 8 Hz), 6.80 (1H, d, J = 9 Hz), 5.72 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.39-5.32 (2H, m), 5.25-5.15 (2H, m), 4.95-4.90 (1H, m), 4.85-4.75 (4H, m), 4.60 (1H, m), 4.32-4.30 (2H, m), 3.89 (1H, brs), 3.32 (3H, s), 3.07 (3H, s), 3.03 (6H, s), 3.00 (3H, s), 2.72 (3H, s), 2.50 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.8 (4H, m), 1.9-0.8 (55H, m), 1.61 (3H, d, J = 6 Hz), 1.30 (3H, d, J = 6 Hz), 1.12 (3H, d, J = 6.5 Hz), 1.02 (3H, d, J = 7 Hz), 1.01 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 42 7.82 (1H, brd, J = 9 Hz), 7.6-7.5 (5H, m), 6.85 (1H, d, J = 9 Hz), 6.90 (2H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.39-5.32 (2H, m), 5.15-5.05 (2H, m), 5.11 (2H, m), 4.95-4.90 (1H, m), 4.9-4.7 (4H, m), 4.63 (1H, m), 4.37-4.32 (2H, m), 3.75-3.70 (2H, m), 3.88 (1H, brs), 3.36 (3H, s), 3.16 (6H, s), 3.06 (6H, s), 3.20 (3H, s), 3.19 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.8 (4H, m), 1.9-0.8 (52H, m), 1.66 (3H, d, J = 6 Hz), 1.33 (3H, d, J = 6 Hz), 1.14 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 43 8.15 (1H, brd, J = 9 Hz), 7.95 (1H, d, J = 9 Hz), 7.85 (1H, d, J = 9 Hz), 7.20 (1H, d, J = 9 Hz), 6.90 (2H, d, J = 8 Hz), 5.80 (1H, d, J = 3 Hz), 5.52-5.2 (4H, m), 5.1-4.85 (3H, m), 4.75-4.70 (2H, m), 4.65-4.51 (4H, m), 4.2-4.0 (4H, m), 3.55 (1H, brs), 3.13 (3H, s), 3.16 (6H, s), 3.06 (6H, s), 2.76 (3H, s), 2.4-2.2 (3H, m), 2.2-1.8 (4H, m), 1.9-0.8 (58H, m), 1.66 (3H, d, J = 6 Hz), 1.50 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 6.5 Hz), 1.25 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 44 8.62 (1H, brd, J = 9 Hz), 7.70 (1H, brd, J = 9 Hz), 7.50 (1H, brd, J = 9 Hz), 7.15 (1H, d, J = 9 Hz), 7.05 (1H, d, J = 8 Hz), 6.62 (1H, d, J = 9 Hz), 5.71 (1H, d, J = 3 Hz), 5.55-5.45 (2H, m), 5.39-5.30 (2H, m), 5.20-5.15 (2H, m), 5.08-4.80 (4H, m), 4.73-4.60 (1H, m), 4.62-4.52 (1H, m), 4.45-4.25 (2H, m), 3.50 (1H, brs), 3.25 (3H, s), 3.06 (3H, s), 3.01 (3H, s), 2.95 (3H, s), 2.93 (3H, s), 2.31 (1H, brd, J = 5 Hz), 2.2-2.0 (2H, m), 2.0-1.75 (4H, m), 1.9-0.8 (55H, m), 1.55 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.12 (3H, d, J = 6.5 Hz) 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz) (for a major conformer) 45 8.13 (1H, brd, J = 9 Hz), 7.75 (1H, brd, J = 9 Hz), 7.32 (1H, d, J = 9 Hz), 7.25 (1H, d, J = 8 Hz)), 7.05 (2H, d, J = 8 Hz), 5.81 (1H, d, J = 3 Hz), 5.55-5.45 (2H, m), 5.42-5.28 (2H, m), 5.10-5.05 (1H, m), 5.03-4.90 (2H, m), 4.80-4.70 (3H, m), 4.65-4.51 (2H, m), 4.30-4.21 (2H, m), 3.55 (1H, brs), 3.52 (3H, s), 3.16 (3H, s), 3.08 (6H, s), 2.75 (3H, s), 2.39-2.05 (3H, m), 2.0-1.75 (4H, m), 1.9-0.8 (55H, m), 1.57 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 7.5 Hz), 1.23 (3H, d, J = 6 Hz), 1.12 (3H, d, J = 6.5 Hz), 1.07 (3H, d, J = 7 Hz), 0.74 (3H, d, J = 6 Hz) (for a major conformer) 46 8.50 (1H, brd, J = 9 Hz), 7.75 (1H, brd, J = 9 Hz), 7.35 (1H, d, J = 9 Hz), 7.35-7.25 (5H, m), 7.32 (1H, d, J = 8 Hz)), 7.20 (1H, d, J = 8 Hz), 7.02 (1H, d, J = 9 Hz), 5.71 (1H, d, J = 3 Hz), 5.55-5.45 (2H, m), 5.39-5.30 (2H, m), 5.20-5.15 (2H, m), 5.08-4.80 (4H, m), 4.73-4.60 (1H, m), 4.62-4.52 (1H, m), 4.3-4.48 (2H, m), 4.4-4.25 (2H, m), 3.75-3.50 (2H, m), 3.65 (1H, brs), 3.25 (3H, s), 3.15 (3H, s), 3.11 (3H, s), 3.05 (3H, s), 2.95 (3H, s), 2.31 (1H, brd, J = 5 Hz), 2.2-2.0 (2H, m), 2.0-1.75 (4H, m), 1.9-0.8 (46H, m), 1.55 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.12 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 0.74 (3H, d, J = 6 Hz) (for a major conformer) 52 8.16 (1H, d, J = 9 Hz), 7.88 (1H, d, J = 9 Hz), 7.11 (1H, d, J = 7 Hz), 7.02 (1H, d, J = 9 Hz), 6.98 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.52-5.26 (5H, m), 5.04-4.91 (3H, m), 4.80 (1H, d, J = 15 Hz), 4.76-4.66 (2H, m), 4.57 (1H, m), 4.21 (1H, m), 4.00-3.88 (2H, m), 3.56 (1H, brd, J = 5 Hz), 3.48 (3H, s), 3.44 (3H, s), 3.15 (3H, s), 3.13-3.05 (2H, m), 3.08 (3H, s), 3.05 (3H, s), 2.78 (3H, s), 2.38-2.26 (2H, m), 2.10-1.90 (4H, m), 1.86-1.56 (3H, m), 1.63 (3H, brd, J = 6 Hz), 1.54-1.0 (7H, m), 1.35 (3H, d, J = 7 Hz), 1.19 (3H, d, J = 7 Hz), 1.14 (3H, d, J = 6 Hz), 1.10 (3H, d, J = 6 Hz), 1.09 (9H, s), 1.01 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.88 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.78 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.76 (3H, d, J = 7 Hz) 53 8.06 (1H, d, J = 9 Hz), 7.57 (1H, d, J = 9 Hz), 7.35-7.20 (5H, m), 6.98 (1H, d, J = 7 Hz), 6.92 (1H, d, J = 9 Hz), 6.78 (1H, d, J = 8 Hz), 5.58 (1H, d, J = 11 Hz), 5.46-5.21 (5H, m), 5.05-4.87 (4H, m), 5.02-4.75 (2H, m), 4.67 (2H, m), 4.48-4.42 (1H, m), 4.22-4.15 (1H, m), 3.72 (1H, m), 3.45 (1H, m), 3.35-3.08 (2H, m), 3.12 (3H, s), 3.09 (3H, s), 3.02 (3H, s), 3.24-2.95 (2H, m), 3.00 (3H, s), 2.99 (3H, s), 2.83 (3H, m), 2.81 (3H, s), 2.58-2.22 (4H, m), 2.15-1.82 (3H, m), 1.86-1.62 (6H, m), 1.61 (3H, brd, J = 6 Hz), 1.68-1.05 (7H, m), 1.31 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 55 8.15 (1H, d, J = 9 Hz), 8.07 (1H, d, J = 9 Hz), 7.07 (1H, d, J = 7 Hz), 6.99 (1H, d, J = 9 Hz), 6.87 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.54-5.75 (5H, m), 5.04-4.85 (3H, m), 4.80-4.50 (3H, m), 4.32-4.03 (6H, m), 3.46 (6H, s), 3.35-2.60 (6H, m), 3.15 (3H, s), 3.07 (3H, s), 3.04 (3H, s), 2.74 (3H, s), 2.42-2.22 (2H, m), 210-0.65 (58H, m), 1.68 (3H, d, J = 6 Hz), 1.63 (3H, d, J = 6 Hz), 1.18 (3H, d, J = 7 Hz) 56 8.12 (1H, d, J = 9 Hz), 7.95 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.83 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.52-5.21 (5H, m), 5.05-4.91 (3H, m), 4.77 (1H, d, J = 15 Hz), 4.76-4.68 (2H, m), 4.57 (1H, m), 4.48 (1H, m), 4.23-4.20 (2H, m), 3.97-3.88 (1H, m), 3.48 (3H, s), 3.44 (3H, s), 3.28 (3H, s), 3.21-2.97 (2H, m), 3.12 (3H, s), 3.11-2.98 (2H, m,), 3.09 (3H, s), 2.78 (3H, s), 2.38-2.26 (2H, m), 2.17-1.92 (4H, m), 1.86-1.62 (3H, m), 1.63 (3H, brd, J = 6 Hz), 1.57-1.0 (11H, m), 1.33 (3H, d, J = 7 Hz), 1.21 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 57 8.12 (1H, d, J = 8 Hz), 7.92 (1H, d, J = 8 Hz), 7.35-7.25 (4H, m), 7.20 (2H, d, J = 6 Hz), 7.10 (1H, d, J = 6 Hz), 6.99 (1H, d, J = 8 Hz), 6.86 (1H, d, J = 7 Hz), 5.86 (1H, d, J = 9 Hz), 5.54-5.25 (5H, m), 5.09-4.83 (3H, m), 4.79-4.65 (2H, m), 4.62-4.37 (3H, m), 4.32 (1H, d, J = 9 Hz), 4.28-4.17 (1H, m), 3.98-3.80 (2H, m), 3.45 (3H, s), 3.40-3.00 (3H, m), 3.38 (3H, s), 3.14 (3H, s), 3.05 (3H, s), 3.02 (3H, s), 2.63 (3H, s), 2.38-2.75 (1H, m), 2.12-1.89 (4H, m), 1.85-0.70 (52H, m), 1.63 (3H, d, J = 6 Hz), 1.34 (3H, d, J = 7 Hz) 58 8.11 (1H, d, J = 9 Hz), 7.95 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 7.02 (1H, d, J = 9 Hz), 6.82 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.51-5.25 (5H, m), 5.01-4.82 (3H, m), 4.72 (1H, d, J = 15 Hz), 4.68-4.61 (2H, m), 4.55 (1H, m), 4.21 (2H, m), 3.97-3.92 (1H, m), 3.68-3.53 (4H, m), 3.48-3.45 (4H, m), 3.48 (3H, s), 3.47 (3H, s), 3.15 (3H, s), 3.21-2.97 (2H, m), 3.09 (3H, s), 3.07 (3H, m), 2.81 (3H, s), 2.35-2.26 (2H, m), 2.19-1.95 (4H, m), 1.86-1.62 (3H, m), 1.59 (3H, brd, J = 6 Hz), 1.57-1.0 (8H, m), 1.33 (3H, d, J = 7 Hz), 1.18 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 59 8.14 (1H, d, J = 9 Hz), 7.82 (1H, d, J = 9 Hz), 7.11 (1H, d, J = 7 Hz), 6.98 (1H, d, J = 9 Hz), 6.84 (1H, d, J = 8 Hz), 5.82 (1H, d, J = 11 Hz), 5.55-5.15 (5H, m), 5.06-4.65 (6H, m), 4.64-4.50 (1H, m), 4.32-4.15 (2H, m), 4.07-3.96 (1H, m), 3.76-3.53 (2H, m), 3.46 (3H, s), 3.42 (3H, s), 3.20-3.05 (2H, m), 3.15 (3H, s), 3.06 (3H, s), 3.03 (3H, s), 2.76 (3H, s), 2.38-2.22 (2H, m), 2.08-0.80 (44H, m), 1.63 (3H, d, J = 6 Hz), 1.34 (3H, d, J = 7 Hz), 1.13 (9H, s), 1.00 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 7 Hz) 60 9.03 (1H, d, J = 9 Hz), 7.67 (1H, d, J = 9 Hz), 6.98 (1H, d, J = 6 Hz), 6.90 (1H, d, J = 9 Hz), 6.84 (1H, d, J = 8 Hz), 5.83 (1H, d, J = 11 Hz), 5.55-5.26 (5H, m), 5.23-5.14 (1H, m), 5.08-4.49 (5H, m), 4.30-4.15 (2H, m), 4.05-3.94 (1H, m), 3.45 (3H, s), 3.30-3.03 (2H, m), 3.16 (3H, s), 3.15 (3H, s), 3.05 (3H, s), 2.96 (3H, s), 2.90 (3H, s), 2.45-2.24 (2H, m), 2.10-0.75 (61H, m), 1.19 (3H, d, J = 7 Hz), 1.05 (3H, d, J = 7 Hz), 0.80 (3H, d, J = 7 Hz), 0.72 (3H, d, J = 7 Hz) 61 8.13 (1H, d, J = 8 Hz), 8.03 (1H, d, J = 8 Hz), 7.10 (1H, d, J = 6 Hz), 7.00 (1H, d, J = 8 Hz), 6.88 (1H, d, J = 7 Hz), 5.87 (1H, d, J = 9 Hz), 5.55-5.26 (5H, m), 5.09-4.84 (3H, m), 4.78-4.64 (2H, m), 4.62-4.50 (1H, m), 4.28-4.16 (2H, m), 3.99-3.89 (1H, m), 3.47 (3H, s), 3.45 (3H, s), 3.27-2.98 (4H, m), 3.15 (3H, s), 3.07 (3H, s), 3.04 (3H, s), 2.74 (3H, s), 2.43-2.16 (2H, m), 2.12-1.88 (4H, m), 1.85-0.70 (54H, m), 1.64 (3H, d, J = 6 Hz), 1.36 (3H, d, J = 7 Hz), 1.18 (3H, d, J = 7 Hz) 62 8.13 (1H, d, J = 9 Hz), 8.05 (1H, d, J = 9 Hz), 7.11 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.91 (1H, d, J = 8 Hz), 5.90 (1H, d, J = 11 Hz), 5.53-5.28 (5H, m), 5.07-4.79 (4H, m), 4.77-4.66 (2H, m), 4.64-4.50 (2H, m), 4.21 (2H, brd, J = 11 Hz), 3.47 (3H, s), 3.45 (3H, s), 3.17 (3H, s), 3.07 (3H, s), 3.04 (3H, s), 2.82-2.75 (1H, m), 2.74 (3H, s), 2.39-2.26 (2H, m), 2.15-0.78 (57H, m), 1.63 (3H, d, J = 6 Hz), 1.18 (3H, d, J = 7 Hz) 1.14 (3H, d, J = 7 Hz), 0.78 (3H, d, J = 7 Hz), 0.76 (3H, d, J = 7 Hz) 63 9.33 (1H, brd, J = 9 Hz), 8.14, 7.98 (1H, brd, J = 9 Hz), 7.52-7.15 (5H, m), 7.12 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 6.42 (1H, brs), 5.57-5.17 (5H, m), 5.07-4.82 (4H, m), 4.78-4.50 (3H, m), 4.34-4.15 (2H, m), 4.08-3.97 (1H, m), 3.75 (1H, brs), 3.47, 3.42 (3H, s), 3.24 (3H, s), 3.22-2.93 (2H, m), 