Anticancer compounds

Abstract

Provided are anticancer compounds of general formula I and their derivatives. #imgabs0#

Description

Technical Field

[0001] The present invention relates to novel anticancer compounds, their use as anticancer drugs, their pharmaceutical compositions and their synthesis methods. Background Art

[0002] In 1957, Yamaguchi et al. reported the isolation of isothiomycin from a new species of Streptomyces belonging to the species isothiomyces (Yamaguchi, H et al., J. of Antibiotics A, 1957, 10, 195-200). This document also disclosed its antibacterial activity against Gram-positive and Gram-negative bacteria.

[0003] Its structure was elucidated by Umezawa et al. in 1974 (Journal of Antibiotics, 1974, 27, 897-899).

[0004]

[0005] The cytotoxic activity of isothiomycin against several gastric and hepatoma cell lines is described in International Patent Application Publication No. WO2002066046. In particular, the IC values of isothiomycin against the gastric cancer cell lines SNU-638, SNU-216 and AGS were 50 values (0.77 μM, 0.77 μM, and 0.85 μM, respectively) and IC values for the liver cancer cell lines HepG2, Hep3B, and SK-HEP-1 50 The values (1.43 μM, 0.88 μM, and 0.81 μM, respectively) were in the micromolar range.

[0006] International patent application publication WO2010137351 discloses compounds AD having T-type calcium channel or voltage sodium channel blocking activity as tetrodotoxin-sensitive (TTX-S) blockers, such as Na V1.3 and Na V1.7 , where IC 50 The values are in the micromolar range. The patent application also discloses the use of these compounds in the treatment of several diseases, including cancer.

[0007]

[0008] International Patent Application Publication No. WO2005014537 discloses compounds having the following general formula:

[0009]

[0010] where R 1 -R 10 、R 15 -R 19 、R24 -R 25 , X, Y, Z, m, and n have multiple meanings;

[0011] These compounds are modulators of chemokine receptor activity and are disclosed for use in preventing or treating inflammatory and immunoregulatory conditions and diseases.

[0012] Because cancer is a leading cause of death in animals and humans, efforts have been and continue to be made to obtain further anti-cancer treatments that are both effective and safe for administration to patients suffering from cancer. Summary of the Invention

[0013] In a first aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt or ester thereof

[0014]

[0015] in:

[0016] R1 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0017] R2 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, -OR a 、-OSO2R b 、-NR c R d 、-NR c (C=O)R f , and -NR c SO2R b , wherein the optional substituents are one or more substituents R x ;

[0018] R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, halogen substituted or unsubstituted C2-C 12 Alkenyl, halogen substituted or unsubstituted C2-C 12 Alkynyl and substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I;

[0019] R4 is selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0020] R5 is selected from -C(OR e )2R g 、-C(SR e )2R g 、-CH(OR a )R g 、-CH(O-(C=O)R f )R g 、-CH(NR c R d )R g 、-CH(NR c -(C=O)R f )R g 、-CH(NR c -OR h )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-(C=O)OR a )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=O)OR a 、-(C=O)NR c -OR h 、-(C=O)NR c R d 、-(C=CH2)R g , and -(C=CH2)OR a ; R5 is group, wherein m is 0, 1 or 2 and each E group is independently selected from O and S;

[0021] Y and Z are independently selected from -O-, -S-, -(NH)-, and -(NProtNH )-, where Prot NH It is a protecting group for amino group;

[0022] Each group R a independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, and -(CH2CH2O) p CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ;

[0023] Each group R b independently selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic, wherein the optional substituents are one or more substituents R x ;

[0024] Each group R c and R d are independently selected from hydrogen, amino protecting groups, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ; or R c and R d Together with the nitrogen atom to which they are attached, they form a heterocyclic group;

[0025] Each group R e is substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ;

[0026] Each group R f are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12Alkynyl, -CH2O(CH2CH2O) p CH2CH3, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x , and groups of the following formula:

[0027]

[0028] wherein each R group is independently selected at each occurrence from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(C=O)-(C1-C6)alkyl, and substituted or unsubstituted -(C=O)NH(C1-C6)alkyl, wherein the optional substituents are one or more substituents R x ; or two adjacent OR groups form an isopropylidene ketal or an acetal group selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal;

[0029] Each group R g are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0030] Each group Rh is independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted heterocyclic-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, -(CH2CH2O) p CH3 wherein p is 1 to about 25, and a substituted or unsubstituted monosaccharide residue, wherein the optional substituents are one or more substituents R x ;

[0031] Substituent R x Choose from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, halogen atom, oxo group, thio group, cyano group, nitro group, OR y , OCORy 、OCOOR y 、COR y 、COOR y 、OCONR y R z 、CONR y R z SR y 、S(=O)R y 、SO2R y 、OSO2OR y 、SSR y 、P(=O)(R y )OR z , OP(=O)(ORy)2, NR y R z NR y C(=O)Rz、NR y C(=O)OR z NR y C(=O)NR y R z NR y C(=NR y )NR y R z , aryl, aralkyl, aralkyloxy, and a 5- to 14-membered saturated or unsaturated heterocyclic group, the C1-C 12 The alkyl group is optionally substituted with at least one group R y Substitution, the C2-C 12 The alkenyl group is optionally substituted by at least one group R y Substitution, the C2-C 12 The alkynyl group is optionally substituted by at least one group R y substituted, the aryl group having 6 to 18 carbon atoms in one or more rings, the aryl group being optionally substituted with one or more selected from R y , OR y , OCOR y 、OCOOR y NR y R z NR y COR z , and NR y C(=NR y )NR y R zThe arylalkyl group includes an alkyl group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the arylalkyloxy group includes an alkoxy group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the 5- to 14-membered saturated or unsaturated heterocyclic group has one or more rings and includes at least one oxygen, nitrogen or sulfur atom in the one or more rings, and the heterocyclic group is optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and

[0032] Each R y and R z independently selected from hydrogen, C1-C 12 Alkyl, C1-C 12 Alkyl, including C1-C12 substituted with aryl having 6 to 18 carbon atoms in one or more rings 12 Aralkyl, C1-C1-C2-alkyl substituted with a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen, or sulfur atom in the one or more rings. 12 Heterocycloalkyl of alkyl.

[0033] In another aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt or ester thereof.

[0034]

[0035] in:

[0036] R1 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0037] R2 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, -OR a 、-OSO2R b 、-NR c R d 、-NR c (C=O)R f , and -NR cSO2R b , wherein the optional substituents are one or more substituents R x ;

[0038] R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, halogen substituted or unsubstituted C2-C 12 Alkenyl, halogen substituted or unsubstituted C2-C 12 Alkynyl and substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I;

[0039] R4 is selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0040] R5 is selected from -C(OR e )2R g 、-C(SR e )2R g 、-CH(OR a )R g 、-CH(O-(C=O)R f )R g 、-CH(NR c R d )R g 、-CH(NR c -(C=O)R f )R g 、-CH(NR c -OR h )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=N-NR c R d )R g 、-(C=O)OR a 、-(C=O)NR c -OR h , and -(C=O)NRc R d ; R5 is group, wherein m is 0, 1 or 2 and each E group is independently selected from O and S;

[0041] Y and Z are independently selected from -O-, -S-, -(NH)-, and -(NProt NH )-, where Prot NH It is a protecting group for amino group;

[0042] Each group R a independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, and -(CH2CH2O) p CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ;

[0043] Each group R b independently selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic, wherein the optional substituents are one or more substituents R x ;

[0044] Each group R c and R d are independently selected from hydrogen, amino protecting groups, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ; or R c and R d Together with the nitrogen atom to which they are attached, they form a heterocyclic group;

[0045] Each group R e is substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ;

[0046] Each group R f are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, -CH2O(CH2CH2O) p CH2CH3, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x ;

[0047] Each group R g are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0048] Each group R h independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, -(CH2CH2O) p CH3 wherein p is 1 to about 25, and a substituted or unsubstituted monosaccharide residue, wherein the optional substituents are one or more substituents R x ;

[0049] Substituent R x Choose from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, halogen atom, oxo group, thio group, cyano group, nitro group, OR y , OCOR y 、OCOOR y 、COR y 、COOR y 、OCONR y R z 、CONR y R z SR y、S(=O)R y 、SO2R y 、SSR y 、P(=O)(R y )OR z NR y R z NR y COR z NR y C(=O)NR y R z NR y C(=NR y )NR y R z , aryl, aralkyl, aralkyloxy, and a 5- to 14-membered saturated or unsaturated heterocyclic group, the C1-C 12 The alkyl group is optionally substituted with at least one group R y Substitution, the C2-C 12 The alkenyl group is optionally substituted by at least one group R y Substitution, the C2-C 12 The alkynyl group is optionally substituted by at least one group R y substituted, the aryl group having 6 to 18 carbon atoms in one or more rings, the aryl group being optionally substituted with one or more selected from R y , OR y , OCOR y 、OCOOR y NR y R z NR y COR z , and NR y C(=NR y )NR y R z The arylalkyl group includes an alkyl group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the arylalkyloxy group includes an alkoxy group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the 5- to 14-membered saturated or unsaturated heterocyclic group has one or more rings and includes at least one oxygen, nitrogen or sulfur atom in the one or more rings, and the heterocyclic group is optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and

[0050] Each R y and R z independently selected from hydrogen, C1-C 12Alkyl, C1-C 12 Alkyl, including C1-C12 substituted with aryl having 6 to 18 carbon atoms in one or more rings 12 Aralkyl, C1-C1-C2-alkyl substituted with a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen, or sulfur atom in the one or more rings. 12 Heterocycloalkyl of alkyl.

[0051] In another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound according to the present invention or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.

[0052] In yet another aspect of the present invention, there is provided a dosage form comprising the pharmaceutical composition according to the present invention.

[0053] In a further aspect of the present invention there is provided a compound, pharmaceutical composition or dosage form according to the present invention for use as a medicament.

[0054] In yet another aspect of the present invention, there is provided a compound, pharmaceutical composition or dosage form according to the present invention for use in the treatment of cancer.

[0055] In another aspect of the present invention, there is provided the use of a compound, pharmaceutical composition or dosage form according to the present invention for the preparation of a medicament, preferably for the treatment of cancer.

[0056] In another aspect of the present invention, a method for preventing or treating cancer is provided, which comprises administering an effective amount of a compound according to the present invention, administering an effective amount of a pharmaceutical composition according to the present invention, or administering an effective amount of a dosage form according to the present invention to a patient in need, particularly a human.

[0057] In yet another aspect of the present invention, there is provided the use of a compound according to the present invention in the treatment of cancer.

[0058] In another aspect of the present invention, a kit is provided, comprising a therapeutically effective amount of a compound according to the present invention and a pharmaceutically acceptable carrier. The kit is preferably used for the treatment of cancer.

[0059] In another aspect of the present invention, there is provided a method for obtaining a compound of formula I or a pharmaceutically acceptable salt or ester thereof, which comprises coupling a compound of formula II with a compound of formula III according to Scheme I:

[0060]

[0061] Plan I

[0062] wherein R1, R2, R3, R4, R5, Y and Z are as defined in the compound of formula I or are appropriately protected groups as required.

[0063] In another aspect of the present invention, there is provided the use of an intermediate compound of formula II or a salt thereof:

[0064]

[0065] Wherein, when preparing the compound of formula I as defined herein or a pharmaceutically acceptable salt or ester thereof, R1, R2, R3 and Y are as defined in the compound of formula I or are appropriately protected groups as required.

[0066] In another aspect of the present invention, there is provided an intermediate compound of the general formula IIa:

[0067]

[0068] in:

[0069] R1 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0070] R2 is selected from hydrogen, halogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, -OR a 、-OSO2R b 、-NR c R d 、-NR c (C=O)R f , and -NR c SO2R b , wherein the optional substituents are one or more substituents R x ;

[0071] R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, halogen substituted or unsubstituted C2-C 12 Alkenyl, halogen substituted or unsubstituted C2-C 12 Alkynyl and substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R xand the halogen substituents are one or more substituents independently selected from F, Cl, Br and I;

[0072] R6 is selected from hydrogen and a carbamate protecting group of an amino group;

[0073] Y is selected from -O-, -S-, -(NH)-, and -(NProt NH )-, where Prot NH is a protecting group for an amino group, and when R2 is hydrogen, Y is selected from -O- and -S-;

[0074] Ra is selected from hydrogen, a protecting group of OH, a substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, and -(CH2CH2O) p CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ;

[0075] Each group R b independently selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic, wherein the optional substituents are one or more substituents R x ;

[0076] Each group R c and R d are independently selected from hydrogen, amino protecting groups, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ; or R c and R d Together with the nitrogen atom to which they are attached, they form a heterocyclic group;

[0077] R f are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, -CH2O(CH2CH2O) p CH2CH3, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x ;

[0078] Substituent R x Choose from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, halogen atom, oxo group, thio group, cyano group, nitro group, OR y , OCOR y 、OCOOR y 、COR y 、COOR y 、OCONR y R z 、CONR y R z SR y 、S(=O)R y 、SO2R y 、OSO2OR y 、SSR y 、P(=O)(R y )OR z OP(=O)(OR y )2、NR y R z NR y C(=O)R z NR y C(=O)OR z NR y C(=O)NR y R z NR y C(=NR y )NR y R z , aryl, aralkyl, aralkyloxy, and a 5- to 14-membered saturated or unsaturated heterocyclic group, the C1-C 12 The alkyl group is optionally substituted with at least one group R y Substitution, the C2-C 12 The alkenyl group is optionally substituted by at least one group R y Substitution, the C2-C 12 The alkynyl group is optionally substituted by at least one group R y substituted, the aryl group having 6 to 18 carbon atoms in one or more rings, the aryl group being optionally substituted with one or more selected from Ry , OR y , OCOR y 、OCOOR y NR y R z NR y COR z , and NR y C(=NR y )NR y R z The arylalkyl group includes an alkyl group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the arylalkyloxy group includes an alkoxy group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the 5- to 14-membered saturated or unsaturated heterocyclic group has one or more rings and includes at least one oxygen, nitrogen or sulfur atom in the one or more rings, and the heterocyclic group is optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and

[0079] Each R y and R z independently selected from hydrogen, C1-C 12 Alkyl, C1-C 12 Alkyl, including C1-C12 substituted with aryl having 6 to 18 carbon atoms in one or more rings 12 Aralkyl, C1-C1-C2-alkyl substituted with a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen, or sulfur atom in the one or more rings. 12 heterocycloalkyl of an alkyl group;

[0080] or a salt thereof.

[0081] In another aspect of the present invention, there is provided the use of an intermediate compound of the general formula IIc or a salt thereof:

[0082]

[0083] Wherein, when manufacturing a compound of formula I as defined herein or a pharmaceutically acceptable salt or ester thereof, R1, R2, R3 and Y are as defined in the compound of formula I or are appropriately protected groups as required, and R6 is selected from hydrogen and amino carbamate protecting groups.

[0084] In another aspect of the present invention, there is provided the use of an intermediate compound of formula III or a salt thereof:

[0085]

[0086] Wherein, when preparing the compound of formula I as defined herein or a pharmaceutically acceptable salt or ester thereof, R4, R5 and Z are as defined in the compound of formula I or are appropriately protected groups as required.

[0087] In another aspect of the present invention, there is provided an intermediate compound of formula IIIa:

[0088]

[0089] wherein R4 is selected from unsubstituted C1-C 12 Alkyl, unsubstituted C2-C 12 Alkenyl and unsubstituted C2-C 12 Alkynyl;

[0090] R5 is selected from -C(OR e )2R g 、-C(SR e )2R g 、-CH(OR a )R g 、-CH(O-(C=O)R f )R g 、-CH(NR c -(C=O)R f )R g 、-CH(NR c -OR h )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-(C=O)OR a )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=O)OR a 、-(C=O)NR c -OR h 、-(C=O)NR c R d 、-(C=CH2)R g, and -(C=CH2)OR a ; R5 is wherein m is 0, 1 or 2, and each E group is independently selected from O and S;

[0091] Z is selected from -O-, -S-, -(NH)-, and -(NProt NH )-, where Prot NH It is a protecting group for amino group;

[0092] Each group R a independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, and -(CH2CH2O) p CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ;

[0093] Each group R c and R d are independently selected from hydrogen, amino protecting groups, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ; or R c and R d Together with the nitrogen atom to which they are attached, they form a heterocyclic group;

[0094] Each group R e is substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ;

[0095] Each group R f are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, -CH2O(CH2CH2O) p CH2CH3, -CH2O(CH2CH2O) pCH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x , and groups of the following formula:

[0096]

[0097] wherein each R group is independently selected at each occurrence from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(C=O)-(C1-C6)alkyl, and substituted or unsubstituted -(C=O)NH(C1-C6)alkyl, wherein the optional substituents are one or more substituents R x ; or two adjacent OR groups form an isopropylidene ketal or an acetal group selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal;

[0098] Each group R g are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C2-C 12 Alkynyl, wherein the optional substituents are one or more substituents R x ;

[0099] Each group R h independently selected from hydrogen, a protecting group for OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted heterocyclic-C1-C 12 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, -(CH2CH2O) p CH2CH3, -(CH2CH2O) p CH3 wherein p is 1 to about 25, and a substituted or unsubstituted monosaccharide residue, wherein the optional substituents are one or more substituents R x ;

[0100] Substituent R x Choose from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, halogen atom, oxo group, thio group, cyano group, nitro group, CR y , OCOR y 、OCOOR y 、COR y 、COORy 、OCONR y R z 、CONR y R z SR y 、S(=O)R y 、SO2R y 、OSO2OR y 、SSR y 、P(=O)(R y )OR z OP(=O)(OR y )2、NR y R z NR y C(=O)R z NR y C(=O)OR z NR y C(=O)NR y R z NR y C(=NR y )NR y R z , aryl, aralkyl, aralkyloxy, and a 5- to 14-membered saturated or unsaturated heterocyclic group, the C1-C 12 The alkyl group is optionally substituted with at least one group R y Substitution, the C2-C 12 The alkenyl group is optionally substituted with at least one group Ry, wherein the C2-C 12 The alkynyl group is optionally substituted by at least one group R y substituted, the aryl group having 6 to 18 carbon atoms in one or more rings, the aryl group being optionally substituted with one or more selected from R y , OR y , OCOR y 、OCOOR y NR y R z NR y COR z , and NR y C(=NR y )NR y R zwherein the arylalkyl group comprises an alkyl group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the arylalkyloxy group comprises an alkoxy group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, the 5- to 14-membered saturated or unsaturated heterocyclic group has one or more rings and includes at least one oxygen, nitrogen or sulfur atom in the one or more rings, the heterocyclic group is optionally substituted by one or more substituents Ry, and when there is more than one optional substituent on any given group, the optional substituents Ry may be the same or different; and

[0101] Each R y and R z independently selected from hydrogen, C1-C 12 Alkyl, C1-C 12 Alkyl, including C1-C12 substituted with aryl having 6 to 18 carbon atoms in one or more rings 12 Aralkyl, C1-C1-C2-alkyl substituted with a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen, or sulfur atom in the one or more rings. 12 heterocycloalkyl of an alkyl group; or

[0102] Its salt.