3.16 (3H, s), 3.12 (3H, s), 3.06 (3H, s), 2.92 (3H, s), 2.55-2.22 (3H, m), 2.17-0.80 (45H, m), 1.67 (3H, d, J = 6 Hz), 1.34 (3H, d, J = 7 Hz), 0.82 (3H, d, J = 7 Hz), 0.72 (3H, d, J = 7 Hz) 64 8.16 (1H, d, J = 9 Hz), 8.01 (1H, d, J = 9 Hz), 7.18 (1H, d, J = 7 Hz), 7.12 (1H, d, J = 9 Hz), 7.02 (1H, d, J = 8 Hz), 5.87 (1H, d, H, J = 11 Hz), 5.54-5.27 (5H, m), 5.06-4.87 (4H, m), 4.77-4.68 (2H, m), 4.61-4.54 (1H, m), 4.32-4.14 (2H, m), 3.98-3.92 (1H, m), 3.77-3.70 (1H, m), 3.47 (3H, s), 3.45 (3H, s), 3.17 (3H, s), 3.16-3.07 (2H, m), 3.09 (3H, s), 3.05 (3H, s), 2.75 (3H, s), 2.45-2.20 (3H, m), 2.10-0.75 (53H, m), 1.64 (3H, d, J = 6 Hz), 1.35 (3H, d, J = 7 Hz), 1.18 (3H, d, J = 7 Hz), 1.00 (3H, d, J = 7 Hz), 0.95 (3H, d, J = 7 Hz) 65 8.15 (1H, d, J = 9 Hz), 7.99 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.92 (1H, d, J = 8 Hz), 5.89 (1H, d, J = 11 Hz), 5.51-5.28 (5H, m), 5.03-4.85 (3H, m), 4.76-4.68 (3H, m), 4.61-4.51 (1H, m), 4.21 (1H, m), 3.97-3.85 (1H, m), 3.71 (1H, brd, J = 5 Hz), 3.48 (3H, s), 3.46 (3H, s), 3.18 (3H, s), 18-3.02 (2H, m), 3.09 (3H, s), 3.07 (3H, s), 2.92 (3H, s), 2.38-2.24H, m), 2.17-1.92 (4H, m), 1.86-1.62 (3H, m), 1.65 (3H, brd, J = 6 Hz), 1.57-1.0 (7H, m), 1.33 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.05 (9H, s), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 66 8.15 (1H, d, J = 9 Hz), 8.08 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 6.98 (1H, d, J = 9 Hz), 6.87 (1H, d, J = 8 Hz), 5.87 (1H, d, J = 11 Hz), 5.54-5.25 (5H, m), 5.04-4.84 (3H, m), 4.75-4.65 (2H, m), 4.60-4.50 (1H, m), 4.32-4.15 (2H, m), 4.03-3.88 (2H, m), 3.46 (6H, s), 3.45-2.85 (6H, m), 3.16 (3H, s), 3.07 (3H, s), 3.04 (3H, s), 2.75 (3H, s), 2.40-2.24 (2H, m), 2.08-1.86 (4H, m), 1.82-0.73 (48H, m), 1.65 (3H, d, J = 6 Hz), 1.61 (3H, d, J = 6 Hz), 1.33 (3H, d, J = 7 Hz), 1.17 (3H, d, J = 7 Hz) 67 8.13 (1H, d, J = 9 Hz), 7.90 (1H, d, J = 9 Hz), 7.11 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.60-5.22 (5H, m), 5.08-4.50 (7H, m), 4.30-4.15 (1H, m), 4.00-3.89 (1H, m), 3.78-3.68 (1H, m), 3.65-3.53 (1H, m), 3.46 (3H, s), 3.42 (3H, s), 3.34-2.20 (4H, m), 3.17 (3H, s), 3.09 (3H, s), 3.06 (3H, s), 2.80 (3H, s), 2.42-2.22 (2H, m), 2.12-0.62 (59H, m), 1.64 (3H, d, J = 7 Hz), 1.35 (3H, d, J = 7 Hz) 68 8.16 (1H, d, J = 9 Hz), 7.92 (1H, d, J = 9 Hz), 7.09 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.89 (1H, d, J = 8 Hz), 5.89 (1H, d, J = 11 Hz), 5.51-5.25 (5H, m), 5.05-4.89 (3H, m), 4.77 (1H, d, J = 15 Hz), 4.75-4.65 (2H, m), 4.59 (1H, m), 4.31-4.15 (3H, m), 3.97-3.89 (2H, m), 3.75-3.69 (2H, m), 3.68 (1H, m), 3.48 (3H, s), 3.44 (3H, s), 3.32-2.97 (2H, m), 3.32 (3H, s), 3.15 (3H, s), 3.07 (3H, m), 3.05 (3H, s), 2.81 (3H, s), 2.38-1.92 (6H, m), 1.86-1.65 (3H, m), 1.62 (3H, brd, J = 6 Hz), 1.59-1.03 (6H, m), 1.33 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.14 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.94 (3H, d, J = 7 Hz), 0.92 (3H, d, J = 7 Hz), 0.89 (3H, d, J = 7 Hz), 0.86 (3H, d, J = 7 Hz), 0.83 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 69 8.16 (1H, d, J = 9 Hz), 7.95 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 9 Hz), 6.87 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.51-5.25 (5H, m), 5.05-4.87 (3H, m), 4.77 (1H, d, J = 15 Hz), 4.76-4.55 (2H, m), 4.57 (1H, m), 4.21 (1H, m), 3.97-3.88 (1H, m), 3.71 (1H, brd, J = 5 Hz), 3.70 (1H, m), 3.48 (3H, s), 3.44 (3H, s), 3.28 (3H, s), 3.21-2.97 (2H, m), 3.15 (3H, s), 3.07 (3H, s), 3.05 (3H, m), 2.81 (3H, s), 2.38-2.26 (2H, m), 2.17-1.92 (4H, m), 1.86-1.62 (3H, m), 1.63 (3H, brd, J = 6 Hz), 1.57-1.0 (7H, m), 1.33 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 6 Hz), 1.11 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 70 8.12 (1H, d, J = 9 Hz), 7.93 (1H, d, J = 9 Hz), 7.07 (1H, d, J = 7 Hz), 7.01 (1H, d, J = 9 Hz), 6.87 (1H, d, J = 8 Hz), 5.88 (1H, d, J = 11 Hz), 5.51-5.27 (5H, m), 5.05-4.87 (3H, m), 4.77 (1H, d, J = 15 Hz), 4.76-4.65 (2H, m), 4.61-4.51 (1H, m), 4.25-4.18 (1H, m), 3.97-3.88 (1H, m), 3.71 (1H, brd, J = 5 Hz), 3.70 (1H, m), 3.50 (3H, s), 3.45 (3H, s), 3.16 (3H, s), 3.21-2.97 (2H, m), 3.07 (3H, s), 3.03 (3H, s), 2.95-2.92 (6H, m), 2.81 (3H, s), 2.38-2.26 (2H, m), 2.17-1.92 (4H, m), 1.86-1.62 (3H, m), 1.62 (3H, brd, J = 6 Hz), 1.57-1.0 (7H, m), 1.32 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 7 Hz), 1.11 (3H, d, J = 6 Hz), 1.10 (3H, d, J = 6 Hz), 1.09 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 0.99 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.87 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 6 Hz), 0.78 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz) 74 9.15 (1H, brd, J = 9 Hz), 7.78 (1H, brd, J = 9 HZ), 6.95 (1H, d, J = 9 Hz), 6.90 (1H, d, J = 8 Hz), 6.72 (1H, d, J = 9 Hz), 5.67 (1H, d, J = 3 Hz), 5.6-5.4 (2H, m), 5.39-5.32 (2H, m), 5.15 (1H, dd, J = 10 and 4 Hz), 5.07 (1H, dd, J = 10 and 4 Hz), 4.95-4.90 (1H, m), 5.05-4.75 (3H, m), 4.73 (1H, m), 4.57 (1H, m), 4.32 (1H, m), 4.22 (1H, m), 3.88 (1H, brs), 3.17 (3H, s), 3.06 (3H, s), 3.04 (3H, s), 2.98 (3H, s), 2.90 (3H, s), 2.76 (3H, s), 2.51 (1H, brd, J = 5 Hz), 2.4-2.3 (2H, m), 2.2-1.8 (4H, m), 1.9-0.8 (46H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.14 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.08 (3H, d, J = 6 Hz), 0.74 (3H, d, J = 7 Hz) (for a major conformer) 77 8.93 (1H, brd, J = 9 Hz), 7.66 (1H, brd, J = 9 Hz), 6.99 (1H, d, J = 9 Hz), 6.89 (1H, d, J = 8 Hz), 6.76 (1H, d, J = 9 Hz), 5.66 (1H, d, J = 3 Hz), 5.50-5.28 (4H, m), 5.13 (1H, dd, J = 10 and 4 Hz), 5.09-4.84 (5H, m), 4.70 (1H, m), 4.53 (1H, m), 4.28-4.20 (3H, m), 3.68 (1H, brs), 3.21-3.16 (6H, s), 3.11-3.00 (10H, m), 2.96-2.89 (7H, m), 2.79 (3H, s), 2.50 (1H, brd, J = 5 Hz), 2.45-2.31 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.65 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.35 (3H, d, J = 6 Hz), 1.15 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) 78 8.93 (1H, brd, J = 9 Hz), 7.66 (1H, brd, J = 9 Hz), 6.98 (1H, d, J = 9 Hz), 6.89 (1H, d, J = 8 Hz), 6.76 (1H, d, J = 9 Hz), 5.66 (1H, d, J = 3 Hz), 5.50-5.28 (4H, m), 5.13 (1H, dd, J = 10 and 4 Hz), 5.09-4.83 (5H, m), 4.71 (1H, m), 4.54 (1H, m), 4.28-4.20 (3H, m), 3.71 (1H, brs), 3.18-3.16 (6H, s), 3.07-3.01 (9H, m), 2.91-2.89 (6H, m), 2.79 (3H, s), 2.50 (1H, brd, J = 5 Hz), 2.45-2.31 