[0103] In yet another aspect of the present invention, there is provided a method for isolating Compound 1 from a sponge in the genus Discodermia (Du Bocage 1869), family Theonellidae, order Lithistida, and forming derivatives from the isolated compound.

[0104] In yet another aspect of the present invention, purified Compound 1 is provided.

[0105] In yet another aspect of the present invention, isolated Compound 1 is provided.

[0106] In yet another aspect of the invention, provided is Compound 1 having a purity greater than about 80%, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%.

[0107] In yet another aspect of the present invention, there is provided Compound 1 in an amorphous form.

[0108] In yet another aspect of the present invention, there is provided Compound 1 in crystalline form.

[0109] In another aspect, provided are compositions comprising a crystalline form of Compound 1. In yet another embodiment, the composition can comprise at least 30% crystalline form, at least 50% crystalline form, at least 75% crystalline form, at least 90% crystalline form, at least 95% crystalline form, at least 99% crystalline form, or about 100% crystalline form of Compound 1.

[0110] In yet another aspect of the present invention, a pharmaceutically acceptable salt or ester of Compound 1 is provided.

[0111] In yet another aspect of the present invention, a solvate of Compound 1, such as a hydrate, is provided.

[0112] In yet another aspect of the present invention, a stable composition of Compound 1 is provided.

[0113] In another aspect of the present invention, provided are solid pharmaceutical compositions (including tablets, pills, capsules or granules) or liquid compositions (including solutions, suspensions or emulsions) of Compound 1 or a pharmaceutically acceptable salt or ester.

[0114] In another aspect of the present invention, a pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt or ester thereof suitable for oral, external or injection administration is provided. DETAILED DESCRIPTION

[0115] The following examples apply to all aspects of the present invention.

[0116] In compounds defined by the Markush formula in this specification, groups may be selected according to the following guidelines:

[0117] The alkyl group can be branched or straight chain and preferably has 1 to about 24 carbon atoms. A preferred class of alkyl groups has 1 to about 12 carbon atoms. A more preferred class of alkyl groups has 1 to about 8 carbon atoms or 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1, 2, 3, or 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, and isobutyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, unless otherwise indicated, the term alkyl refers to cyclic and non-cyclic groups, although cyclic groups will contain at least three carbon ring members.

[0118] Cycloalkylalkyl is a non-cyclic alkyl group substituted with a cycloalkyl group. A preferred class of cycloalkylalkyl groups has a cycloalkyl moiety and an alkyl moiety, wherein the cycloalkyl moiety has 3 to about 6 carbon ring atoms and the alkyl moiety has 1 to about 12 carbon atoms. A more preferred class of cycloalkylalkyl groups has a cycloalkyl moiety and an alkyl moiety, wherein the cycloalkyl moiety has 3 to about 4 carbon ring atoms and the alkyl moiety has 1 to about 6 carbon atoms. Cyclopropylmethyl is a particularly preferred cycloalkyl group in the compounds of the present invention.

[0119] Preferred alkenyl and alkynyl groups in the compounds of the present invention can be branched or straight chain, have one or more unsaturated bonds and 2 to about 12 carbon atoms. A more preferred class of alkenyl and alkynyl groups has 2 to about 8 carbon atoms or 2 to about 6 carbon atoms. Even more preferred are alkenyl and alkynyl groups having 2, 3 or 4 carbon atoms. As used herein, the terms alkenyl and alkynyl refer to cyclic and non-cyclic groups, although cyclic groups will contain at least three carbon ring members.

[0120] Suitable aryl groups in the compounds of the present invention include monocyclic and polycyclic compounds, wherein polycyclic compounds include polycyclic compounds containing separated and / or fused aryl groups. Typical aryl groups contain 1 to 3 separated and / or fused rings and 6 to about 18 carbon ring atoms. Preferred aryl groups contain 6 to about 14 carbon ring atoms. Particularly preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthrenyl and substituted or unsubstituted anthryl. Most preferred aryl groups are substituted or unsubstituted phenyl.

[0121] Suitable heterocyclic groups may be saturated or unsaturated and include heteroaromatic and heteroalicyclic groups, the latter of which may be partially unsaturated, both aromatic and alicyclic heterocyclic groups containing 1 to 3 separated and / or fused rings and 5 to about 18 ring atoms. Preferably, the heteroaromatic and heteroalicyclic groups contain 5 to about 10 ring atoms, more preferably 5, 6 or 7 ring atoms. Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, for example, coumarinyl including 8-coumarinyl, quinolyl including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxalinyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiirane alkyl (thiepanyl), oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolinyl.

[0122] Heterocycloalkyl is a non-cyclic alkyl group substituted with a heterocyclic group. A preferred class of heterocycloalkyls has a heterocyclic ring portion having 5 to about 10 ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, and an alkyl portion having 1 to about 6 carbon atoms. A more preferred class of cycloalkylalkyls has a heterocyclic ring portion having 5 to 6 ring atoms and 1 or 2 heteroatoms independently selected from O and N, and an alkyl portion having 1 to about 6 carbon atoms. Even more preferred are substituted or unsubstituted morpholinyl-C3-C5 alkyl and substituted or unsubstituted piperazinyl-C3-C5 alkyl. Among the compounds of the present invention, the most preferred heterocycloalkyl is [4λ 2-morpholinyl]-(CH2)4 and [1-methyl-4λ 2 -piperazinyl]-(CH2)3.

[0123] Suitable monosaccharides include aldoses (sugars carrying an aldehyde function in the terminal position), more specifically aldohexoses (sugars with 6 carbon atoms) or aldopentoses (sugars with 5 carbon atoms), preferably aldohexoses. Thus, they are particularly allose, altrose, glucose, mannose, gulose, idose, galactose, talose, ribose, arabinose, xylose or lyxose in the D or L form. The monosaccharide is preferably in cyclized form, in particular in the pyranose form (6-membered ring) or in the furanose form (5-membered ring). In these cases, the aldehyde function carried by the sugar is in the hemiacetal form, also known as a pseudoaldehyde function. Particularly preferred is the pyranose form.

[0124] In the context of the present invention, "monosaccharide residue" refers to a monosaccharide portion that is linked via its carbon atom 1 to the rest of the molecule following a condensation reaction between the aldehyde or pseudoaldehyde function and the hydroxyl (OH) function of the monosaccharide (as defined above).

[0125] Suitable halogen groups or substituents in the compounds of the present invention include F, Cl, Br and I. Fluorine is the most preferred halogen group in the compounds of the present invention.

[0126] The term halogen-substituted group refers to a group substituted by one or more halogen atoms at one or more suitable positions, wherein the halogen atoms in each halogen-substituted group may be the same or different.

[0127] The terms "pharmaceutically acceptable salt" and "ester" refer to any pharmaceutically acceptable salt or ester that, upon administration to a patient, provides (directly or indirectly) a compound described herein. However, it will be understood that non-pharmaceutically acceptable salts also fall within the scope of the present invention, as these salts can be used to prepare pharmaceutically acceptable salts. Salts can be prepared by methods known in the art.

[0128] For example, provided herein are pharmaceutically acceptable salts of compounds synthesized by conventional chemical methods from the parent compound containing an alkaline or acidic moiety. Typically, such salts are prepared, for example, by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture thereof. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfonate, nitrate, phosphate, and organic acid addition salts, such as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of base addition salts include inorganic salts such as sodium salts, potassium salts, calcium salts and ammonium salts, and organic base salts such as ethylenediamine salts, ethanolamine salts, N,N-dialkylenethanolamine salts, triethanolamine salts and basic amino acid salts.

[0129] The compounds of the present invention may be in amorphous or crystalline form as free compounds or solvates (eg hydrates), and all forms are within the scope of the present invention. Solvation methods are well known in the art.

[0130] Asymmetric stereochemistry about the asymmetric carbon is possible, so in this case, the asymmetric carbon can have (R) or (S) configuration. All diastereomers and mixtures thereof produced by the specific configuration of other asymmetric carbons present in this asymmetric carbon and the molecule are considered to be within the scope of the present invention. Stereoisomers (geometric isomers) about double bonds are also possible, so in some cases molecules can exist as (E)-isomers or (Z)-isomers. If the molecule contains several double bonds, each double bond will have its own stereoisomerism, which can be the same or different from the stereoisomerism of other double bonds of the molecule. In addition, the compounds mentioned herein can exist as atropisomers. Single stereoisomers and mixtures thereof including diastereomers, geometric isomers and atropisomers of compounds described herein fall within the scope of the present invention.

[0131] In addition, the compounds mentioned herein may exist in isotopically labeled forms. All pharmaceutically acceptable salts, esters and isotopically labeled forms of the compounds mentioned herein, and mixtures thereof, are considered to be within the scope of the present invention.

[0132] Protected forms of the compounds disclosed herein are considered to be within the scope of the present invention. Suitable protecting groups are well known to those skilled in the art. Protecting groups in organic chemistry are reviewed by Wuts, PGM, and Greene TW in Protecting Groups in Organic Synthesis, 4th edition, Wiley-Interscience, and by Kocienski PJ in Protecting Groups, 3rd edition, Georg Thieme Verlag. These references provide sections on protecting groups for OH and amino groups. All of these references are incorporated herein by reference in their entirety.

[0133] In the context of the present invention, a protecting group for OH is defined as an O-bonded moiety produced by protecting an OH group by forming a suitable protected OH group. Examples of such protected OH groups include ethers, silyl ethers, esters, sulfonates, sulfenates and sulfinates, carbonates and carbamates. In the case of ethers, the protecting group for OH may be selected from methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, [(3,4-dimethoxybenzyl)oxy]methyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, [(R)-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxy-phenoxy)methyl, guaiacylmethyl, [(p-phenylphenyl)oxy]methyl, tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl l), 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, menthyloxymethyl, o-bis(2-acetoxyethoxy)methyl, tetrahydropyranyl, fluorotetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxy-tetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)-phenyl]-4-methoxy 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylbenzofuran-2-yl (2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl), -yl), 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromoethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1-dimethoxyphenyl-2,2,2-trichloroethyl (1,1-dianisyl-2,2,2-trichloroethyl), 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tert-butyl, cyclohexyl, 1-methyl-1′-cyclopropylmethyl, allyl, isoprenyl, cinnamyl, 2-phenylallyl (phenallyl), propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, pentadienylnitrobenzyl, pentadienyl Nitropiperonyl, halobenzyl, 2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-difluorobenzyl, p-cyanobenzyl, fluorobenzyl, 4-fluoroalkoxybenzyl, trimethylsilyldimethylphenyl, p-phenylbenzyl, 2-phenyl-2-propyl, p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-siletanylbenzyl, 4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-naphthylmethyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, 2-quinolylmethyl, 6-methoxy 2-(4-methylphenyl)-4-quinolinylmethyl, 1-pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl, 4-phenyldiphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, tris(4-tert-butylphenyl)methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4′-bromobenzoyloxy)phenyldiphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(artoyloxyphenyl)methyl triphenylmethyl, 4,4'-dimethoxy-3"-[N-(imidazolylmethyl)]trityl, 4,4'-dimethoxy-3"-[N-(imidazolylethyl)carbamoyl]trityl, bis(4-methoxyphenyl)-1'-pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4"-dimethoxytrityl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioanthryl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and 4,5-bis(ethoxycarbonyl)-[1,3]-dioxolane-2-yl, benzisothiazolyl S, S-dioxide. In the case of silyl ethers, the protecting group of OH can be selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl(2,3-dimethyl-butane-2-yl)silyl (dimethylthexylsilyl), 2-norbornyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl (tri-p-xylylsilyl) silyl), triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, di(tert-butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, and fluorosilyl. In the case of esters, the protecting group for OH and the oxygen atom of the unprotected OH group to which it is attached together form an ester which may be selected from the group consisting of formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trichloroacetamidates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, phenoxyacetates, p-chlorophenoxyacetates, phenylacetates, diphenylacetates, 3-phenylpropionates, difluoropropionyl groups, 4-pentenoates, 4-oxopentanoates, 4,4-(ethylenedisulfide)pentanoates, 5-[3-bis(4-methoxyphenyl)-hydroxymethylphenoxy]levulinates, pivaloates, 1-adamantyl esters, benzoyl benzoate ... betanate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate, 4-bromobenzoate, 2,5-difluorobenzoate, p-nitrobenzoate, picolinate, nicotinate, 2-(azidomethyl)benzoate, 4-azidobutyrate, (2-azidomethyl)phenylacetate, 2-{[(tritylthio)oxy]methyl}benzoate, 2-{[(4-methoxytritylthio)oxy]methyl}benzoate,2-{[methyl(tritylthio)amino]methyl}benzoate, 2-{{[(4-methoxytrityl)thio]methylamino}-methyl}benzoate, 2-(allyloxy)phenyl acetate, 2-(isopentenyloxymethyl)benzoate, 6-(levulinyloxymethyl)-3-methoxy-2-nitrobenzoate, 6-(levulinyloxymethyl)-3-methoxy-4-nitrobenzoate, 4-benzyloxybutyrate, 4-trialkylsilyloxybutyrate, 4-acetoxy-2,2-dimethylbutyrate, 2,2-dimethyl-4-pentenoate, 2-iodobenzoate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 4-(methylthiomethyl)benzoate benzoate, 2-(chloroacetoxymethyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethyl-phosphorodiamidate, 2-chlorobenzoate. In the case of sulfonates, sulfenates and sulfinates, the protecting group of OH and the oxygen atom of the unprotected OH group to which it is attached are taken together to form a group selected from sulfonates, allylsulfonates, methanesulfonates, benzylsulfonates, toluenesulfonates, 2-[(4-nitrophenyl)ethyl]sulfonates, 2-trifluoromethylsulfonates, 4-monomethoxytritylsulfenates, alkyl 2,4-dinitrophenylsulfenates, and 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinates. In the case of carbonates, the protecting group of OH and the oxygen atom of the unprotected OH group to which it is attached are taken together to form a carbonate group selected from methyl carbonate, methoxymethyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-Trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphino)ethyl carbonate, cis-[4-[[(-methoxytrityl)sulfinyl]oxy]-tetrahydrofuran-3-yl]oxy carbonate, isobutyl carbonate, tert-butyl carbonate, vinyl carbonate, allyl carbonate, cinnamyl carbonate, propargyl carbonate, p-chlorophenyl carbonate, p-nitrophenyl carbonate, 4-ethoxy-1-naphthyl carbonate, 6-bromo-7-hydroxycoumarin-4-yl methyl carbonate, benzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, p- Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, anthraquinone-2-yl methyl carbonate, 2-dansyl ethyl carbonate, 2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl carbonate, 2-(2-nitrophenyl)propyl carbonate, alkyl 2-(3,4-methylenedioxy-6-nitrophenyl)propyl carbonate, 2-cyano-1-phenylethyl carbonate, 2-(2-pyridyl)amino-1-phenylethyl carbonate, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethyl carbonate, phenacyl carbonate, 3',5'-dimethoxybenzoin carbonate, methyldithiocarbonate, and S-benzylthiocarbonate. And in the case of carbamate, the protecting group of OH and the oxygen atom of the unprotected OH group connected thereto together form a carbamate, which can be selected from dimethylthiocarbamate, N-phenylcarbamate, N-methyl-N-(o-nitrophenyl)carbamate.

[0134] Within the scope of the present invention, the protecting group of an amino group is defined as an N-bonded moiety that is formed to protect an amino group by forming a suitable protected amino group. Examples of such protected amino groups include carbamates, ureas, amides, heterocyclic ring systems, N-alkylamines, N-alkenylamines, N-alkynylamines, N-arylamines, imines, enamines, N-metal derivatives, NN derivatives, NP derivatives, N-Si derivatives, and NS derivatives. In the case of carbamates, the protecting group of the amino group together with the nitrogen atom of the unprotected amino group to which it is attached forms a carbamate that can be selected from methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate, 2,6-di-tert-butyl-9-fluorenyl methyl carbamate, 2,7-bis(trimethylsilyl)fluorenyl methyl carbamate, 9-(2-sulfo)fluorenyl methyl carbamate, 9-( 2,7-dibromo)fluorenylcarbamate, methyl 17-tetrabenzo[a,c,g,i]fluorenylcarbamate, methyl 2-chloro-3-indenylcarbamate, methyl benzo[f]indenyl-3-ylcarbamate, methyl 1,1-dioxybenzo[b]-thiophen-2-ylcarbamate, methyl 2-methylsulfonyl-3-phenyl-1-propan-2-ylcarbamate, 2,7-di-tert-butyl-[9-(10,1 methyl (2-(2-dihydro-10,10,10,10-tetrahydrothioxanthenyl))carbamate, 2,2,2-trichloroethyl carbamate, 2-trimethylsilylethyl carbamate, (2-phenyl-2-trimethylsilyl)ethyl carbamate, 2-phenylethyl carbamate, 2-chloroethyl carbamate, 1,1-dimethyl-2-halogenated ethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate , 1,1-dimethyl-2,2,2-trichloroethyl carbamate, ethyl 2-(2′-pyridyl)carbamate, ethyl 2-(4′-pyridyl)carbamate, ethyl 2,2-bis(4′-nitrophenyl)carbamate, ethyl 2-[(2-nitrophenyl)dithio]-1-phenylcarbamate, ethyl 2-(N,N-dicyclohexylcarbamyl)carbamate, tert-butylcarbamate, C8F 19CH2CH2C(CH3)2-carbamate, 1-adamantylcarbamate, 2-adamantylcarbamate, 1-(1-adamantyl)-1-methylethylcarbamate, 1-methyl-1-(4-biphenylyl)ethylcarbamate, 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate, triisopropylsilylcarbamate, vinylcarbamate, allylcarbamate, isoprenylcarbamate, 1-isopropylallylcarbamate, cinnamylcarbamate esters, 4-nitrocinnamylcarbamate, 3.(3′-pyridyl)prop-2-enylcarbamate, hexadienylic acid ester, propargylcarbamate, but-2-ynyldicarbamate, 8-quinolinylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate, 3,5-di-tert-butylbenzylcarbamate, p-methoxybenzylcarbamate, p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate, 4-trifluoromethylbenzylcarbamate, C e F 17 CH2CH2-C6H4-CH2-carbamate, (C8F 17methyl CH2CH2)3Si-C6H4-CH2-carbamate, methyl 2-naphthylcarbamate, methyl 9-anthrylcarbamate, methyl diphenylcarbamate, 4-phenylacetoxybenzylcarbamate, 4-azidobenzylcarbamate, 4-azido-methoxybenzylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, methyl 5-benzoxazolylcarbamate, methyl 2-(trifluoromethyl)-6-chromonylcarbamate, ethyl 2-methylthiocarbamate, ethyl 2-methylsulfonylcarbamate, ethyl 2-(p-toluenesulfonyl)carbamate, ethyl 2-(4-nitrophenylsulfonyl)carbamate, ethyl 2-(2,4-dinitrophenylsulfonyl)carbamate, ethyl 2-(4-trifluoromethylphenylsulfonyl)carbamate, methyl [2-(1,3-dithianyl)]carbamate, ethyl 2-phosphinocarbamate, ethyl 2-[phenyl(methyl)sulfonylcarbamate, ethyl 1-methyl-2-(triphenylphosphino)carbamate, ethyl 1,1-dimethyl-2-cyanocarbamate, ethyl 2-danylcarbamate, ethyl 2-(4-nitrophenyl)carbamate, 4-methylthiophenylcarbamate, 2,4-dimethylthiophenylcarbamate, m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)carbamate phenyl)carbamate, d-methylnitropiperidylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, methyl phenyl(o-nitrophenyl)carbamate, ethyl 2-nitrophenylcarbamate, 6-nitroveratrylcarbamate, 4-methoxyphenacylcarbamate, 3′,5′-dimethoxybenzoincarbamate, methyl 9-thioxanthenylcarbamate, tert-amylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, methyl 1-methyl-1-cyclopropylcarbamate, cyclobutylcarbamate, cyclopentylcarbamate, cyclohexylcarbamate, isobutylcarbamate, isobutylcarbamate 1-methyl-1-(4′-pyridyl)carbamate, 1-methyl-1-(p-phenylazophenyl)carbamate, p-(p′-methoxyphenylazo)benzylcarbamate, p-(phenylazo)benzylcarbamate, 2,4-dimethyl-1-(4′-pyridyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)carbamate, 1-methyl-1-(p′-methoxyphenylazo)benzylcarbamate, 1-methyl-1-(p- ...6-trimethylbenzylcarbamate, isonicotinoylcarbamate, 4-(trimethylammonio)benzylcarbamate, p-cyanobenzylcarbamate, methyl di(2-pyridyl)carbamate, methyl 2-furylcarbamate, phenylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, ethyl 1-methyl-1-phenylcarbamate and S-benzylthiocarbamate. In the case of urea, the protecting group of the amino group may be selected from phenothiazinyl-(10)-carbonyl, N′-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl, 4-hydroxyphenylaminocarbonyl, 3-hydroxytryptaminocarbonyl and N′-phenyl-aminothiocarbonyl. In the case of amides, the amino protecting group and the nitrogen atom of the unprotected amino group to which it is attached together form an amide group which may be selected from formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pent-4-eneamide, pyridineamide, 3-pyridinecarboxamide, N-benzoylphenylalanyl, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, 2,2-dimethyl-2-(o-nitrophenyl)acetamide, o-nitrophenoxyacetamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, o-nitrobenzamide, 3- (4-tert-butyl-2,6-dinitrophenyl)-2,2-dimethylpropionamide, o-benzoyloxymethyl)benzamide, 2-(acetoxymethyl)benzamide, 2-[(tert-butyldiphenylsilyloxy)methyl]benzamide, 3-(3′,6′-dioxo-2′,4′,5′-trimethylcyclohexa-1′,4′-diene)-3,3-dimethylpropionamide, o-hydroxytrans-cinnamamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, acetoacetamide, 3-(p-hydroxyphenyl)propionamide, (N′-dithiobenzyloxycarbonylamino)acetamide, and N-acetylmethionine amide. In the case of a heterocyclic system, the amino protecting group and the nitrogen group of the unprotected amino group to which it is attached together form a heterocyclic system which may be selected from 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl, N-dithiosuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsilyloxy)pyrrole, N-1,1,4,4-tetramethyldisilazide adduct (N-1,1,4,4-tetramethyldisilvlazacyclopentaneadduct), N-1,1,3,3-tetramethyl-1,3-disilazane isoindoline, N-diphenylsilyl diethylene, N-5-substituted-1,3-dimethyl-1,3,5-triazacyclohexyl-2-one, N-5-substituted-1,3-benzyl-1,3,5-triazacyclohexyl-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine. In the case of N-alkyl, N-alkenyl, N-alkynyl or N-arylamines, the amine protecting group may be selected from N-methyl, N-tert-butyl, N-allyl, N-isoprenyl, N-cinnamyl, N-phenylallyl, N-propargyl, N-methoxymethyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-cyanomethyl, N-2-azanorbornene, N-2,4-dinitrophenyl, o-methoxyphenyl, p-methoxyphenyl, N- benzyl, N-4-methoxybenzyl, N-2,4-dimethoxybenzyl, N-2-hydroxybenzyl, N-9-phenylfluorenyl, N-fluorenyl, N-ferrocenylmethyl, N-2-picolylamine, N′-oxide, N-7-methoxycoumar-4-ylmethyl, N-diphenylmethyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-trityl, N-(4-methylphenyl)diphenylmethyl, and N-(4-methoxyphenyl)diphenylmethyl. In the case of imines, the amine protecting group may be selected from N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[2-pyridyl)mesityl]methylene, N-(N′,N′-dimethylaminomethylene), N-(N′,N′-dibenzylaminomethylene), N-(N′-tert-butylaminomethylene), N,N′-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylene, and N-tert-butylidene. In the case of enamines, the amino protecting group may be selected from N-(5,5-dimethyl-3-oxo-1-cyclohexenyl), N-2,7-dichloro-9-fluorenylmethylene, N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, N-(1,3-dimethyl-2,4,6-(1H,3H,5H)-trioxopyrimidin-5-ylidene)methyl, N-4,4,4-trifluoro-3-oxo-1-butenyl, and N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl). In the case of using an N-metal derivative, the amino protecting group forms a derivative together with the nitrogen atom of the unprotected amino group.The derivative may be selected from N-borane derivatives, N-diphenylboronic acid derivatives, N-diethylboronic acid derivatives, N-9-boronic acid bicyclononane derivatives (N-9-borabicyclononane derivatives), N-difluoroboric acid derivatives, and 3,5-bis(trifluoromethyl)phenylboronic acid derivatives; and also includes N-[phenyl(pentacarbonylchromium)]carbenyl, N-[phenyl(pentacarbonyltungsten)]carbenyl, N-[methyl(pentacarbonylchromium)]carbenyl, N-[methyl(pentacarbonyltungsten)]carbenyl, N-copper chelates, N-zinc chelates and 18-crown-6-derivatives. In the case of NN derivatives, the amine protecting group and the nitrogen atom of the unprotected amine group to which it is attached form a derivative, which may be selected from N-nitro derivatives, N-nitroso derivatives, N-oxide derivatives, azide derivatives, triazene derivatives, and N-trimethylsilylmethyl-N-benzylhydrazine derivatives. In the case of NP derivatives, the amine protecting group and the nitrogen atom of the unprotected amine group to which it is attached form NP derivatives together, and the NP derivatives can be selected from N-diphenylphosphinamide, dimethylthiophosphinamide, diphenylthiophosphinamide, dialkylphosphinamide, dibenzylphosphinamide, diphenylphosphinamide, and iminotriphenylphosphine. In the case of N-Si derivatives, the amine protecting group can be selected from tert-butyldiphenylsilyl and triphenylsilyl. In the case of NS derivatives, the amine protecting group and the nitrogen atom of the unprotected amine group to which it is attached form NS derivatives together, and the NS derivatives can be selected from N-sulfonyl or N-sulfonyl derivatives. The N-sulfenyl derivative can be selected from benzenesulfenamide, 2-nitrobenzenesulfenamide, 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 1-(2,2,2)-trifluoro-1,1-diphenyl)ethylsulfenamide, and N-3-nitro-2-pyridinesulfenamide. The N-sulfonyl derivative may be selected from methanesulfonamide, trifluoromethanesulfonamide, tert-butylsulfonamide, benzylsulfonamide, 2-(trimethylsilyl)ethanesulfonamide, p-toluenesulfonamide, benzylsulfonamide, o-anisylsulfonamide, 2-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, 2,4-dinitrobenzenesulfonamide, 2-naphthalenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)phenylsulfonamide, 2-(4-methylphenyl)-6-methoxy-4-methylsulfonamide, 9-anthracenesulfonamide, pyridine-2-sulfonamide, benzothiazole-2-sulfonamide, phenacylsulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide, 2,4,6-trimethoxybenzenesulfonamide, 2,6-dimethyl-4-methoxybenzenesulfonamide, pentamethylbenzenesulfonamide, 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide, 4-methoxybenzenesulfonamide, 2,4,6-trimethylbenzenesulfonamide, 2,6-dimethoxy-4-methylbenzenesulfonamide, 3-methoxy-4-tert-butylbenzenesulfonamide, and 2,2,5,7,8-pentamethylchroman-6-sulfonamide.

[0135] The mention of these groups should not be construed as limiting the scope of the present invention, as they are mentioned merely as illustrations of OH protecting groups and amine protecting groups, but other groups having the described functions may be known to those skilled in the art, and they should be understood to be encompassed by the present invention.

[0136] Suitable coupling agents are well known to those skilled in the art. Examples of coupling agents are N,N′-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) and its salts, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC methyl iodide), N,N′-diisopropylcarbodiimide, 1-tert-butyl-3-ethylcarbodiimide, N-cyclohexyl-N′-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC), N,N′-di-tert-butylcarbodiimide, 1,3-di-p-tolylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), 1,1′-carbonyl-bis-(1,2,4-triazole) (CDT), diimidazole oxalate, 2-chloro-1,3-dimethylimidazolidinium chloride (DMC) chloride), 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), 2-fluoro-1,3-dimethylimidazolinium hexafluorophosphate (DFIH), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolylphosphonium hexafluorophosphate, 7-azabenzotriazol-1-yloxy)tripyrrolylphosphonium hexafluorophosphate Pyrophosphonium hexafluorophosphate (PyAOP), tris(dimethylamino)-phosphonium hexafluorophosphate bromide (BRoP), chlorotripyrrophosphonium hexafluorophosphate (PyClOP), bromotripyrrophosphonium hexafluorophosphate, 3-(diethoxyphosphinoyloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), O-benzotriazol-1-yl-N,N,N′,N′-bis(pentamethylene)uronium hexafluorophosphate ( ,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium (TCTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), O-(6-chloro-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium (TCTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TDBTU), O-(2-oxo-1(2H)pyridinyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HOTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TO TU), N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), dipyrrolyl(N-succinimidyloxy)carbonium (HSPyU), and S-(1-oxo-2-pyridyl)-N,N,N′,N′-tetramethylthiouronium tetrafluoroborate (TOTT).

[0137] In order to provide a more concise description, some quantitative expressions given herein are not qualified with the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein is intended to refer to the actual given value, and it also means an approximate value based on such a given value that would be reasonably inferred by a person of ordinary skill in the art, including equivalent values and approximate values due to the experimental and / or measurement conditions of such a given value.

[0138] Particularly preferred stereochemistry of the compounds of formula I is as follows

[0139]

[0140] In another embodiment, particularly preferred compounds of formula I are those compounds also having formula Ia or pharmaceutically acceptable salts or esters thereof

[0141]

[0142] wherein R2, R3, R4, R5, Y and Z have the same meanings as above.

[0143] Particularly preferred stereochemistry of the compounds of formula Ia is as follows

[0144]

[0145] In another embodiment, the compound of formula I, Ia or Ib is not a natural product, more preferably the compound of formula I, Ia or Ib is not a compound of formula 1

[0146]

[0147] In the compounds of general formula I, it is particularly preferred that R1 is selected from hydrogen, halogen and substituted or unsubstituted C2-C6 alkynyl, more preferably R1 is hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents Rx; hydrogen is the most preferred R1 group.

[0148] In the compounds of formula I, Ia and Ib, it is particularly preferred that R2 is hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 alkenyl, -ORa and -NRcRd, wherein the optional substituent is one or more substituents Rx; wherein R5, R c and R d As defined herein. Further particularly preferred R2 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, wherein the optional substituents are one or more substituents Rx; -OR a and -NR c R d ; where R a A silyl ether protecting group selected from hydrogen, OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, -(CH2CH2o) p CH2CH3, wherein p is 1 to about 15, and the optional substituents are one or more R x Substituent; R c and R d are independently selected from substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents Rx. Particularly preferred R a is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, -(CH2CH2O) pCH2CH3, wherein p is 1 to about 10, and the optional substituents are one or more substituents Rx, and a silyl ether protecting group for OH selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylyl Silyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, di(tert-butyl)-1-pyridylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, and fluorosilyl. Particularly preferred R c and R d independently selected from substituted or unsubstituted C1-C4 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R2 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted vinyl, substituted or unsubstituted allyl, wherein the optional substituents are one or more substituents R x , -OR a and -NR c R d , wherein R is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted n-heptyl, substituted or unsubstituted allyl, substituted or unsubstituted 1-methyl-2-propenyl, substituted or unsubstituted 2-methyl-2-propenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted 3-butenyl, substituted or unsubstituted propargyl, substituted or unsubstituted 1-methyl-2-propynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted 3-butynyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted 2-cyclopropylethyl, and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 5, optionally substituted by one or more substituents R x ; R c and R dis selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents Rx. Most preferably R2 is hydrogen, methyl, vinyl, allyl, NEt2 and OR a , where R a Selected from hydrogen, methyl, ethyl, n-butyl, n-heptyl, allyl, propargyl, cyclopropylmethyl, -(CH2)3NHBoc, (CH2)3NH2, and -(CH2CH2O)3CH2CH3.

[0149] In another embodiment, in the compounds of formula I, Ia and Ib, it is particularly preferred that R2 is hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, -OR a and -NR c R d , wherein the optional substituents are one or more substituents R x ; wherein Ra, Rc and Rd are defined herein, except when R2 is -OR a When R is not unsubstituted methyl. Further particularly preferred R is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, wherein the optional substituent is one or more substituents R x , -OR a and -NR c R d Wherein Ra is selected from hydrogen, OH silyl ether protecting group, substituted C1-C 12 Alkyl, unsubstituted C2-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 15, and the optional substituents are one or more substituents R x ; Rc and Rd are independently selected from substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x Particularly preferred Ra is hydrogen, substituted or unsubstituted C2-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, -(CH2CH2O) pCH2CH3, wherein p is 1 to about 10, and the optional substituents are one or more substituents R x , and a silyl ether protecting group for OH, the silyl ether protecting group for OH being selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, di(tert-butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, and fluorosilyl. Particularly preferred R c and R d independently selected from substituted or unsubstituted C1-C4 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R2 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted vinyl, substituted or unsubstituted allyl, wherein the optional substituents are one or more substituents R x , -OR a and -NR c R d , where R a is selected from hydrogen, substituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted n-heptyl, substituted or unsubstituted allyl, substituted or unsubstituted 1-methyl-2-propenyl, substituted or unsubstituted 2-methyl-2-propenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted 3-butenyl, substituted or unsubstituted propargyl, substituted or unsubstituted 1-methyl-2-propynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted 3-butynyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted 2-cyclopropylethyl, and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 5, optionally substituted by one or more substituents R x ; R c and R dis selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x The most preferred R2 groups are hydrogen, methyl, vinyl, allyl, NEt2 and OR a , where R a Selected from hydrogen, ethyl, n-butyl, n-heptyl, allyl, propargyl, cyclopropylmethyl, -(CH2)3NHBoc, -(CH2)3NH2, and -(CH2CH2O)3CH2CH3.

[0150] In the compounds of formula I, Ia and Ib, particularly preferred R3 is selected from halogen-substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituents are one or more substituents R x and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I. More preferably, R3 is halogen-substituted or unsubstituted methyl, halogen-substituted or unsubstituted ethyl, halogen-substituted or unsubstituted n-propyl, halogen-substituted or unsubstituted isopropyl, halogen-substituted or unsubstituted n-butyl, halogen-substituted or unsubstituted tert-butyl, halogen-substituted or unsubstituted isobutyl and halogen-substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x , halogen substituents are one or more substituents independently selected from F, Cl, Br and I. Most preferably R3 is n-propyl, 3,3,3-trifluoropropyl and isobutyl.

[0151] In the compounds of formula I, Ia and Ib, particularly preferred R4 is hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R4 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x The most preferred R4 groups are hydrogen and methyl.

[0152] In the compounds of formula I, Ia and Ib, particularly preferred R5 is selected from C(OR e )2R g 、-CH(NR c R d )R g 、-(C=O)R g、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-(C=O)OR a )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)R g , and -(C=CH2)OR a ; R5 is selected from -CH(OR a )R g 、-CH(NR c R d )R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=N-NR c R d )R g ; or R5 is selected from -CH(OR a )R g 、-(C=NR c )R g 、-(C=N-OR h )R g ;

[0153] in:

[0154] R h A protecting group selected from hydrogen, OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted heterocyclic-C1C6 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 15, and substituted or unsubstituted monosaccharide residues of the following general formula:

[0155]

[0156] wherein each R group is independently selected at each occurrence from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(C=O)-(C1-C6)alkyl, and substituted or unsubstituted -(C=O)NH(C1-C6)alkyl, wherein the optional substituents are one or more substituents Rx; or two adjacent OR groups form an isopropylidene ketal or acetal group selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene, and p-methoxybenzylidene acetal;

[0157] R g is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ;

[0158] R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ;

[0159] R a is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ;

[0160] R e is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ;and

[0161] R f Selected from substituted or unsubstituted C1-C6 alkyl, -CH2O(CH2CH2O) p CH3, wherein p is 1 to about 15 and the optional substituents are one or more substituents R x , and groups of the following formula:

[0162]

[0163] wherein each R group is independently selected at each occurrence from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(C=O)-(C1-C6)alkyl, and substituted or unsubstituted -(C=O)NH(C1-C6)alkyl, wherein the optional substituents are one or more substituents R x or two adjacent OR groups form an isopropylidene ketal or acetal group, the acetal group being selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal.

[0164] More preferably, R his hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted heterocyclic-C1-C6 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 10, and substituted or unsubstituted monosaccharide residues of the following general formula

[0165]

[0166] wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted -(C=O)-(C1-C6)alkyl; wherein the optional substituents are one or more substituents R x or two adjacent OR groups form an isopropylidene ketal or acetal group, the acetal group being selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal.

[0167] More preferably, R g is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x .

[0168] More preferably, R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x .

[0169] More preferably, R c and R d independently selected from hydrogen and substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x .

[0170] More preferably, R e is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents Rx .

[0171] More preferably, R f is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, CHO(CHCHO)pCH3, wherein p is 1 to about 10, and the optional substituents are one or more substituents Rx, and groups of the following formula:

[0172]

[0173] wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted C1-C6 alkyl; or two adjacent OR groups form an isopropylidene ketal or acetal group selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal.

[0174] More preferably, R5 is selected from -CH(NR c R d )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-(C=O)OR a )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)R g , and -(C=CH2)OR a ,in:

[0175] R h A protecting group selected from hydrogen, OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted heterocyclic-C1-C6 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 15, and substituted or unsubstituted monosaccharide residues of the following general formula:

[0176]

[0177] wherein each R group is independently selected at each occurrence from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(C=O)-(C1-C6)alkyl, and substituted or unsubstituted -(C=O)NH(C1-C6)alkyl; wherein the optional substituents are one or more substituents R x or two adjacent OR groups form an isopropylidene ketal or acetal group, the acetal group being selected from methylene, methoxymethylene, ethoxymethylene, ethylene, benzylene and p-methoxybenzylidene acetal.

[0178] R g is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ;

[0179] R a is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ;

[0180] R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ;and

[0181] R f Selected from substituted or unsubstituted C1-C6 alkyl and -CH2O(CH2CH2O) p CH3, wherein p is 1 to about 15, optionally substituted by one or more substituents R x .