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.66 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 7.5 Hz), 1.33 (3H, d, J = 6 Hz), 1.15 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) 79 8.54 (1H, brd, J = 9 Hz), 7.71 (1H, brd, J = 9 Hz), 6.97 (1H, d, J = 9 Hz), 6.84 (1H, d, J = 8 Hz), 6.72 (1H, d, J = 9 Hz), 5.66 (1H, d, J = 3 Hz), 5.50-5.28 (4H, m), 5.09-4.84 (6H, m), 4.71 (1H, m), 4.59-4.42 (2H, m), 4.28-4.20 (3H, m), 3.65 (1H, brs), 3.16-3.14 (5H, s), 3.12-3.05 (12H, m), 2.95-2.90 (3H, m), 2.61 (1H, brd, J = 5 Hz), 2.45-2.31 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.65 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.35 (3H, d, J = 6 Hz), 1.15 (3H, d, J = 6.5 Hz), 1.25-1.21 (3H, m), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) 80 8.50 (1H, brd, J = 9 Hz), 7.69 (1H, brd, J = 9 Hz), 6.95 (1H, d, J = 9 Hz), 6.81 (1H, d, J = 8 Hz), 6.61 (1H, d, J = 9 Hz), 5.65 (1H, d, J = 3 Hz), 5.50-4.80 (13H, m), 5.13 (1H, dd, J = 10 and 4 Hz), 4.70 (1H, m), 4.53 (1H, m), 4.28-4.20 (3H, m), 3.71 (1H, brs), 3.22-3.04 (17H, s), 2.99-2.89 (8H, m), 2.50 (1H, brd, J = 5 Hz), 2.45-2.31 (2H, m), 2.2-1.9 (4H, m), 1.9-1.1 (10H, m), 1.65 (3H, d, J = 6 Hz), 1.40 (3H, d, J = 7.5 Hz), 1.35 (3H, d, J = 6 Hz), 1.15 (3H, d, J = 6.5 Hz), 1.09 (3H, d, J = 7 Hz), 1.09 (3H, d, J = 6 Hz), 1.0-0.8 (30H, m), 0.74 (3H, d, J = 7 Hz) 81 9.24 (1H, d, J = 9.3 Hz), 7.57 (1H, d, J = 9.1 Hz), 6.96 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 7.5 Hz), 6.76 (1H, d, J = 8.4 Hz), 5.68 (1H, d, J = 3.2 Hz), 5.36-5.26 (2H, m), 5.08-5.00 (1H, m), 5.00-4.75 (5H, m), 4.74-4.65 (1H, m), 4.58-4.48 (1H, m), 4.28-4.19 (2H, m), 4.19-4.14 (2H, m), 3.32 (3H, s), 3.23 (3H, s), 3.20 (3H, s), 3.06 (3H, s), 3.04 (3H, s), 3.04 (3H, s), 2.91 (3H, s), 2.49 (1H, d, J = 4.8 Hz), 2.45-1.50 (18H, m), 1.50-1.00 (4H, m), 1.41 (3H, d, J = 7.3 Hz), 1.32 (3H, d, J = 6.9 Hz), 1.11 (3H, d, J = 7.0 Hz), 1.09 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.5 Hz), 1.02-0.83 (30H, m), 0.81 (3H, d, J = 6.5 Hz), 0.81 (3H, d, J = 6.5 Hz), 0.71 (3H, d, J = 6.8 Hz) (for a major isomer) 82 9.38 (1H, d, J = 9.2 Hz), 7.51 (1H, d, J = 9.1 Hz), 6.96 (1H, d, J = 8.8 Hz), 6.86 (1H, d, J = 9.2 Hz), 6.69 (1H, d, J = 8.3 Hz), 5.67 (1H, d, J = 3.4 Hz), 5.34-5.26 (1H, m), 5.08-5.00 (1H, m), 5.00-4.75 (5H, m), 4.74-4.66 (1H, m), 4.60-4.50 (2H, m), 4.29-4.19 (2H, m), 3.75-3.70 (1H, brs), 3.31 (3H, s), 3.21 (3H, s), 3.06 (3H, s), 3.05 (3H, s), 3.03 (3H, s), 2.90 (3H, s), 2.49 (1H, d, J = 4.8 Hz), 2.45-1.90 (6H, m), 1.90-1.04 (12H, m), 1.41 (3H, d, J = 7.4 Hz), 1.32 (3H, d, J = 7.4 Hz), 1.18 (9H, s), 1.11 (3H, d, J = 6.9 Hz), 1.08 (3H, d, J = 6.2 Hz), 1.08 (3H, d, J = 6.4 Hz), 1.04-0.84 (32H, m), 0.81 (3H, d, J = 6.5 Hz), 0.71 (3H, d, J = 6.8 Hz) (for a major isomer) 83 8.97 (1H, d, J = 9.3 Hz), 7.65 (1H, d, J = 9.0 Hz), 6.97 (1H, d, J = 8.9 Hz), 6.93 (1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 7.5 Hz), 5.68 (1H, d, J = 3.4 Hz), 5.36-4.48 (12H, m), 4.26-4.16 (2H, m), 3.28 (3H, s), 3.19 (3H, s), 3.06 (9H, s), 2.92 (3H, s), 2.50-1.50 (16H, m), 1.50-1.03 (9H, m), 1.43 (3H, d, J = 7.5 Hz), 1.32 (3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 6.8 Hz), 1.09 (3H, d, J = 6.5 Hz), 1.02-0.72 (30H, m), 0.81 (3H, d, J = 6.4 Hz), 0.72 (3H, d, J = 6.8 Hz) (for a major isomer)

The structure of the compounds of the invention are shown in the following Table 44. These compounds can be easily prepared by the above preparation methods, methods described in Examples or Preparations, or methods that are well-known to one skilled in the art, or its variations.

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Ex. Ra A1 H A2 tBu

Claims

1. A cyclic peptide compound of the following general formula (I):
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wherein
X is
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in which
R1 is hydrogen or lower alkyl;
R2 is hydrogen, aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, optionally substituted carbamoyloxy, and optionally substituted amino;
and
embedded image
is N-containing heterocyclic group;
embedded image
Y is
in which
R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
and
R4 and R5 are each independently hydrogen or lower alkyl;
and
--- represents single bond or double bond;
or a salt thereof,
provided that,
when R2 is hydrogen, R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, lower alkoxymethyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower)alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino and —OC(O)NR6R7 (wherein R6 and R7 are each as defined above).
X is
in which
R1 is hydrogen or lower alkyl;
R2 is hydrogen, aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, optionally substituted carbamoyloxy, and optionally substituted amino;
and
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, optionally substituted carbamoyloxy, and optionally substituted amino;
and
Y is
in which
R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
and
R4 and R5 are each independently hydrogen or lower alkyl;
and
--- represents single bond or double bond;
or a salt thereof,
provided that,
when R2 is hydrogen, R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, lower alkoxymethyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower)alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino and —OC(O)NR6R7 (wherein R6 and R7 are each as defined above).
in which
R3 is cyclo(lower)alkyl, aryl, optionally substituted heterocyclic group, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
and
R4 and R5 are each independently hydrogen or lower alkyl;
and
--- represents single bond or double bond;
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, optionally substituted amino, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
and
R4 and R5 are each independently hydrogen or lower alkyl;
2. A compound of claim 1,
wherein
X is
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in which
R1 is hydrogen or lower alkyl;
and
R2 is aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl, benzyloxycarbonyl, and t-butoxycarbonyl;
and
Y is
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in which
R3 is cyclo(lower)alkyl, aryl, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, and aryl(lower)alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
or a salt thereof.