[0182] Even more preferably R5 is -CH(NR c R d )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-(C=O)OR a )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)Rg , and -(C=CH2)OR a ,in:

[0183] R h is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted morpholinyl-n-butyl, substituted or unsubstituted piperazinyl-n-propyl, -(CH2CH2O) p CH2CH3 (wherein p is 1 to about 5), and substituted or unsubstituted monosaccharide residues of the following general formula:

[0184]

[0185] wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted -(C=O)-(C1-C6)alkyl; wherein the optional substituents are one or more substituents Rx; or two adjacent OR groups may form an isopropylidene ketal;

[0186] Each R g The groups are independently selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x ;

[0187] R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x ;

[0188] R c and R d Rx is independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents Rx; and

[0189] Rf is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, -CH2O(CH2CH2O) p CH3, wherein p is 1 to about 5, and the optional substituents are one or more substituents Rx, and groups of the following formula:

[0190]

[0191] wherein each R group is hydrogen at each occurrence or two adjacent OR groups form an isopropylidene ketal.

[0192] The most preferred R5 is -CH(NH2)Me, -(C=O)Me, -(C=NR c )Me, -(C=N-OR h )Me, -(C=NO(C=O)R f )Me, -(C=N-NH2)Me, -(C=NO-(C=O)OR a )Me, -(C=NO-[(P=O)(OR a )2])Me, -(C=CH2)Me, or -(C=CH2)OR a , wherein Ra is ethyl or benzyl, Rc is -(CH2)3NHBoc, and Rf is -(CH2)5-NHBoc, -CH2O(CH2CH2O)2Me or a group of the following formula:

[0193]

[0194] And R h Selected from hydrogen, methyl, allyl, propargyl, -(CH2)3NHBoc, -(CH2)3NH2, -(CH2)3SH, -(CH2)4OH, -(CH2)4OP(=O)(OH)2, -(CH2)4OP(=O)(O t -Bu)2, -(CH2)4-[4λ2-morpholine], -(CH2)3--[1-methyl-4λ 2 -piperazine], -(CH2CH2O)3CH2CH3, and monosaccharide residues of the following general formula:

[0195]

[0196] In the compounds of formula I, Ia and Ib, it is particularly preferred that Y is -O- or -NH-. It is most preferred that Y is -O-.

[0197] In the compounds of formula I, Ia and Ib, it is particularly preferred that Z is -S- or -O-. It is most preferred that Z is -S-.

[0198] In further preferred embodiments, the above preferences for different substituents are combined. The present invention also relates to such combinations of the above preferred substituents of formula I, Ia or Ib.

[0199] Particularly preferred compounds of the general formula I, Ia or Ib are the following compounds:

[0200]

[0201]

[0202]

[0203] as well as

[0204] or a pharmaceutically acceptable salt or ester thereof.

[0205] More preferred compounds of the present invention are the following compounds:

[0206]

[0207]

[0208]

[0209] as well as

[0210] or a pharmaceutically acceptable salt or ester thereof.

[0211] Even more preferred compounds of the present invention are selected from:

[0212]

[0213]

[0214]

[0215] as well as

[0216] or a pharmaceutically acceptable salt or ester thereof.

[0217] Particularly preferred compounds include compounds 1, 2, 64, 70, 71, 71a, 72, 72a, 73a, 74, 74a, 75, 75a, 76, 76a, 78, 93, 94, 95, 98, 107, 110, 111, 113, 115, 116, 128, 136, 137, 141, 144, 145, 147, 148, 149, 152, 153, 154, 155, 156, 157, 158, 159, 161, 163, 164, 165, 166, 170, 172, 175, 178, 179, 182, 183, 185, 191 and 192, or a pharmaceutically acceptable salt or ester thereof. Further preferred compounds include compounds 71, 74, 74a, 75, 75a, 76, 76a, 113, 115, 149, 153, 154, 156, 158, 161, 163, 170, 179 and 192, or pharmaceutically acceptable salts or esters thereof.

[0218] Preferred compounds of formula I also include the following compounds, wherein:

[0219] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ; The most preferred R1 group is hydrogen;

[0220] R3 is selected from halogen substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituent is one or more substituents R x , and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0221] R2, R4, R5, Y and Z are defined herein.

[0222] Further preferred compounds of formula I include the following compounds, wherein:

[0223] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ;

[0224] Hydrogen is the most preferred R1 group;

[0225] R3 is selected from halogen substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituent is one or more substituents R x , and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0226] R4 is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; most preferably hydrogen and methyl.

[0227] and R2, R5, Y and z are defined herein.

[0228] Further preferred compounds of formula I include the following compounds, wherein:

[0229] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ; Hydrogen is the most preferred R1 group;

[0230] R3 is selected from halogen substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituent is one or more substituents R x , and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0231] R4 is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; most preferably hydrogen and methyl;

[0232] Y is O;

[0233] and R2, R5 and Z are defined herein.

[0234] Further preferred compounds of formula I include the following compounds, wherein:

[0235] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ; Hydrogen is the most preferred R1 group;

[0236] R3 is selected from halogen-substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituents are one or more substituents Rx, and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0237] R4 is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; most preferably hydrogen and methyl;

[0238] Y is O;

[0239] Z is S;

[0240] and R2 and R5 are defined herein.

[0241] Further preferred compounds of formula I include the following compounds, wherein:

[0242] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ; Hydrogen is the most preferred R1 group;

[0243] R3 is selected from halogen substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituent is one or more substituents R x , the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0244] R4 is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; most preferably hydrogen and methyl;

[0245] Y is O;

[0246] Z is S;

[0247] R2 is selected from hydrogen, methyl, vinyl, allyl, NET2 and OR a , where R a Selected from hydrogen, methyl, ethyl, n-butyl, n-heptyl, allyl, propargyl, cyclopropylmethyl, (CH2)3NHBoc, -(CH2)3NH2, and -(CH2CH2O)3CH2CH3;

[0248] and R5 is defined herein.

[0249] Further preferred compounds of formula I include the following compounds, wherein:

[0250] R1 is selected from hydrogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituents are one or more substituents R x ; Hydrogen is the most preferred R1 group;

[0251] R3 is selected from halogen substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituent is one or more substituents R x , the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; most preferably n-propyl, 3,3,3-trifluoropropyl, and isobutyl;

[0252] R4 is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl; most preferably hydrogen and methyl;

[0253] Y is O;

[0254] Z is S;

[0255] R5 is selected from -CH(NH2)Me, -(C=O)Me, -(C=NR c )Me, -(C=N-OR h )Me, -(C=NO(C=O)R f )Me, -(C=N-NH2)Me, -(C=NO-(C=O)OR a )Me, -(C=NO-[(P=O)(OR a )2])Me, -(C=CH2)Me, or -(C=CH2)OR a , where R a is ethyl or benzyl, R c -(CH2)3NHBoc, R f -(CH2)5-NHBoc, -CH2O(CH2CH2O)2Me or a group of the following formula:

[0256]

[0257] And R h Selected from hydrogen, methyl, allyl, propargyl, -(CH2)3NHBoc, -(CH2)3NH2, -(CH2)3SH, -(CH2)4OH, -(CH2)4OP(=O)(OH)2, -(CH2)4OP(=O)(O t -Bu)2、-(CH2)4-[4λ 2 -morpholine], -(CH2)3--[1-methyl-4λ 2 -piperazine], -(CH2CH2O)3CH2CH3, and monosaccharide residues of the following general formula:

[0258]

[0259] R2 is defined herein.

[0260] Compounds of general formula I:

[0261]

[0262] Wherein R1, R2, R3, R4, R5, Y and Z are as defined above. The compound of the general formula I can be synthesized by coupling an amine of the general formula II with a carboxylic acid of the general formula III:

[0263]

[0264] wherein R1, R2, R3, R4, R5, Y and Z in the compounds of formula II and III are as defined above in the compounds of formula I or as required by appropriate protecting groups.

[0265] In the process for preparing the compound of formula I, the intermediates R1, R2, R3 and Y of formula II and the intermediates R4, R5 and Z of formula III are particularly preferably suitable protecting groups as defined above in the preferred embodiments of the compound of formula I or as required; particularly preferably R5 is selected from -C(OR e )2R g and A group wherein m is 0, 1 or 2 and each E group is independently selected from O and S, Re is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituents are one or more substituents R x , and Rg is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R5 is -C(OR e )2R g Group, where R g and R e are independently substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R g and R e is independently substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x The most preferred R5 is -C(OEt)2Me.

[0266] In addition, when the compound of formula I has the formula -C(OR e )2R g When the R5 group is -(c=O)R g The compound of general formula I.

[0267] In addition, when the compound of formula I has the formula -(C=O)R g When the R5 group is R, the method may further comprise reacting with hydroxylamine, hydrazine, primary amine, methylenating agent or orthoester to obtain a general formula of -(C=N-OH)Rg or -(C=N-NR c R d )R g 、-(C=NR c )R g , -(C=CH2)Me, or -(C=CH2)OR a of compounds.

[0268] In addition, when the compound of the general formula has the general formula -(C=N-OH)R g When the R5 group is oxime, the method may further comprise alkylation, acylation or phosphorylation of the OH group of the oxime to obtain the corresponding ether, ester or phosphate.

[0269] In addition, the present invention provides a novel intermediate of the general formula IIa:

[0270]

[0271] wherein R1, R2, R3, R6 and Y of the intermediate of formula IIa are as defined above in the previous disclosure.

[0272] In another embodiment, particularly preferred intermediates of formula IIa are those also having formula IIb or salts thereof

[0273]

[0274] In the intermediate of general formula IIa, particularly preferred R1 is selected from hydrogen, halogen and substituted or unsubstituted C2-C6 alkynyl, wherein the optional substituent is one or more substituents R x ; The most preferred R1 group is hydrogen.

[0275] In the intermediates of formula IIa, IIb or IIc, it is particularly preferred that R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, wherein the optional substituents are one or more substituents R x 、-OR a 、-OSO2R b , and -NR c R d ; where R a A silyl ether protecting group selected from hydrogen, OH, a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, and -(CH2CH2O) pCH2CH3, wherein p is 1 to about 15 and the optional substituents are one or more R x Substituent; R b is selected from substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted aryl, wherein the optional substituent is one or more substituents R x ; and R c and R d independently selected from substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x . Particularly preferred R a is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 10, and the optional substituents are one or more substituents R x , and a silyl ether protecting group for OH, the silyl ether protecting group for OH being selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, di(tert-butyl)-1-pyridylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, and fluorosilyl. Particularly preferred R b is selected from substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted phenyl, wherein the optional substituent is one or more substituents R x . Particularly preferred R c and R d independently selected from substituted or unsubstituted C1-C4 alkyl, wherein the optional substituents are one or more substituents R x More preferably, R2 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted vinyl, substituted or unsubstituted allyl, wherein the optional substituents are one or more substituents R x 、-OR a 、OSO2R b and -NR cRd; where R a is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted n-heptyl, substituted or unsubstituted allyl, substituted or unsubstituted 1-methyl-2-propenyl, substituted or unsubstituted 2-methyl-2-propenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted 3-butenyl, substituted or unsubstituted propargyl, substituted or unsubstituted 1-methyl-2-propynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted 3-butynyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted 2-cyclopropylethyl, and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 5, optionally substituted by one or more substituents R x ; R b is selected from substituted or unsubstituted methyl and substituted or unsubstituted phenyl, wherein the optional substituents are one or more substituents R x ; R c and R d independently selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents Rx. Most preferably R2 is hydrogen, methyl, vinyl, allyl, OTosyl, ONs, OTf, NEt2 and OR a , where R a are hydrogen, methyl, ethyl, n-propyl, n-butyl, n-heptyl, allyl, propargyl, cyclopropylmethyl, -(CH2)3NHBoc, -(CH2)3NH2 and -(CH2CH2O)3CH2CH3.

[0276] In the intermediates of formula IIa, IIb or IIc, particularly preferred R3 is selected from halogen-substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C4 cycloalkyl-C1-C4 alkyl, wherein the optional substituents are one or more substituents R xand the halogen substituents are one or more substituents independently selected from F, Cl, Br and I. Particularly preferred R3 is halogen-substituted or unsubstituted C1-C6 alkyl, wherein the halogen substituents are one or more substituents independently selected from F, Cl, Br and I. More preferred R3 is selected from halogen-substituted or unsubstituted methyl, halogen-substituted or unsubstituted ethyl, halogen-substituted or unsubstituted n-propyl, halogen-substituted or unsubstituted isopropyl, halogen-substituted or unsubstituted n-butyl, halogen-substituted or unsubstituted tert-butyl, halogen-substituted or unsubstituted isobutyl and halogen-substituted or unsubstituted sec-butyl, wherein the halogen substituents are one or more substituents independently selected from F, Cl, Br and I. Most preferred R3 is n-propyl, 3,3,3-trifluoropropyl and isobutyl.

[0277] In the intermediates of formula IIa, IIb or IIc, it is particularly preferred that R6 is hydrogen or tert-butyloxycarbonyl.

[0278] In the intermediates of formula IIa, IIb or IIc, it is particularly preferred that -Y- is -O- or -NH-, provided that R2 is hydrogen, Y is -O-. Most preferably, Y is -O-.

[0279] In further preferred embodiments, the above preferences for different substituents are combined. The present invention also relates to such combinations of the above preferred substitutions of formula IIa, IIb or IIc.

[0280] Particularly preferred intermediates of formula IIa, IIb or IIc are selected from:

[0281] as well as or a salt thereof.

[0282] In addition, through the present invention, we provide a novel intermediate of formula IIIa

[0283]

[0284] wherein R4, R5 and Z of the intermediate of formula IIIa are as defined above in the previous disclosure.

[0285] Particularly preferred stereochemistry of the intermediate of formula IIIa is as follows

[0286]

[0287] In the intermediate of formula IIIa or IIIb, particularly preferred R4 is unsubstituted C1-C6 alkyl. More preferred R4 is selected from unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstituted tert-butyl, unsubstituted isobutyl and unsubstituted sec-butyl. Most preferred R4 is methyl.

[0288] In the intermediate of formula IIIa or IIIb, it is particularly preferred that R5 is selected from -C(OR e )2R g and A group wherein m is 0, 1 or 2, each E group is independently selected from -O- and -S-; wherein each R g and R e The group is independently substituted or unsubstituted C1-C6 alkyl, wherein the optional substituent is one or more substituents R x . Particularly preferred R g and R e is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x Particularly preferred m is 0 or 1, and particularly preferred E is -O-. More preferred R5 is -C(OR e )2R g , where R e and R g independently selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl, wherein the optional substituents are one or more substituents R x The most preferred R5 is -C(OEt)2Me.

[0289] In the intermediates of formula IIIa or IIIb, particularly preferred Z groups are -O- or -S-. The most preferred Z group is -S-.

[0290] In further preferred embodiments, the above preferences for different substituents are combined. The present invention also relates to such combinations of the above preferred substituents of formulae IIIa and IIIb.

[0291] A particularly preferred intermediate of formula IIIa is

[0292]

[0293] Even more preferred intermediates of formula IIIb are

[0294]

[0295] In the present description and definitions, when several groups R, R a 、R c 、R d 、R e 、R f , R, R x 、R y or R z Unless otherwise specified, it should be understood that they are independent of each other in the given definition, that is, R a These do not necessarily represent the same groups that are present simultaneously in a given compound of the invention.

[0296] Compound 1 was originally isolated from a sponge from the genus Discodermia (Du Bocage 1869), family Theonellidae, order Lithistida. The sponge was collected manually using a scuba diving system at depths ranging from 6 to 73 meters on Halmahera Island, Indonesia (2°16.307′N / 127°44.466′E). The specimen is deposited at the Centre for Advanced Studies of Blanes in Girona, Spain, under the reference code HALM-706.

[0297] Description: Massive, irregular sponge containing various fouling organisms, red in color, averaging approximately 5 cm thick and 12 x 6 cm in diameter. Sparsely and irregularly distributed drainage holes, oval in shape, 0.5-0.8 mm in diameter. Smaller, circular holes, 0.20-0.25 mm in diameter, are sparsely and irregularly distributed throughout the surface.

[0298] Megascleres :

[0299] - Round spikes (sponge spicules) (Discotriaenes) 250-350 μm in diameter, with short tapered rhabs 87-108 μm long.

[0300] -Desmas tetraclones are approximately 300-450 μm in size and 100-110 μm in thickness.

[0301] Microscleres :

[0302] - Acanthorhabds are small, fusiform, blocky, 15-22 μm long and 2-4.5 μm thick.

[0303] Skeleton arrangement:

[0304] The surface is smooth and covered with round to oval spicules (discotriaenes) with a dense crust-like outer neuron (ectosomal).

[0305] The reticular bone sheets form a relatively dense skeleton with a mesh width of approximately 500-600 μm.

[0306] In addition, the compounds of the present invention can be obtained by total synthesis, or by modifying compound 1 that has already been obtained from natural sources, or by further modifying compounds that have already been modified using various chemical reactions. Thus, hydroxyl groups can be acylated by standard coupling or acylation methods, for example, by using acetic acid, acetyl chloride, or acetic anhydride in pyridine or the like. Formate groups can be obtained by heating a hydroxyl precursor with an isocyanate. Hydroxyl groups can be converted to halogen groups via intermediate sulfonates of iodide, bromide, or chloride, or directly using sulfur trifluoride as the fluoride; or they can be reduced to hydrogen by reduction of the intermediate sulfonate. Hydroxyl groups can also be converted to alkoxy groups by alkylation using alkyl bromides, iodine, or sulfonates, or by using, for example, protected 2-bromoethylamine to convert them to amino lower alkoxy groups. Amide groups can be alkylated or acylated by standard alkylation or acylation methods, for example, by using KH and methyl iodide or acetyl chloride, respectively, in pyridine or the like. Ester groups can be hydrolyzed to carboxylic acids or reduced to aldehydes or alcohols. Carboxylic acids can be coupled with amines to provide amides by standard coupling or acylation methods. If necessary, suitable protecting groups may be used on the substituents to ensure that the active groups are not affected. The methods and reactants required to prepare these derivatives are known to those skilled in the art and can be found in general textbooks, such as March's Advanced Organic Chemistry by Wiley Interscience, 6th edition, 2007.

[0307] An important feature of the compounds of Formula I, Ia, or Ib described above is their biological activity, particularly their cytotoxic activity against tumor cells. Therefore, the present invention provides pharmaceutical compositions comprising compounds of Formula I, Ia, or Ib, or pharmaceutically acceptable salts or esters thereof, having cytotoxic activity, and their use as anticancer agents. The present invention further provides pharmaceutical compositions comprising compounds of Formula I, Ia, or Ib, or pharmaceutically acceptable salts or esters thereof, and a pharmaceutically acceptable carrier or diluent.

[0308] Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions, or emulsions) compositions for oral, external, or injectable administration.

[0309] Administration of the compound of Formula I, Ia or Ib or the composition of the present invention may be by any suitable method, such as intravenous infusion, oral formulations, and intraperitoneal and intravenous administration.

[0310] The correct dosage of the compound will vary depending on the specific formulation, mode of application, and the specific site, host, and tumor being treated. Other factors such as age, body weight, sex, diet, time of administration, excretion rate, host condition, drug combination, reaction sensitivity, and disease severity should be considered. Administration can be continuous or periodic within the maximum tolerated dose.

[0311] The compounds of the present invention have anticancer activity against several cancer types including, but not limited to, solid tumors, lung cancer, colon cancer, breast cancer, and pancreatic cancer.

[0312] Therefore, in an alternative embodiment of the present invention, the pharmaceutical composition comprising the compound of formula I and the kit as defined above are used to treat solid tumors, lung cancer, colon cancer, breast cancer and pancreatic cancer.

[0313] As used herein, "cancer" is intended to include tumors, neoplasias, and any other malignant disease involving malignant tissues or cells.

[0314] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, relieving, or inhibiting the progression of the disease or condition to which the term applies, or one or more symptoms of the disease or condition. As used herein, the term "treatment" means the act of treating as defined above, unless otherwise indicated.

[0315] Compounds and compositions according to the present invention can be administered to animals that have undergone surgery to treat cancer. In one embodiment of the present invention, the additional therapeutic approach is radiation therapy.

[0316] In a specific embodiment of the present invention, the compound or composition according to the present invention is administered simultaneously with radiotherapy. In another specific embodiment, radiotherapy is administered before or after administering the compound or composition of the present invention, preferably before or after administering the compound or composition of the present invention at least 1 hour, 3 hours, 5 hours, 12 hours, a day, a week, a month, more preferably several months (e.g., up to three months).

[0317] Depending on the type of cancer being treated, any radiation therapy regimen can be used. For example, but not limited to, x-ray radiation can be administered; in particular, high-energy megavoltage (radiation with energies greater than 1 MeV) can be used for deep-seated tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers. Gamma-emitting radioisotopes, such as radium, cobalt, and other elements, can also be administered.

[0318] Example

[0319] Example 1: Description of marine life and collection location

[0320] Sponges of the genus Discodermia (Du Bocage 1869) were hand-collected using a scuba diving system at depths ranging from 6 to 73 meters on Halmahera Island, Indonesia (2°16.307′N / 127°44.466′E). The faunal material was identified by Dr. María Jesús Uriz (Centro Superiore Blanes). The specimens are deposited at the Centro Superiore Blanes in Girona, Spain, with the reference code HALM-706.

[0321] Description: Massive, irregular sponge containing various fouling organisms, red in color, averaging approximately 5 cm thick and 12 x 6 cm in diameter. Sparsely and irregularly distributed drainage holes, oval in shape, 0.5-0.8 mm in diameter. Smaller, circular holes, 0.20-0.25 mm in diameter, are sparsely and irregularly distributed throughout the surface.

[0322] Megascleres :

[0323] - Round spikes (sponge spicules) (Discotriaenes) 250-350 μm in diameter, with short tapered rhabs 87-108 μm long.

[0324] -Desmas tetraclones are approximately 300-450 μm in size and 100-110 μm in thickness.

[0325] Microscleres :

[0326] - Acanthorhabds are small, fusiform, blocky, 15-22 μm long and 2-4.5 μm thick.

[0327] Skeleton arrangement:

[0328] The surface is smooth and covered with round to oval spicules (discotriaenes) with a dense crust-like outer neuron (ectosomal).

[0329] The reticular bone sheets form a relatively dense skeleton with a mesh width of approximately 500-600 μm.

[0330] Example 2: Isolation of Compound 1

[0331] The frozen sample of Example 1 was sliced and extracted at room temperature with a mixture of 1:1 CH2Cl2 / CH3OH (3×500 mL) and then with H2O (1×300 mL) under magnetic stirring. The organic and aqueous extracts were evaporated to give 5.3 g and 213 mg of dry residues, respectively.

[0332] The organic extracts were subjected to VLC on a Lichroprep RP-18 with a step gradient from H2O to CH3OH and then from CH3OH to CH2Cl2.

[0333] The fraction eluted with H2O / CH3OH 1:3 (80.4 mg) was subjected to semi-preparative reverse phase HPLC (XBridge C18, 5 μm, 10×150 mm, isocratic H2O+0.04% TFA / CH3CN+0.04% TFA (65:35) for 3 min, gradient from 35% to 60% CH3CN+0.04% TFA in 19 min, from 65% to 100% CH3CN+0.04% TFA in 3 min, UV detection, flow rate 3 mL / min).

[0334] Component H5 was then purified by semi-preparative reverse phase HPLC with a retention time of 14.2 minutes (SymmetryPrep C18, 7 μm, 7.8×150 mm, isocratic H2O+0.04% TFA / CH3CN+0.04% TFA (75:25) for 3 minutes, gradient from 25% to 80% CH3CN+0.04% TFA over 18 minutes, UV detection, flow rate 1.8 mg / min) to provide compound 1 (14.1 mg, retention time 11.3 minutes).

[0335] Compound 1: white powder. (+)ESIMS m / z 382.3[M+H] + ,404.1[M+Na] + ,785.2[2M+Na] + , 157.2[C6H9N2OS] + ,181.2[C 10 H 13 O3] + ;(+)HRESIMS m / z 382.1430[M+H] + (cald forC 17 H 24N3O5S 382.1431, Δ=0.36ppm); 1 H(500MHz)and 13 C NMR (125 MHz) see Table 1.

[0336]

[0337] Table 1: Compound 1 in CD3OD and CD3CN 1 H and 13 C NMR data.

[0338]

[0339] The absolute configuration of the amino acid residues in Compound 1 was determined by Marfey analysis (Marfey, P. Carlsberg Res. Commun. 1984, 49, 591-596).

[0340] In a sealed vial, 0.3mg of compound 1 was dissolved in 0.5mL of 6N HCl and heated at 110°C for 16 hours. Under N stream, the solvent was evaporated and the residue was dissolved in 50 μL of water and added into 100 μL of acetone and 40 μL of 1N NaHCO 0.7mg of fluoro-dinitrophenyl-5-L-alaninamide (L-FDAA, Marfey reagent) in the aqueous solution. The resulting mixture was heated at 40°C for 1 hour and, after cooling at room temperature, neutralized with 100 μL of 2N HCl. Finally, the mixture was diluted with 700 μL of water and filtered (45 μm filter) before HPLC-MS analysis.

[0341] Standards of all stereoisomers of the amino acid residues present in compound 1 were derivatized in the same manner as for the hydrolysis of the compound. Racemic methyl 4-methyl-2-(pyridin-3-yl)-4,5-dihydrothiazole-4-carboxylate was prepared according to the method described by Singh et al., J. Org. Chem. 2004, 69, 4551-4554.

[0342] The relative retention times of the derivative hydrolysis and derivative amino acid standards to unreacted L-FDAA were determined by reverse phase HPLC-MS: Symmetry C18, 5 μm, 4.6×150 mm, gradient H2O+0.04% TFA / CH3CN+0.04% TFA from 20% to 50% CH3CN+0.04% TFA over 30 min, UV (215 nm and 350 nm) and (+)ESIMS detection, flow rate 0.8 mL / min.

[0343] Comparison of these retention times clearly confirms the presence of 2-methyl-L-cysteine in compound 1.

[0344] Since the norvaline residue could not be obtained by simple hydrolysis of compound 1, the compound was first subjected to an oxidative ozonolysis protocol. To this end, a stream of ozone in O₂ was bubbled through a solution of compound 1 (0.3 mg) in CH₂Cl₂ (3 mL) for 5 minutes. The solvent was evaporated under a stream of N₂, and the residue was dissolved in 2 mL of hydrogen peroxide (35%):formic acid (1:9) at 0°C for 2 hours. The solvent was then removed under a stream of N₂; the resulting residue was hydrolyzed under acidic conditions and immediately subjected to Marfey derivatization as described above. Finally, the non-oxidized sample was analyzed by HPLC-MS under the same conditions as previously described.

[0345] Comparison of the relative retention times of the amino acid residues of authentic standards of L-norvaline and D-norvaline derivatized by the same procedure with those of the natural sample confirmed the presence of D-norvaline in compound 1.

[0346] These results were confirmed by the total synthesis of compound 1 described in Example 7.

[0347] Example 3: Scale-up of the isolation of compound 1

[0348] A second sample (926 g) of the sample of Example 1 was sliced and extracted at room temperature with a mixture of 1:1 CH2Gl2 / GH3OH (6 x 500 mL) and then with H2O (2 x 300 mL) under magnetic stirring. The organic extracts were evaporated to give three dry residues A (19.5 g), B (16.8 g) and C (10.7 g), while the aqueous extract gave a residue of 2.4 g.

[0349] Residues A, B, and C were subjected to VLC on Lichroprep RP-18 using a step gradient from H O to CH OH, and then from CH OH to CH Cl . For residue A, fractions eluting with H O / CH OH 1:3 (172.0 mg), CH OH (800.0 mg), and CH OH / CH Cl 1:1 (619.8 mg) contained compound 1. For residues B and C, fractions eluting with CH OH / H O 1:1 (445.6 mg B, 225.1 mg C), CH OH / H O 3:1 (286.3 mg B, 149.5 mg C), CH OH (2.1 g B, 962.5 mg C), and CH OH / CH Cl 1:1 (3.26 g B, 618.8 mg C) contained compound 1. All these fractions were subjected to normal phase flash chromatography (12 g silica gel column, 70:30 hexane / EtOAc isocratic for 8-9 minutes, 30% to 70% EtOAc in 27-29 minutes, 70% EtOAc isocratic for 6-8 minutes, then 70% to 100% EtOAc in 4-7 minutes, wavelength 254 and 280 nm, flow rate 30 mL / min) to give compound 1 (196 mg, retention time 8-13 minutes).

[0350] Example 4: Methylation of Compound 1

[0351] To a solution of compound 1 (1.4 mg) in anhydrous DMF (1.5 mL) was added Cs2CO3 (5 mg) and methyl iodide (40 μL). The reaction mixture was stirred at room temperature overnight. The solution was then subjected to HPLC analysis (Symmetry C18, 5 μm, 4.6x150 mm, 3 min isocratic H2O+0.04% TFA / CH3CN+0.04% TFA (75:25), gradient from 25% to 80% CH3CN+0.04% TFA in 18 min, UV detection, flow rate 1 mL / min) to afford compound 2 (0.5 mg).

[0352] Compound 2: white powder. (+)ESIMS m / z 396.2[M+H] + ,418.1[M+Na] + ;(+)HRESIMS m / z396.1582[M+H] + (cald for c 18 H 26 N3O5S 396.1588, Δ=1.5ppm); 1 H (500MHz) see Table 2.

[0353]

[0354] Table 2: Compound 2 in CD3OH and CDCl3 1 H NMR data.

[0355]

[0356]

[0357] Example 5: Synthesis of the intermediate of formula II

[0358] Scheme 2 provides some examples of the synthesis of intermediates of general formula II and some (S)-analogs used to confirm the stereochemistry of compound 1.

[0359]

[0360] Option 2

[0361] Synthesis of intermediate (R)-3

[0362] To the mixture was added -78°C pre-cooled LiHMDS (368 mL, 1.0 M in THF, 368 mmol, 4.0 equiv) (368 mL, 4 mL / mmol). The reaction mixture was stirred at -78°C for 1 hour. ZnCl2 (31.3 g, 230 mmol, 2.5 equiv) was added in one portion and the reaction mixture was stirred at -78°C for 30 minutes. Finally, the previously prepared intermediate solution was added via cannula at -78°C. The reaction mixture was stirred at -78°C for 4 hours. Saturated aqueous NH4Cl solution was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered and concentrated under vacuum. The crude product obtained was purified by column chromatography (CH2Cl2: EtOAc, 9: 1) to give pure (R)-3 (12.9 g, 41% yield).

[0363] 1 H NMR (300MHz, CDCl3): δ5.35 (s, 1H), 5.02 (d, J=7.9Hz, 1H), 4.27 (td, J=7.9, 4.7Hz, 1H), 3.4 3(s, 2H), 1.77(m, 2H), 1.68(s, 6H), 1.58-1.28(m, 2H), 1.43(s, 9H), 0.94(t, J=7.2Hz, 3H).

[0364] 13C NMR (75MHz, CDCl3): δ203.2, 164.5, 160.8, 155.7, 107.4, 97.1, 80.4, 59.8, 43.9, 33.0, 28.5, 25.2, 18.8, 13.9.

[0365] MS (ES): m / z 364.3 [M+Na] + .

[0366] R f :0.13 (Hex:EtOAc 4:1).

[0367] Synthesis of analogue (S)-3

[0368] The reaction mixture was stirred at -78°C for 4 h and then quenched with saturated aqueous NH4Cl. Extraction with EtOAc and drying of the organic layer over Na2SO4 gave a crude product, which was purified by silica gel flash chromatography (hexane / EtOAc from 9 / 1 to 7 / 3) to afford (S)-3 (2.0 g, 64% yield).

[0369] 1 H NMR (300MHz, CDCl3): δ5.35 (s, 1H), 5.02 (d, J=7.9Hz, 1H), 4.27 (td, J=7.9, 4.7Hz, 1H), 3.4 3(s, 2H), 1.77(m, 2H), 1.69(s, 6H), 1.58-1.28(m, 2H), 1.43(s, 9H), 0.94(t, J=7.2Hz, 3H).

[0370] 13 C NMR (75MHz, CDCl3): δ203.2, 164.5, 160.8, 155.7, 107.4, 97.1, 80.4, 59.8, 43.9, 33.0, 28.5, 25.2, 18.8, 13.9.

[0371] MS (ES): m / z 364.3 [M+Na] + ,705.2[2M+Na] + .

[0372] R f :0.5 (Hex:EtOAc 6:4).

[0373] Synthesis of intermediate (R)-4

[0374] (2.67 g, 29.4 mmol). After 30 minutes, the first mixture was added via cannula. The reaction was stirred at -78°C for 4 h and then quenched with saturated aqueous NH4Cl. Extraction with EtOAc and drying of the organic layer over Na2SO4 gave a crude product, which was purified by flash chromatography on silica gel (CH2Cl2 / EtOAc 9 / 1) to give pure (R)-4 (0.42 g, 12% yield).

[0375] 1 H NMR (300MHz, CDCl3): δ5.35 (s, 1H), 4.87 (d, J = 8.0Hz, 1H), 4.38-4.21 (m, 1H), 3.44 (d, J =3.5Hz, 2H), 1.70 (s, 6H), 1.55 (m, 2H), 1.44 (s, 9H), 1.37 (m, 1H), 0.96 (d, J = 6.5Hz, 6H).

[0376] (s, 1H), 3.91 (s, 1H), 1.74 (s, 6H), 1.73-1.53 (m, 1H), 1.44 (s, 2H), 1.43 (s, 9H), 1.49-1.31 (m, 1H), 0.94 (t, J=7.3Hz, 3H).

[0377] 13 C NMR (101MHz, CDCl3): δ168.0, 162.9, 157.5, 155.9, 105.7, 86.6, 28.4, 25.7, 25.5, 19.5, 13.8.

[0378] MS (ES): m / z 341.3 [M+H] + .

[0379]

[0380] 1 H NMR (500MHz, CD3OD): δ5.95 (d, J=2.21Hz, 1H), 5.66 (d, J=2.2Hz, 1H), 4.36 (s, 1H), 1.71-1.55 (m, 4H), 1.43 (s, 12H), 0.95 (t, J=7.4Hz, 3H).

[0381] 13 C NMR (125MHz, CD3OD): δ171.1, 168.0, 157.8, 153.4, 99.2, 80.7, 53.5, 37.7, 32.8, 28.7, 23.7, 20.5, 14.4, 13.9.

[0382] MS (ES): m / z 283.3 [M+H] + .

[0383] R f :0.26(CH2Cl2:MeOH 9:1).

[0384] Synthesis of intermediate (R)-7

[0385] (s, 1H), 5.23 (d, J=8.5Hz, 1H), 4.36 (q, J=7.8Hz, 1H), 1.78 (s, 1H), 1.67 (s, 1H), 1.43 (s, 9H), 0.92 (t, J=7.3Hz, 3H).

[0386] 13 C NMR (75MHz, CDCl3): δ171.6, 166.9, 165.2, 155.8, 129.2, 128.4, 125.5, 100.9, 90.9, 80.9, 53.0, 35.3, 28.5, 19.3, 13.8.

[0387] MS (ES): m / z 306.1 [M+Na] + .

[0388] R f :0.35(CH2Cl2:MeOH 9:1).

[0389] Optical rotation: [α D ]+101.6 (c 0.018, MeOH).

[0390] Synthesis of analogue (S)-7

[0391] 1.00-0.81 (m, 3H).

[0392] Synthesis of intermediate (R)-8

[0393] 2H), 4.41(m, 1H), 1.59(m, 3H), 1.41(s, 9H), 0.91(m, 6H).

[0394] MS (ES): m / z 320.3 [M+Na] + .

[0395] Scheme 3 provides further examples of the synthesis of intermediates of general formula II and some (S) analogs used to confirm the stereochemistry of compound 1.

[0396]

[0397] Option 3

[0398] Synthesis of intermediate (R)-9

[0399] Step yield 60%).

[0400] 1 H NMR (400MHz, CDCl3): δ5.93 (d, J=2.2Hz, 1H), 5.42 (d, J=2.2Hz, 1H), 5.30 (s, 1H), 4.88 (d, J=8.8Hz, 1H), 4.38 (q, J=8.0Hz, 1H ), 3.80 (s, 3H), 1.79 (ddt, J=13.3, 9.3, 6.5Hz, 1H), 1.70-1.61 (m, 1H), 1.43 (s, 9H), 1.42-1.21 (m, 2H), 0.93 (t, J=7.3Hz, 3H).

[0401] 13 C NMR (75MHz, CDCl3): δ171.3, 164.6, 163.7, 155.1, 103.3, 100.0, 88.5, 56.2, 53.6, 52.7, 35.4, 29.9, 28.5, 19.3, 13.8.

[0402] MS (ES): m / z 320.0 [M+Na] + .

[0403]

[0404] A mixture of (S)-7 (560 mg, 1.98 mmol), acetone (20 mL), KCO (1.37 g, 9.88 mmol) and dimethyl sulfate (0.94 mL, 9.88 mmol) was stirred at 23° C. for 2 h. Filtered through celite and washed with CHCl to give a crude product, which was purified by flash chromatography on silica gel (hexane / EtOAc from 8 / 2 to 6 / 4) to give (S)-9 (268 mg, 48% yield over two steps).

[0405] 1H NMR (300MHz, CDCl3): δ5.91 (d, J=2.2Hz, 1H), 5.40 (dd, J=2.2, 0.6Hz, 1H), 4.94 (d, J=8.8Hz, 1H), 4.43-4.24 (m, 1H), 3.77 (d, J=0.6Hz, 3H), 1 .75 (ddd, J=13.4, 9.4, 6.8Hz, 1H), 1.66-1.56 (m, 1H), 1.39 (d, J=0.6Hz, 10H), 1.31 (ddd, J=8.7, 4.9, 1.5Hz, 1H), 0.89 (dd, J=7.7, 7.0Hz, 3H).

[0406] Synthesis of intermediate (R)-10

[0407]

[0408] 1 H NMR (300MHz, CDCl3): δ5.94 (d, J=2.2Hz, 1H), 5.41 (d, J=2.2Hz, 1H), 4.87 (d, J=8.9Hz, 1H), 4.43 (q, J=7.9Hz, 1H), 3.78 (s, 3H), 1.61 (m, 3H), 1.41 (s, 9H), 0.97-0.85 (m, 6H).