wherein
X is
in which
R1 is hydrogen or lower alkyl;
and
R2 is aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl, benzyloxycarbonyl, and t-butoxycarbonyl;
and
Y is
in which
R1 is hydrogen or lower alkyl;
and
R2 is aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl, benzyloxycarbonyl, and t-butoxycarbonyl;
R1 is hydrogen or lower alkyl;
and
R2 is aryl or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl, benzyloxycarbonyl, and t-butoxycarbonyl;
hydroxy, cyclo(lower)alkyl, lower alkoxy, aryl, aryl(lower)alkoxy, di(lower)alkylcarbamoyloxy, and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl, benzyloxycarbonyl, and t-butoxycarbonyl;
in which
R3 is cyclo(lower)alkyl, aryl, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, and aryl(lower)alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
or a salt thereof.
in which
R3 is cyclo(lower)alkyl, aryl, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, and aryl(lower)alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
R3 is cyclo(lower)alkyl, aryl, or lower alkyl which is optionally substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, and aryl(lower)alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
hydroxy, lower alkoxy, and aryl(lower)alkoxy;
3. A compound of claim 2,
wherein
R1 is lower alkyl;
R2 is lower alkyl;
Y is
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in which
R3 is aryl or lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
and
----- moiety is double bond;
or a salt thereof.
wherein
R1 is lower alkyl;
R2 is lower alkyl;
Y is
Y is
in which
R3 is aryl or lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
R4 is hydrogen;
and
R5 is lower alkyl;
in which
4. A compound of claim 3,
wherein
R3 is lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
or a salt thereof.
wherein
R3 is lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
or a salt thereof.
R3 is lower alkyl which is optionally substituted by hydroxy or lower alkoxy;
5. A compound of claim 1,
wherein
X is
embedded image
in which
R1 is lower alkyl;
and
R2 is hydrogen;
and
Y is
embedded image
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, (lower)alkoxy(lower)alkyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower) alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower) alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl and benzyloxycarbonyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
wherein
X is
in which
R1 is lower alkyl;
and
R2 is hydrogen;
and
Y is
in which
R1 is lower alkyl;
and
R2 is hydrogen;
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, (lower)alkoxy(lower)alkyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower) alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower) alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl and benzyloxycarbonyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, (lower)alkoxy(lower)alkyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower) alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower) alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl and benzyloxycarbonyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, (lower)alkoxy(lower)alkyl, aryl(lower)alkyl, t-butyl, sec-butyl, cyclo(lower)alkyl(lower) alkyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower) alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl and benzyloxycarbonyl;
hydroxy, lower alkoxy, aryl(lower) alkoxy, lower alkoxy(lower)alkoxy, —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl), and amino which is optionally substituted by one or two suitable substituent(s) selected from the group consisting of:
 lower alkyl and benzyloxycarbonyl;
6. A compound of claim 5,
wherein
Y is
embedded image
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, t-butyl, sec-butyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
R4 is hydrogen
and
R5 is lower alkyl;
and
----- moiety is double bond;
or a salt thereof.
wherein
Y is
Y is
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, t-butyl, sec-butyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
R4 is hydrogen
and
R5 is lower alkyl;
and
----- moiety is double bond;
in which
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, t-butyl, sec-butyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
R4 is hydrogen
and
R5 is lower alkyl;
R3 is cyclo(lower)alkyl, aryl, heterocyclic group which is optionally substituted by lower alkoxy carbonyl, t-butyl, sec-butyl, or ethyl substituted by a suitable substituent selected from the group consisting of:
hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
hydroxy, lower alkoxy, aryl(lower)alkoxy, lower alkoxy(lower)alkoxy, and —OC(O)NR6R7 (wherein R6 and R7 are each independently hydrogen or lower alkyl, or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group which is optionally substituted by a lower alkyl);
7. A compound of claim 1
wherein
X is
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and
Y is
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in which
R3 is lower alkyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
wherein
X is
and
Y is
in which
R3 is lower alkyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
in which
R3 is lower alkyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
R3 is lower alkyl;
and
R4 and R5 are each independently hydrogen or lower alkyl;
or a salt thereof.
8. A compound of claim 7,
wherein
X is
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R4 is hydrogen;
R5 is lower alkyl;
and
----- moiety is double bond;
or a salt thereof.
wherein
X is
R4 is hydrogen;
R5 is lower alkyl;
and
----- moiety is double bond;
9. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.
10. A process of manufacturing a medicament comprising admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or excipient.
11. A compound of claim 1, wherein the compound is
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or a salt thereof.