[0409] Synthesis of intermediate (R)-11

[0410]

[0411] 1 H NMR (300MHz, CDCl3): δ5.91 (d, J=2.2Hz, 1H), 5.37 (d, J=2.2Hz, 1H), 4.92 (d, J=8.9Hz, 1H), 4.35 (q, J=7.8Hz, 1H), 3.99 (q, J=7. 0Hz, 2H), 1.76 (dq, J=9.2, 6.8Hz, 1H), 1.62 (1d, J=8.3, 7.4, 3.4Hz, 1H), 1.40 (s, 9H), 1.45-1.17 (m, 4H), 0.90 (t, J=7.3Hz, 3H).

[0412] Synthesis of intermediate (R)-12

[0413]

[0414] 1H NMR (300MHz, CDCl3): δ5.93 (d, J=2.2Hz, 1H), 5.39 (dd, J=2.3, 0.8Hz, 1H), 4.98-4.81 (m, 1H), 4.37 (q, J=7.9Hz, 1H), 3.89 (t, J=6.5Hz, 2H), 1.79 (m, 4H), 1.42 (s, 9H), 1.40-1.19 (m, 2H), 1.01 (td, J=7.5, 0.8Hz, 3H), 0.92 (td, J=7.3, 0.8Hz, 3H).

[0415] Synthesis of intermediate (R)-13

[0416] 1H), 4.88 (d, J=8.9Hz, 1H), 4.37 (q, J=7.9Hz, 1H), 3.93 (t, J=6.5Hz, 2H), 1.86 -1.66 (m, 3H), 1.62 (s, 1H), 1.54-1.27 (m, 11H), 0.94 (dt, J=13.8, 7.4Hz, 6H).

[0417] MS (ES): m / z 362.3 [M+Na] + ,701.5[2M+Na] + .

[0418] R f :0.37 (Hex:EtOAc 7:3).

[0419] Synthesis of intermediate (R)-14

[0420] rate 84%).

[0421] 1 H NMR (400MHz, CDCl3): δ5.92 (d, J=2.2Hz, 1H), 5.38 (d, J=2.2Hz, 1H), 4.90 (d, J=8.9Hz, 1H), 4.36 (q, J=7.8Hz, 1H), 3.91(t, J=6.5Hz, 2H), 1.85-1.68(m, 3H), 1.71-1.55(m, 1H), 1.42(s, 9H), 1.41-1.21(m, 10H), 0.98-0.83(m, 6H).

[0422] 13C NMR (100MHz, CDCl3): δ170.4, 164.6, 163.3, 154.9, 100.0, 88.6, 80.0, 69.0, 52.5, 35.2, 31.6, 28.8, 28.4, 28.3, 25.7, 22.5, 19.0, 14.0, 13.5.

[0423] Synthesis of intermediate (R)-15

[0424] -15 (93 mg, 80% yield).

[0425] 1 H NMR (400MHz, CDCl3): δ5.92 (d, J=2.2Hz, 1H), 5.38 (d, J=2.2Hz, 1H), 4.90 (d, J=8.9Hz, 1H), 4.36 (q, J=7.9Hz, 1H), 3.91(t, J=6.5Hz, 2H), 1.83-1.72(m, 3H), 1.76-1.55(m, 1H), 1.42(s, 9H), 1.47-1.22(m, 30H), 0.96-0.80(m, 6H).

[0426] 13 C NMR (100MHz, CDCl3): δ170.4, 164.5, 163.3, 154.9, 100.0, 88.6, 80.0, 69.1, 52.5, 35.2, 3 1.9, 29.7, 29.6(x2), 29.5(x2), 29.3, 29.2(x2), 28.4, 28.3, 25.8, 22.7, 19.0, 14.1, 13.6.

[0427]

[0428] 1 H NMR (400MHz, CDCl3): δ6.03-5.91 (m, 2H), 5.46-5.27 (m, 3H), 4.87 (d, J=9.0Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 4.37 (m , 1H), 1.79 (ddt, J=13.4, 9.5, 6.6Hz, 2H), 1.43 (d, J=0.5Hz, 9H), 1.33 (td, J=15.1, 7.4Hz, 2H), 1.00-0.81 (m, 3H).

[0429] 13C NMR (100MHz, CDCl3): δ169.8, 164.3, 163.7, 154.9, 130.6, 119.4, 99.8, 89.1, 80.0, 69.5, 52.5, 35.1, 28.3, 19.0, 13.5.

[0430] MS (ES+): m / z 346.3 [M+Na] + .

[0431] Optical rotation: [α D ]+82.1(c 0.045, MeOH).

[0432] R f :0.31 (Hex:EtOAc 7:3).

[0433] (R)-17 (2.31 g, 71% yield).

[0434] 1 H NMR (400MHz, CDCl3): δ5.96 (d, J=2.2Hz, 1H), 5.55 (dd, J=2.4, 0.7Hz, 1H), 4.95 (d, J=8.8Hz, 1H), 4.66 (d, J=2.5Hz, 2H), 4.42 (q, J=7 .8Hz, 1H), 2.62 (td, J=2.6, 0.9Hz, 1H), 1.87-1.71 (m, 1H), 1.74-1.60 (m, 1H), 1.42 (s, 9H), 1.40-1.21 (m, 2H), 0.93 (t, J=7.3Hz, 3H).

[0435] 13 C NMR (100MHz, CDCl3): δ168.9, 164.0, 154.9, 99.5, 89.8, 80.1, 77.6, 75.7, 56.4, 52.5, 35.1, 28.3, 19.0, 13.5.

[0436] MS (ES+): m / z 344.2 [M+Na] + .

[0437] R f :0.37 (Hex:EtOAc 7:3).

[0438] Synthesis of intermediate (R)-18

[0439]

[0440] 11H NMR (400 MHz, CDCl3): δ 5.95 (d, J = 2.2 Hz, 1H), 5.34 (d, J = 2.2 Hz, 1H), 4.91 (d, J = 8.9 Hz, 1H), 4.37 (q, J = 7.6 Hz, 1H), 3.75 (dd, J = 7.1, 1.3 Hz, 2H), 1.77 (ddt, J = 13.3, 9.5, 6.5 Hz, 1H), 1.69 - 1.53 (m, 1H), 1.41 (s, 9H), 1.46 - 1.13 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.72 - 0.59 (m, 2H), 0.39 - 0.26 (m, 2H).

[0441] 13 13C NMR (100 MHz, CDCl3): δ 170.2, 164.5, 163.5, 154.9, 99.9, 88.5, 80.0, 73.7, 52.5, 35.1, 28.3, 19.0, 13.5, 9.4, 3.3 (x2).

[0442] MS (ES+): m / z 360.2 [M+Na] + .

[0443] Optical rotation: [α D +82.1 (c 0.046, MeOH).

[0444] R f : 0.32 (Hex∶EtOAc 7∶3).

[0445]

[0446] 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.77 (m, 2H), 7.42 - 7.34 (m, 2H), 6.09 (d, J = 2.2 Hz, 1H), 5.90 (d, J = 2.2 Hz, 1H), 4.85 (d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.8 Hz, 1H), 2.46 (s, 3H), 1.75 (ddt, J = 13.7, 9.6, 6.3 Hz, 1H), 1.67 - 1.53 (m, 1H), 1.42 (s, 9H), 1.36 - 1.18 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0447] 13C NMR (100MHz, CDCl3): δ166.0, 162.3, 161.7, 154.8, 146.7, 131.5, 130.3, 128.4, 101.3, 99.5, 80.3, 52.6, 35.0, 28.2, 21.8, 18.9, 13.5.

[0448] The mixture was stirred for 24 hours and diluted with 1N HCl. The layers were separated, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by automated flash chromatography (SiO2) to afford (R)-20 (791 mg, 80% yield).

[0449] 1 H NMR (400MHz, CDCl3): δ8.60-8.38 (m, 2H), 8.31-8.06 (m, 2H), 6.10 (dd, J=2.0, 1.3Hz, 1H), 5.96 (d, J=2.3Hz, 1H), 4.8 0 (d, J=8.0Hz, 1H), 4.36 (d, J=8.0Hz, 1H), 1.63 (d, J=5.9Hz, 2H), 1.47-1.38 (m, 9H), 1.25 (s, 2H), 0.98-0.89 (m, 3H).

[0450] 13 C NMR (100MHz, CDCl3): δ161.3, 151.7, 140.3, 130.0, 125.0, 102.0, 99.3, 80.7, 77.4, 52.9, 35.0, 29.9, 28.4, 19.2, 13.7, 1.2.

[0451] MS (ES+): m / z 491.1 [M+Na] + .

[0452] R f :0.55 (Hex:EtOAc 7:3).

[0453]

[0454] 1 H NMR (300MHz, CD3OD): δ6.38 (t, J=1.8Hz, 1H), 5.99 (dd, J=2.4, 1.2Hz, 1H), 4.21 (td, J =7.5, 1.3Hz, 1H), 2.06-1.80 (m, 2H), 1.49-1.24 (m, 3H), 0.98 (td, J = 7.4, 1.3Hz, 3H).

[0455] MS(ES):m / z 387.2[2M+Na] + .

[0456]

[0457] 1 H NMR(300MHz,CD3OD):δ6.33(d,J=1.0Hz,1H),4.92(s,1H),4.36-3.98(m,1H),2.02-1.74(m,2H),1.54-1.18(m,2H),0.99(td,J=7.3,1.9Hz,3H).

[0458]

[0459] 1 H NMR(300MHz,CDCl3):δ6.16(s,1H),5.54(s,1H),4.13(t,J=7.5Hz,1H),3.84(s,3H),1.92(q,J=7.7Hz,2H),1.29(m,2H),0.93(t,J=7.3Hz,3H),0.87(m,2H).

[0460] 13 C NMR(75MHz,CDCl3):δ171.5,165.4,157.5,141.6,117.7,104.0,103.3,89.8,56.7,53.1,33.2,29.9,18.8,13.3.

[0461]

[0462] 1 H NMR(300MHz,CD3OD):δ6.35(dd,J=2.3,0.8Hz,1H),5.69(dd,J=2.3,0.8Hz,1H),4.26-4.10(m,1H),3.89(d,J=0.8Hz,3H),2.04-1.76(m,2H),1.47-1.23(m,2H),1.03-0.89(m,3H).

[0463] 4.07(dd,J=9.7,5.8Hz,1H),3.81(s,3H),1.82(dd,J=9.3,5.2Hz,1H),1.74-1.60(m,1H),1.56-1.42(m,1H),0.91(d,J=6.5Hz,6H).

[0464]

[0465] 1 H NMR(300MHz,CD3OD)δ6.33(dd,J=2.3,1.2Hz,1H),5.65(d,J=1.9Hz,1H),4.14(dd,J=7.2,1.2Hz,3H),2.04-1.76(m,2H),1.46-1.24(m,4H),0.98(td,J=7.3,1.3Hz,3H).

[0466] Hz,1H),4.31(dd,J=9.2,5.5Hz,1H),4.00(t,J=6.4Hz,2H),1.90-1.55(m,4H),1.44(m,2H),1.02(t,J=7.4Hz,3H),0.95(t,J=7.3Hz,3H).

[0467]

[0468] 1 H NMR(300MHz,CD3OD)δ6.35(dd,J=2.2,0.9Hz,1H),5.67(dd,J=2.3,0.9Hz,1H),4.16(ddd,J=9.1,6.3,1.0Hz,1H),4.07(td,J=6.4,0.9Hz,2H),2.04-1.67(m,4H),1.59-1.22(m,4H),0.98(tdd,J=7.4,2.2,0.8Hz,6H).

[0469] 1H),4.13(t,J=7.5Hz,1H),3.95(t,J=6.5Hz,2H),1.91(q,J=7.7Hz,2H),1.83-1.71(m,2H),1.46-1.19(m,10H),0.93(t,J=7.3Hz,3H),0.89(t,J=6.7Hz,3H).

[0470] 13 C NMR(100MHz,CDCl3):δ170.7,165.4,157.2,104.0,89.8,69.9,52.9,32.9,31.6,28.8,28.2,25.6,22.5,18.5,14.0,13.1.

[0471]

[0472] 1H NMR (400MHz, CDCl3): δ6.16 (d, J=2.1Hz, 1H), 5.52 (d, J=2.1Hz, 1H), 4.14 (t, J=7.5Hz, 1H), 3.95 (t, J=6.5Hz, 2H), 1 .92 (q, J=7.5Hz, 2H), 1.77 (dd, J=8.3, 6.2Hz, 2H), 1.44-1.21 (m, 32H), 0.93 (t, J=7.3Hz, 3H), 0.87 (t, J=6.8Hz, 3H).

[0473] 13 C NMR (100MHz, CDCl3): δ170.9, 165.7, 157.1, 104.2, 89.8, 70.0, 53.0, 32.9, 31.9, 29.7(x2), 29.6, 29.5, 29.4, 29.2, 28.3, 25.6, 22.7, 18.6, 14.1, 13.1.

[0474] Synthesis of intermediate (R)-30

[0475] A solution of (R)-16 (5.0 g, 15.46 mmol) in CH2Cl2 (180 mL) and trifluoroacetic acid (55 mL) was stirred at 23°C.

[0476]

[0477] 13 C NMR (100MHz, CDCl3): δ169.8, 163.9, 157.7, 130.9, 118.2, 103.2, 89.9, 69.8, 52.0, 32.7, 18.2, 12.3.

[0478] MS (ES+): m / z 224.1 [M+H] + .

[0479] Optical rotation: [α D ]-14.3 (c 0.015, MeOH).

[0480]

[0481] 1H NMR (400MHz, CDCl3): δ8.48 (brs, 2H), 6.19 (d, J=2.0Hz, 1H), 5.67 (d, J=2.1Hz, 1H), 4.70 (t, J=2.0Hz, 2H), 4 .14 (t, J=7.1Hz, 1H), 2.66 (t, J=2.3Hz, 1H), 1.92 (q, J=7.9Hz, 2H), 1.39-1.26 (m, 2H), 0.93 (t, J=7.3Hz, 3H).

[0482] 13 C NMR (100MHz, CDCl3): δ169.0, 164.6, 157.7, 103.6, 91.2, 78.2, 75.1, 57.0, 52.8, 32.9, 18.5, 13.1.

[0483] 1H), 4.13 (t, J=7.3Hz, 1H), 3.80 (d, J=7.2Hz, 2H), 1.91 (q, J=7.6Hz, 2H), 1.3 8-1.18 (m, 2H), 0.92 (t, J=7.3Hz, 3H), 0.72-0.62 (m, 2H), 0.39-0.30 (m, 2H).

[0484] 13 C NMR (100MHz, CDCl3): δ170.6, 157.2, 104.2, 89.8, 74.7, 52.9, 32.8, 18.5, 13.1, 9.2, 3.4, 3.3.

[0485] Optical rotation: [α D ]-89 (c 0.037, MeOH).

[0486] Scheme 4 provides further examples of the synthesis of intermediates of general formula II.

[0487]

[0488] Option 4

[0489] Synthesis of intermediate (R)-33

[0490]

[0491] 1H NMR (300MHz, CDCl3) δ5.88 (d, J=2.4Hz, 1H), 4.99 (d, J=2.4Hz, 1H), 4.34 (d, J=8.4Hz, 1H), 3.3 2 (dt, J=12.0, 7.2Hz, 4H), 1.89-1.55 (m, 6H), 1.42 (s, 9H), 1.19 (m, 3H), 0.92 (t, J=7.3Hz, 3H).

[0492]

[0493] 1 H NMR (300MHz, CD3OD) δ6.55 (s, 1H), 4.89 (s, 1H), 4.17 (dd, J=9.0, 6.1Hz, 1H), 3.46 (q, J=7.1Hz, 4H) , 3.02 (m, 1H), 2.06-1.74 (m, 2H), 1.49-1.25 (m, 2H), 1.21 (t, J = 7.1Hz, 6H), 0.99 (t, J = 7.3Hz, 3H).

[0494] Synthesis of Intermediate (R)-35

[0495]

[0496] 1 H NMR (300MHz, CDCl3) δ5.99 (d, J=1.5Hz, 2H), 4.91 (d, J=8.9Hz, 1H), 4.37 (q, J=7.9Hz, 1 H), 2.13 (d, J=1.1Hz, 3H), 1.84-1.54 (m, 4H), 1.42 (s, 9H), 0.92 (td, J=7.5, 2.0Hz, 3H).

[0497] MS (ES): m / z 304.1 [M+Na] + .

[0498] Synthesis of intermediate (R)-36

[0499] (m, 1H), 2.16 (d, J=1.4Hz, 3H), 1.89 (t, J=7.8Hz, 2H), 1.46-1.07 (m, 2H), 1.00-0.74 (m, 3H).

[0500] Synthesis of intermediate (R)-37

[0501] Filtration through Celite and washing with Et2O gave the crude product, which was purified on an automated flash chromatography (SiO2) system to afford (R)-37 (158 mg, 51% yield).

[0502] 1 H NMR (400MHz, CDCl3): δ6.53-6.41 (m, 1H), 6.28 (d, J=1.6Hz, 1H), 6.05 (d, J=1.5Hz, 1H), 5.92 (dd, J=17.5, 1.5Hz, 1H), 5.63 (dd, J=10.8, 1.5Hz , 1H), 4.94 (d, J=9.0Hz, 1H), 4.43 (q, J=8.1Hz, 1H), 1.88-1.72 (m, 2H), 1.43 (s, 9H), 1.34 (dt, J=15.8, 8.1Hz, 2H), 0.94 (td, J=7.3, 2.5Hz, 3H).

[0503] 13 C NMR (100MHz, CDCl3): δ163.1, 162.9, 155.1, 151.6, 133.5, 130.5, 128.7, 128.6, 122.9, 111.3, 110.1, 99 .9, 80.3, 77.5, 77.4, 77.2, 76.8, 67.6, 52.9, 35.5, 29.8, 29.6, 28.5, 27.0, 24.0, 22.3, 19.3, 13.7, 1.2.

[0504] MS (ES+): m / z 316.3 [M+Na] + .

[0505] R f :0.25 (Hex:EtOAc 4:1).

[0506] (d, J=17.5Hz, 1H), 5.74 (d, J=10.8Hz, 1H), 4.26 (t, J=7.5Hz, 1H), 1.98 (q, J=7.8Hz, 2H), 1.46-1.28 (m, 2H), 0.98-0.81 (m, 3H).

[0507] 13 C NMR (100MHz, CDCl3): δ163.9, 160.9, 160.5, 160.1, 159.7, 156.4, 152.6, 13 2.5, 125.0, 116.6, 113.7, 112.3, 104.1, 53.6, 33.2, 29.9, 18.8, 17.7, 13.3.

[0508] MS (ES+): m / z 194.3 [M+H] + .

[0509] Example 6 Synthesis of the intermediate of formula III

[0510] Scheme 5 provides some examples of the synthesis of intermediates of formula III.

[0511]

[0512] Option 5

[0513] Synthesis of Intermediate (R)-39

[0514] Dissolve in a minimum amount of H o, cool at 0 ° C, and alkalize to pH 8 with a saturated aqueous solution of NaHCO. The solvent is evaporated in vacuo to obtain the corresponding sodium salt, which is dissolved in a saturated aqueous solution of NaHCO (151 mL, 2 mL / mmol). The aqueous solution is cooled to 0 ° C, and DMF (151 mL, 2 mL / mmol) and 2,2-diethoxypropanenitrile (20 mL, 128 mmol, 1.7 equivalents) are added. The reaction mixture is stirred overnight at 23 ° C. After cooling at 0 ° C, 0.5 M HCl is added until the pH is 2. The aqueous layer is extracted with a mixture of Hex: EtOAc (x3) at 50: 50. The combined organic layers are dried over anhydrous Na SO, filtered, and concentrated in vacuo to obtain a crude product (R)-39 (11.39 g, 57% yield), which can be used in the next step without further purification.

[0515] 1 H NMR (300MHz, CDCl3): δ3.72 (d, J=11.6Hz, 1H), 3.60-3.47 (m, 4H), 3.16 (d, J=11.6Hz, 1H), 1.59 (d, J=1.9Hz, 6H), 1.20 (t, J=7.1, 6H).

[0516] 13 C NMR (100MHz, CDCl3): δ175.6, 163.3, 100.5, 84.5, 57.9, 57.9, 40.7, 24.2, 23.9, 15.4.

[0517] Optical rotation: [α D ]-4.4 (c 0.098, MeOH).

[0518] Synthesis of Intermediate (R)-40

[0519] -40 (191 mg, 37% yield).

[0520] 1 H NMR (300MHz, CDCl3): δ5.31 (dd, J=10.1, 7.5Hz, 1H), 3.74-3.40 (m, 5H), 2.94 (d, J=26.1Hz, 1H), 1.59 (s, 3H), 1.20 (q, J=7.0Hz, 6H).

[0521] 13 C NMR (75MHz, CDCl3): δ182.2, 175.2, 165.8, 103.0, 80.1, 60.3, 60.0, 39.3, 37.1, 34.2, 26.2, 17.7.

[0522] Synthesis of Intermediate (S)-39

[0523] DMF (35.8 mL, 2 mL / mmol) and 2,2-diethoxypropanenitrile (4.7 mL, 30.4 mmol, 1.7 equiv) were added. The reaction mixture was stirred at 23 ° C overnight. After cooling at 0 ° C, 0.5 M HCl was added until the pH was 2. The aqueous layer was extracted with a 50:50 mixture of Hex:EtOAc (x3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product (S)-39 (3.34 g, 71% yield), which was used in the next step without further purification.

[0524] 1 H NMR (400MHz, CDCl3): δ3.69 (dd, J=11.5, 0.7Hz, 1H), 3.54 (m, 4H), 3.12 (dd, J=11.6, 0 .7Hz, 1H), 1.57 (d, J=0.7Hz, 3H), 1.56 (d, J=0.7Hz, 3H), 1.19 (tt, J=7.1, 0.8Hz, 6H).

[0525] 13 C NMR (100MHz, CDCl3): δ176.3, 164.0, 101.5, 85.7, 58.9, 58.8, 37.8, 32.7, 24.9, 16.5, 16.4.

[0526] MS (ES+): m / z 262.3 [M+H] + .

[0527] Optical rotation: [α D ] + 4.6 (c 0.096, MeOH).

[0528] Example 7. Synthesis of Compounds 1 and 1a

[0529] Scheme 6 provides an example of the synthesis of compounds 1 and 1a.

[0530]

[0531] Option 6

[0532] Synthesis of intermediate 41

[0533] The reaction mixture was stirred at 23° C. for 15 hours, diluted with CH Cl and washed with saturated aqueous NaHCO , 0.5 M HCl and saturated aqueous NaCl. The combined organic layers were dried over anhydrous Na SO , filtered and concentrated under vacuum. The crude product obtained was purified by column chromatography (hexane: EtOAc from 8: 2 to 6: 4) to give pure 41 (8.5 g, 89% over two steps).

[0534] 1 H NMR (400MHz, CDCl3): δ7.02 (d, J=9.0Hz, 1H), 5.96-5.70 (m, 1H), 5.45-5.33 (m, 1H) , 4.72 (td, J=8.5, 6.2Hz, 1H), 3.77 (s, 3H), 3.67-3.43 (m, 5H), 3.15 (d, J=11.7Hz, 1 H), 1.87 (ddt, J=13.1, 9.7, 6.4Hz, 1H), 1.71 (ddd, J=9.6, 8.3, 5.5Hz, 2H), 1.61 (s, 3H), 1.53 (s, 3H), 1.44-1.28 (m, 2H), 1.22 (q, J=7.2Hz, 6H), 0.94 (t, J=7.3Hz, 3H).

[0535] 13 cNMR (75MHz, CDCl3): δ177.1, 174.7, 171.0, 164.1, 163.2, 100.5, 99.8, 88.6, 85.4, 58.0, 56.1, 51.0, 40.6, 34.9, 25.5, 24.0, 19.3, 15.4, 13.8.

[0536] MS (ES+): m / z 463.3 [M+Na] + .

[0537] R f :0.29 (Hex:EtOAc 1:1).

[0538]

[0539] 1 H NMR (400MHz, CDCl3): δ7.01 (d, J=8.9Hz, 1H), 5.91 (dd, J=2.2, 0.4Hz, 1H), 5.4 2(t, J=2.1Hz, 1H), 4.74 (q, J=7.8Hz, 1H), 3.82-3.75 (m, 3H), 3.63 (dd, J=12.0 , 2.0Hz, 1H), 3.28 (dd, J=11.9, 0.9Hz, 1H), 2.56 (d, J=0.9Hz, 3H), 1.95-1.73 ( m, 1H), 1.54 (d, J=2.0Hz, 3H), 1.46-1.29 (m, 1H), 0.96 (td, J=7.3, 1.7Hz, 3H).

[0540] 13 C NMR (75MHz, CDCl3): δ193.1, 173.2, 170.8, 170.4, 164.0, 162.0, 100.3, 88.6, 86.1, 56.0, 51.1, 40.1, 34.8, 26.3, 24.5, 19.0, 13.5.

[0541] MS (ES+): m / z 367.1 [M+H] + ,389.1[M+Na] + .

[0542] Synthesis of compounds 1 and 1a

[0543]

[0544] To a solution of 42 (4.25 g, 11.6 mmol) in ethanol (127.6 mL, 11 mL / mmol) and H O (127.6 mL, 11 mL / mmol) at 23° C. was added hydroxylamine hydrochloride (5.96 g, 84.7 mmol, 7.4 equiv) and sodium acetate (4.28 g, 52.2 mmol, 4.5 equiv). The reaction mixture was stirred at 23° C. for 24 hours. The solvent was removed in vacuo, and the obtained residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under vacuum. The crude product was purified by semi-preparative HPLC (X-Bridge Prep C18, 5 μm, 19×150 mm, isocratic H 2 O: CH 3 CN (62: 38) flow rate: 15 mL / min, UV detection) to give 1a (320 mg, 7% yield, retention time: 6.0 min) and 1 (2.72 g, 64% yield, retention time: 9.3 min). Synthesis 1 showed the same physical and spectral characteristics as Example 2 ( 1 H, 13 C NMR and MS) and biological properties.

[0545] Compound 1

[0546] 1 H NMR (500MHz, CD3OD): δ6.08 (dd, J=2.2, 0.7Hz, 1H), 5.55 (d, J=2.2Hz, 1H), 4.72 (dd, J=9.4, 5.4Hz, 1H), 3.84 (s, 3H), 3.59 (d, J=11.7Hz, 1H), 3.22 ( d, J=11.6Hz, 1H), 2.17 (s, 3H), 1.87 (dddd, J=13.7, 9.6, 6.6, 5.4Hz, 1H), 1.82-1.69 (m, 1H), 1.55 (s, 3H), 1.53-1.32 (m, 2H), 0.98 (t, J=7.4Hz, 3H).

[0547] 13 C NMR (75MHz, CDCl3): δ176.5, 173.4, 170.3, 166.7, 165.2, 152.9, 100.8, 88.9, 85.6, 57.0, 52.1, 40.6, 35.2, 25.0, 20.2, 13.8, 11.0.

[0548] MS (ES+): m / z 382.3 [M+H] + ,404.1[M+Na] + .

[0549] Rf :0.36 (Hex:EtOAc 1:1).

[0550] Compound 1a

[0551] 1 H NMR (500MHz, CD3OD): δ6.08 (dd, J=2.2, 0.7Hz, 1H), 5.55 (d, J=2.2Hz, 1H), 4.72 (dd, J=9.4, 5.4Hz, 1H), 3.84 (s, 3H), 3.59 (d, J=11.7Hz, 1H), 3.22 ( d, J=11.6Hz, 1H), 2.17 (s, 3H), 1.87 (dddd, J=13.7, 9.6, 6.6, 5.4Hz, 1H), 1.82-1.69 (m, 1H), 1.55 (s, 3H), 1.53-1.32 (m, 2H), 0.98 (t, J=7.4Hz, 3H).

[0552] 13 C NMR (125MHz, CDCl3): δ173.5, 171.0, 164.6, 164.5, 162.4, 147.2, 100.1, 88.5, 83.6, 56.0, 51.0, 40.9, 35.0, 24.8, 19.2, 19.0, 13.5.

[0553] Example 8. Synthesis of compounds epi-1 and epi-1a

[0554] Scheme 7 provides a comparative example of the synthesis of compounds epi-1 and epi-1a.

[0555]

[0556] Option 7

[0557] Synthesis of Epi-41 analogues

[0558] Dried over anhydrous Na2SO4.The solvent was evaporated to give the crude product, which was purified by flash chromatography on silica gel (hexane / EtOAc from 9 / 1 to 7 / 3) to give epi-41 (33 mg, 73% yield).

[0559] 1H NMR (500MHz, CD3OD): δ6.15 (d, J=2.1Hz, 1H), 5.58 (d, J=2.2Hz, 1H), 4.67 (dd , J=9.3, 5.5Hz, 1H), 3.87 (s, 3H), 3.62 (d, J=11.7Hz, 1H), 3.66-3.47 (m, 4H), 3.24(d, J=11.7Hz, 1H), 1.92-1.79(m, 1H), 1.79-1.70(m, 1H), 1.58(s, 3H), 1 .47 (s, 3H), 1.42-1.26 (m, 2H), 1.22 (t, J = 7.1Hz, 6H), 0.95 (t, J = 7.4Hz, 3H).

[0560] 13 C NMR (125MHz, CD3OD): δ178.0, 176.6, 173.4, 166.6, 165.3, 111.4, 101.6, 100.8, 8 8.9, 86.2, 58.8, 58.8, 57.0, 52.3, 41.2, 35.3, 25.1, 24.2, 20.2, 15.5(x2), 13.8.

[0561]

[0562] 1 H NMR (500MHz, CD3OD): δ6.15 (dd, J=2.2, 0.7Hz, 1H), 5.59 (d, J=2.2Hz, 1H), 4.71 (dd, J=9.3, 5.8Hz, 1H), 3.87 (s, 3H), 3.71 (d, J =11.8Hz, 1H), 3.32 (d, J = 11.9Hz, 1H), 1.96-1.67 (m, 2H), 1.55 (s, 3H), 1.4g (s, 3H), 1.47-1.27 (m, 2H), 0.95 (t, J = 7.4Hz, 3H).

[0563] 13 C NMR (125MHz, CD3OD): δ194.9, 175.6, 173.5, 171.7, 166.8, 165.3, 100.9, 88.9, 87.4, 57.1, 52.4, 41.3, 35.0, 24.5, 20.3, 20.2, 13.8.

[0564] Synthesis of epi-1 and epi-1a analogs

[0565]

[0566] To a solution of epi-44 (8 mg, 0.023 mmol) in ethanol (0.5 mL) and water (0.5 mL) was added NH2OH·HCl (11 mg, 0.16 mmol) and NaOAc (8 mg, 0.10 mmol). After stirring at 23°C for 24 hours, the ethanol was evaporated in vacuo and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and after evaporation of the solvent. The crude product was purified by HPLC using an XBridgeCi8 5μm H2O / CH3CN to give epi-1a (0.6 mg) and epi-1 (1.5 mg, 17% yield).

[0567] epi-1a analogue

[0568] 1 H NMR (500MHz, CD3OD): δ6.16 (dq, J=2.3, 0.8Hz, 1H), 5.61-5.56 (m, 1H), 4.69 (dd, J=9.2, 5.8Hz, 1H), 3.87 (t, J=0.8Hz, 3H), 3.57 (dt, J=11.5 , 0.8Hz, 1H), 3.19 (dt, J=11.5, 0.8Hz, 1H), 2.19 (t, J=0.8Hz, 3H), 1.93-1.68 (m, 2H), 1.51 (t, J=0.9Hz, 3H), 1.35 (m, 1H), 0.98-0.90 (m, 3H).

[0569] 13 C NMR (125MHz, CD3OD): δ176.5, 173.4, 170.1, 166.6, 165.2, 152.8, 100.7, 88.7, 85.4, 56.9, 52.2, 40.5, 35.0, 24.8, 20.1, 13.7, 10.8.

[0570] epi-1 analogue

[0571] 1H NMR (500MHz, CD3OD) δ6.13 (d, J=2.2Hz, 1H), 5.57 (d, J=2.2Hz, 1H), 4.68 (td, J=8.9, 5.6Hz, 1H), 3.86 (s, 3H), 3.60 (d, J=11.7Hz, 1H), 3.21 (d, J=11.6Hz, 1H), 2.16 (s, 3H), 1.82 (dd, J=9.3, 6.0Hz, 1H), 1.73 (dd, J=9.2, 4.8Hz, 1H), 1.52 (s, 4H), 1.46-1.26 (m, 1H), 0.93 (t, J=7.4Hz, 3H).

[0572] Example 9. Synthesis of more compounds of formula I

[0573] Scheme 8 provides another example of the synthesis of more compounds of formula I.

[0574]

[0575] Option 8

[0576] Compound 43

[0577] Purification by chromatography (CH2Cl2 / CH3OH 98 / 2) afforded 43 (46 mg, 100% yield).

[0578] 1 H NMR (300MHz, CD3OD): δ5.90 (m, 1H), 5.66 (m, 1H), 4.76 (q, J=7.7Hz, 1H), 3.71-3.45 (m, 5H), 3.26-3.17 (m, 1H), 1.79 (q, J=7.7Hz, 2H), 1.59 (d, J=1.9Hz, 3H), 1.50 (d, J=0.7Hz, 3H), 1.37 (m, 2H), 1.28-1.14 (m, 6H), 1.06-0.89 (m, 3H).

[0579] MS (ES): m / z 448.3 [M+Na] + , 851.4[2M+H] + .

[0580] Compound 44

[0581] Purification by flash chromatography (CH2Cl2 / CH3OH 98 / 2) afforded 44 (31 mg, 100% yield).

[0582] 1H NMR (400MHz, CDCl3): δ7.21 (d, J=8.9Hz, 1H), 6.04-5.98 (m, 1H), 5.51 (dd, J= 2.2, 0.5Hz, 1H), 4.71 (td, J=8.5, 6.7Hz, 1H), 3.65-3.43 (m, 5H), 3.23-3.12 ( m, 1H), 2.81 (s, 3H), 1.80 (dddd, J=51.2, 17.5, 9.1, 5.1Hz, 1H), 1.52 (s, 3H), 1.51-1.25 (m, 3H), 1.22 (dtd, J=7.8, 7.1, 0.6Hz, 4H), 0.94 (t, J=7.3Hz, 3H).

[0583] 13 C NMR (100MHz, CDCl3): δ177.6, 175.2, 170.7, 170.6, 165.9, 165.4, 163.3, 100.8, 100.4, 91.0, 85. 1, 57.9 (x2), 55.7, 51.4, 43.7, 40.5, 38.8, 34.7, 25.2, 23.9, 19.2, 18.8, 17.4, 15.4, 13.7, 12.7.

[0584] MS (ES): m / z 449.1 [M+Na] + .

[0585] Compound 45

[0586] The mixture was stirred overnight under reduced pressure. Diluted with CH2Cl2, the organic layer was washed with 0.5M HCl and brine, and finally, dried over anhydrous Na2SO4. The solvent was evaporated to give a crude product, which was purified by flash chromatography on silica gel (hexane / EtOAc 9 / 1 to 7 / 3) to give 45 (50 mg, 47% yield).

[0587] 1 H NMR (300MHz, CDCl3): δ7.03 (d, J=8.9Hz, 1H), 5.85 (d, J=2.3Hz, 1H), 5.37 (d, J=2.2Hz, 1H), 4.78 (td, J=8.9, 6.0Hz, 1H), 3.76 (s, 3H), 3.67-3. 41 (m, 5H), 3.14 (d, J=11.7Hz, 1H), 1.74-1.62 (m, 1H), 1.60 (s, 2H), 1.59 (s, 3H), 1.51 (s, 3H), 1.29-1.14 (m, 6H), 0.93 (dd, J=6.2, 3.5Hz, 6H).

[0588] Compound 46

[0589] Purification by ethanol / EtOAc from 9 / 1 to 7 / 3) afforded 46 (38 mg, 73% yield).

[0590] 1 H NMR (300MHz, CDCl3) δ7.00 (d, J=8.9Hz, 1H), 5.81 (d, J=2.0Hz, 1H), 5.34 (dd, J=2. 3, 0.9Hz, 1H), 4.70 (td, J=8.5, 6.2Hz, 1H), 4.03-3.90 (m, 2H), 3.64-3.42 (m, 5H), 3 .13 (dd, J=11.7, 0.9Hz, 1H), 1.84 (m, 1H), 1.68 (m, 1H), 1.59 (d, J=0.9Hz, 3H), 1.5 4-1.48 (m, 3H), 1.37 (td, J=7.0, 0.9Hz, 3H), 1.24-1.14 (m, 6H), 0.97-0.88 (m, 3H).

[0591] MS(ES): m / z 477.2[M+Na] + .

[0592] Compound 47

[0593] Purification by (CH2Cl2 / EtOAc 9 / 1) afforded 47 (48 mg, 100% yield).

[0594] 1 H NMR (300MHz, CDCl3) δ7.02 (d, J=8.9Hz, 1H), 5.82 (dt, J=2.2, 0.6Hz, 1H), 5.3 5(d, J=2.2Hz, 1H), 4.72 (td, J=8.7, 6.2Hz, 1H), 3.90 (t, J=6.4Hz, 2H), 3.67-3 .45(m, 5H), 3.15(dd, J=11.7, 0.6Hz, 1H), 1.97-1.62(m, 4H), 1.60(d, J=0.6H z, 3H), 1.53 (s, 3H), 1.51-1.30 (m, 4H), 1.26-1.13 (m, 6H), 1.00-0.85 (m, 6H).

[0595] MS (ES): m / z 505.3 [M+Na] + .

[0596] R f :0.62 (Hex:EtOAc 1:1).

[0597] Compound 48

[0598] Elution with a mixture of hexane / EtOAc from 100:0 to 50:50 afforded 48 (71 mg, 68% yield).

[0599] 1 H NMR (400MHz, CDCl3): δ7.04 (d, J=8.9Hz, 1H), 5.82 (dd, J=2.2, 0.6Hz, 1H), 5.34 (d, J=2.2Hz, 1H), 4.71 (td, J=8.5, 6.2Hz, 1H), 3.88 (td, J=6.5, 1.1Hz, 2H), 3.60 (d, J=11.7Hz, 1H), 3.60-3.44 (m, 4 H), 3.14 (d, J=11.7Hz, 1H), 1.85 (ddt, J=13.6, 9.6, 6.3Hz, 1H), 1.78-1.61 (m, 3H), 1.59 (s, 3H), 1 .52(s, 3H), 1.44-1.24(m, 10H), 1.24-1.17(m, 6H), 0.92(t, J=7.3Hz, 3H), 0.86(t, J=6.9Hz, 3H).

[0600] 13 C NMR (100MHz, CDCl3): δ176.7, 174.4, 170.1, 164.0, 162.8, 100.2, 99.8, 88.6, 85.2, 69.0, 57 .7, 57.6, 50.7, 40.3, 34.7, 31.6, 28.8, 28.3, 25.7, 25.3, 23.7, 22.5, 19.0, 15.2, 14.0, 13.5.

[0601] Compound 49

[0602] The mixture was diluted and washed with 0.5M HCl. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by automated flash chromatography (SiO2, Hex:EtOAc) to afford 49 (91 mg, 78% yield over 2 steps).

[0603] 1H NMR (400MHz, CDCl3): δ7.03 (d, J=8.9Hz, 1H), 5.83 (d, J=2.1Hz, 1H), 5.35 (d, J=2.2Hz, 1H), 4.72 (td, J=8.6, 6.2Hz, 1H), 3.89 (td, J=6.6, 1.1Hz, 2H), 3.61 (d, J=11.7Hz, 1H), 3.61-3.4 5(m, 4H), 3.15(d, J=11.7Hz, 1H), 1.93-1.79(m, 1H), 1.79-1.62(m, 3H), 1.60(s, 3H), 1.53( s, 3H), 1.44-1.23 (m, 32H), 1.24-1.18 (m, 6H), 0.93 (t, J=7.3Hz, 3H), 0.86 (t, J=6.8Hz, 3H).

[0604] 13 C NMR (100MHz, CDCl3): δ176.8, 174.4, 170.1, 164.0, 162.8, 100.2, 99.9, 88.6, 85.2, 69.0, 57.7, 57.6, 50.8 , 40.3, 34.7, 31.9, 29.7, 29.6, 29.5(x2), 29.3, 29.2, 28.4, 25.8, 25.3, 23.7, 22.7, 19.0, 15.2, 14.1, 13.5.

[0605] Compound 50

[0606] To a solution of (R)-30 (5.20 g, 15.42 mmol) and (R)-39 (4.03 g, 15.42 mmol) in CH2Cl2 (110 mL) at 23°C were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (5.86 g, 15.42 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (2.11 g, 15.42 mmol) and N,N-dimethoxybenzylamine (HATU).

[0607]

[0608] 1H NMR (400MHz, CDCl3): δ7.02 (d, J=8.9Hz, 1H), 6.01-5.88 (m, 1H), 5.86 (dd, J=2.2, 0.6H z, 1H), 5.46-5.24 (m, 3H), 4.72 (td, J=8.5, 6.3Hz, 1H), 4.46 (dt, J=5.5, 1.5Hz, 1H), 3. 70-3.39(m, 5H), 3.16(d, J=11.6Hz, 1H), 1.92-1.83(m, 1H), 1.75-1.66(m, 1H), 1.62(s , 3H), 1.55 (s, 3H), 1.40-1.28 (m, 2H), 1.25-1.17 (m, 6H), 0.93 (td, J=7.4, 2.4Hz, 3H).

[0609] 13 C NMR (100MHz, CDCl3): δ176.8, 174.5, 169.6, 163.8, 163.1, 130.6, 119.5, 100.2, 9 9.7, 89.2, 85.2, 69.5, 57.8, 57.7, 50.8, 40.4, 34.7, 25.3, 23.7, 19.0, 15.2, 13.5.

[0610] MS (ES+): 489.2 [M+Na] + .

[0611] Optical rotation: [α D ]+51.5 (c 0.037, MeOH).

[0612] R f :0.25 (Hex:EtOAc 7:3).

[0613] Compound 51

[0614] The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude product was purified by automated flash chromatography (SiO2, Hex:EtOAc from 10:0 to 50:50) to give 51 (3.37 g, 100% yield over 2 steps).

[0615] 1H NMR (400MHz, CDCl3): δ7.04 (d, J=8.9Hz, 1H), 5.86 (dd, J=2.3, 0.6Hz, 1H), 5.52 (d, J=2.3Hz, 1H ), 4.72 (td, J=8.6, 6.2Hz, 1H), 4.63 (d, J=2.5Hz, 2H), 3.60 (d, J=11.8Hz, 1H), 3.63-3.43 (m, 4H) , 3.15 (d, J=11.8Hz, 1H), 2.62 (t, J=2.4Hz, 1H), 1.86 (ddt, J=13.6, 9.6, 6.3Hz, 1H), 1.76-1.62 (m, 1H), 1.60 (s, 3H), 1.52 (s, 3H), 1.45-1.28 (m, 2H), 1.27-1.16 (m, 6H), 0.93 (t, J=7.3Hz, 3H).

[0616] 13 C NMR (100MHz, CDCl3): δ176.9, 174.5, 168.6, 163.4 (2x), 100.2, 99.3, 89.9, 85. 1, 77.7, 75.6, 57.7, 57.6, 56.4, 50.8, 40.3, 34.6, 25.3, 23.7, 19.0, 15.2, 13.5.

[0617] MS (ES+): 487.3 [M+Na] + .

[0618] R f :0.35 (Hex:EtOAc 50:50).

[0619] Compound 52

[0620] The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product obtained was purified by automated flash chromatography (SiO2, Hex:EtOAc 50:50) to give 52 (12.1 g, 95% yield).

[0621] 1H NMR (400MHz, CDCl3): δ7.03 (d, J=8.9Hz, 1H), 5.85 (dd, J=2.2, 0.5Hz, 1H), 5.31 (d, J=2.2Hz, 1H), 4.71 (t d, J=8.5, 6.2Hz, 1H), 3.80-3.67 (m, 2H), 3.61 (d, J=11.8Hz, 1H), 3.61-3.42 (m, 4H), 3.14 (d, J=11.7Hz, 1H ), 1.86 (ddt, J=13.7, 9.5, 6.3Hz, 1H), 1.75-1.62 (m, 1H), 1.60 (s, 3H), 1.52 (s, 3H), 1.45-1.15 (m, 2H), 1 .22 (t, J=7.1Hz, 3H), 1.20 (t, J=7.1Hz, 3H), 0.92 (t, J=7.3Hz, 3H), 0.74-0.58 (m, 2H), 0.38-0.27 (m, 2H).

[0622] 13 C NMR (100MHz, CDCl3): δ176.8, 174.4, 170.0, 163.9, 162.9, 100.2, 99.8, 88.6, 85. 2, 73.7, 57.7, 57.6, 50.8, 40.3, 34.7, 25.3, 23.7, 19.0, 15.2, 13.5, 9.4, 3.3 (x2).

[0623] MS (ES+): 503.3 [M + Na] + .

[0624] R f :0.49 (Hex:EtOAc 1:1).

[0625] Compound 53

[0626] Purification by (CH2Cl2 / CH3OH 98 / 2) afforded 53 (38 mg, 60% yield).

[0627] 1H NMR (300MHz, CDCl3) δ7.04 (d, J=8.9Hz, 1H), 5.85 (d, J=2.3Hz, 1H), 4.96 (d, J =2.3Hz, 1H), 4.67 (1d, J=8.4, 6.8Hz, 1H), 3.68-3.42 (m, 5H), 3.29 (qd, J=7.3 , 3.5Hz, 4H), 3.14 (d, J=11.7Hz, 1H), 1.95-1.64 (m, 2H), 1.60 (s, 3H), 1.53 (s , 3H), 1.34 (dd, J=9.8, 6.8Hz, 2H), 1.28-1.08 (m, 12H), 0.93 (t, J=7.3Hz, 3H).

[0628] Compound 54

[0629] Purification by chromatography (CH2Cl2 / EtOAc 6 / 4) afforded 54 (7 mg, 100% yield).

[0630] 1 H NMR (300MHz, CDCl3) δ7.08 (d, J=8.9Hz, 1H), 5.96 (t, J=1.3Hz, 1H), 5.93 (d, J=1.5Hz, 1H), 4.72 (td, J=8.5, 6.6Hz, 1H), 3.75-3.45 (m, 5H), 3.36 (d, J = 11.8Hz, 1H), 2.10 (d, J = 1.2Hz, 3H), 1.89-1.68 (m, 2H), 1.66 (s, 3H), 1.46-1.27 (m, 8H), 0.93 (t, J = 7.3Hz, 3H).

[0631] MS (ES): m / z 447.2 [M+Na] + .

[0632] R f :0.33 (Hex:EtOAc 1:1).

[0633] Compound 55

[0634] The mixture was filtered through celite and the filtrate was concentrated under vacuum. The obtained crude product was purified by flash chromatography (SiO2, Hex:EtOAc) automated system to give 55 (1.35 g, 90% yield).

[0635] 1H NMR (400MHz, CDCl3): δ6.45 (dd, J=17.4, 10.8Hz, 1H), 6.33 (d, J=1.5Hz, 1H), 6.04-5.99 (m , 1H), 5.94 (d, J=17.5Hz, 1H), 5.61 (d, J=10.8Hz, 1H), 4.79 (td, J=8.5, 6.3Hz, 1H), 3.81 (d, J=11.8Hz, 1H), 3.64-3.45(m, 4H), 3.19(d, J=11.8Hz, 1H), 1.94-1.83(m, 1H), 1.82-1.70( m, 1H), 1.64 (s, 6H), 1.45-1.29 (m, 2H), 1.23 (td, J=7.1, 2.6Hz, 6H), 0.95 (t, J=7.4Hz, 3H).

[0636] 13 C NMR (75MHz, CDCl3): δ162.6, 151.4, 133.5, 123.1, 111.4, 100.4, 99.7, 58.2, 58.1, 51.6, 40.5, 35.1, 25.5, 24.0, 19.3, 15.3, 13.7.

[0637] MS (ES+): m / z 459.2 [M+Na] + .

[0638] R f :0.43(Hex∶EtOAc 1∶1)..

[0639] Compound 56

[0640]

[0641] Compound 57

[0642] Hz, 1H), 5.58 (d, J=2.1Hz, 1H), 4.75 (td, J=8.5, 7.0Hz, 1H), 3.60 (d, J=11.9Hz, 1H), 3.30 (d, J=11 .9Hz, 1H), 2.57(s, 3H), 1.98-1.76(m, 2H), 1.56(s, 3H), 1.51-1.31(m, 2H), 0.98(t, J=7.4Hz, 3H).

[0643] MS (ES): m / z 375.1 [M+Na] + ,727.1[2M+Na] + .

[0644] Compound 58

[0645]

[0646] 1 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J = 8.9 Hz, 1H), 5.93 (d, J = 2.2 Hz, 1H), 5.43 (d, J = 2.2 Hz, 1H), 4.81 (td, J = 8.5, 6.9 Hz, 1H), 3.85 - 3.70 (m, 3H), 3.62 (d, J = 11.9 Hz, 1H), 3.27 (d, J = 11.9 Hz, 1H), 2.56 (s, 3H), 1.82 - 1.56 (m, 3H), 1.53 (s, 3H), 0.97 (t, J = 6.4 Hz, 6H).

[0647] Compound 59

[0648]

[0649] 1 1H NMR (300 MHz, CDCl3) δ 6.08 (d, J = 2.0 Hz, 1H), 5.55 (d, J = 2.1 Hz, 1H), 5.18 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 2.17 (d, J = 1.1 Hz, 1H), 2.06 (s, 0H), 1.93 - 1.59 (m, 12H), 1.53 (d, J = 1.1 Hz, 1H), 1.49 - 1.29 (m, 16H), 0.92 (t, J = 7.3 Hz, 5H).

[0650] MS (ES): m / z 381.2 [M + H] + , 403.3 [M + Na] + .

[0651] R f : 0.2 (Hex∶EtOAc 6∶4).

[0652]

[0653] 1H NMR(300MHz,CDCl3)δ7.04(d,J=8.9Hz,1H),5.92(d,J=2.2Hz,1H),5.41(d,J=2.2Hz,1H),4.74(q,J=7.8Hz,1H),4.01-3.89(m,2H),3.63(d,J=11.9Hz,1H),3.28(d,J=11.9Hz,1H),2.56(d,J=1.4Hz,3H),1.95-1.65(m,4H),1.64-1.17(m,7H),1.05-0.87(m,6H).

[0654] MS(ES):m / z 409.3[M+H] + ,431.1[M+Na] + .

[0655] R f :0.27(Hex∶EtOAc 6∶4).

[0656]

[0657] 1 H NMR(400MHz,CDCl3):δ7.04(d,J=8.9Hz,1H),5.91(d,J=2.2Hz,1H),5.40(d,J=2.2Hz,1H),4.73(dt,J=8.8,7.5Hz,1H),3.91(td,J=6.5,1.7Hz,2H),3.61(d,J=12.0Hz,1H),3.26(d,J=11.9Hz,1H),2.55(s,3H),1.93-1.67(m,4H),1.53(s,3H),1.47-1.18(m,10H),0.95(t,J=7.3Hz,3H),0.88(t,J=6.8Hz,3H).

[0658] 13 C NMR(100MHz,CDCl3):δ193.2,173.2,170.4,170.3,164.3,161.7,100.8,88.9,86.0,69.2,51.0,40.1,34.8,31.6,29.6,28.8,28.3,26.3,25.7,24.5,22.5,19.0,14.0,13.5.

[0659]

[0660] 1H NMR(400MHz,CDCl3):δ7.03(d,J=9.0Hz,1H),5.90(d,J=2.1Hz,1H),5.39(d,J=2.2Hz,1H),4.73(dt,J=8.8,7.6Hz,1H),3.90(td,J=6.5,1.7Hz,2H),3.61(d,J=11.9Hz,1H),3.26(d,J=11.9Hz,1H),2.55(s,3H),1.93-1.66(m,4H),1.53(s,3H),1.46-1.18(m,32H),0.95(t,J=7.4Hz,3H),0.85(t,J=6.9Hz,3H).

[0661] 13 C NMR(100MHz,CD3OD):δ193.1,173.2,170.4,170.2,164.2,161.7,100.8,88.9,86.0,69.2,51.0,40.1,34.9,31.9,29.6(x3),29.5,29.4,29.3,29.1,28.3,26.3,25.7,24.5,22.6,19.0,14.1,13.5.

[0662]

[0663] 1 H NMR(400MHz,CDCl3):δ7.11(d,J=8.9Hz,1H),5.97(d J=2.2Hz,1H),5.99-5.89(m,1H),5.48(d,J=2.2Hz,1H),5.44-5.28(m,2H),4.75(q,J=7.9Hz,1H),4.49(td,J=5.5,1.5Hz,2H),3.60(d,J=11.9Hz,1H),3.27(d,J=11.9Hz,1H),2.55(s,3H),2.03-1.67(m,2H),1.53(s,3H),1.45-1.26(m,1H),0.95(t,J=7.4Hz,3H).

[0664] 13 C NMR(100MHz,CDCl3):δ193.3,173.3,170.6,169.8,164.1,162.2,130.7,119.9,100.8,89.6,86.3,69.8,51.2,40.3,35.1,26.5,24.8,24.7,19.3(x2),13.7.

[0665] MS(ES+): 393.2 [M+H] + , 415.2 [M+Na] + .

[0666] Optical rotation: [α D +51.0 (c 0.014, MeOH).

[0667] R f : 0.39 (Hex∶EtOAc 1∶1).

[0668]

[0669] 1 1H NMR (400 MHz, CDCl3): δ7.05 (d, J = 8.9 Hz, 1H), 5.95 (d, J = 2.2 Hz, 1H), 5.58 (d, J = 2.3 Hz, 1H), 4.75 (q, J = 8.1 Hz, 1H), 4.66 (d, J = 2.5 Hz, 2H), 3.61 (d, J = 11.9 Hz, 1H), 3.27 (d, J = 11.9 Hz, 1H), 2.63 (t, J = 2.4 Hz, 1H), 2.55 (s, 3H), 1.95 - 1.72 (m, 2H), 1.54 (s, 3H), 1.47 - 1.28 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0670] 13 13C NMR (100 MHz, CDCl3): δ193.2, 173.3, 168.7, 163.8, 163.1, 162.3, 100.3, 90.1, 86.0, 77.8, 75.5, 56.5, 51.0, 40.1, 34.8, 26.3, 24.5, 19.0, 13.5.

[0671] MS(ES+): 391.2 [M+H] + , 413.1 [M+Na] + .

[0672] R f : 0.26 (Hex∶EtOAc 60∶40).

[0673]

[0674] 11H NMR (400 MHz, CDCl3): δ 7.05 (d, J = 8.9 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 5.37 (d, J = 2.3 Hz, 1H), 4.73 (q, J = 7.9 Hz, 1H), 3.76 (dd, J = 7.1, 1.9 Hz, 2H), 3.61 (d, J = 11.9 Hz, 1H), 3.27 (d, J = 12.0 Hz, 1H), 2.55 (s, 3H), 1.94 - 1.73 (m, 1H), 1.66 - 1.53 (m, 1H), 1.53 (s, 3H), 1.52 - 1.16 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.70 - 0.61 (m, 2H), 0.33 (t, J = 5.2 Hz, 2H).

[0675] 13 13C NMR (100 MHz, CDCl3): δ 193.2, 173.2, 170.4, 164.3, 163.0, 161.8, 100.8, 88.9, 86.0, 73.9, 51.0, 40.1, 34.8, 26.3, 24.5, 19.0, 13.5, 9.3, 3.4, 3.3.

[0676] MS (ES+): 407.1 [M+H] + , 429.2 [M+Na] + .

[0677] Optical rotation: [α D +56.2 (c 0.019, MeOH).

[0678] R f : 0.47 (Hex∶EtOAc 1∶1).

[0679]

[0680] 1 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J = 8.8 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.04 (dd, J = 5.5, 2.3 Hz, 1H), 4.80 - 4.60 (m, 1H), 3.63 (d, J = 11.9 Hz, 1H), 3.38 - 3.18 (m, 5H), 2.56 (s, 3H), 1.95 - 1.63 (m, 2H), 1.55 (s, 3H), 1.37 - 1.05 (m, 8H), 0.96 (t, J = 7.3 Hz, 3H).

[0681] MS (ES): m / z 408.2 [M+H]+ .

[0682] Efficient removal of formic acid afforded crude product 67 (100% yield), which was used in the next step without further purification.

[0683] 1 H NMR (400MHz, CDCl3) δ7.03 (d, J=9.0Hz, 1H), 6.04-5.93 (m, 2H), 4.75 (q, J=8.0Hz, 1H), 3.68-3.60 (d, J=11.9Hz, 1H), 3. 28(d, J=11.9Hz, 1H), 2.57(s, 3H), 2.14(s, 3H), 1.94-1.74(m, 2H), 1.55(s, 3H), 1.46-1.27(m, 2H), 1.04-0.90(m, 3H).

[0684] MS (ES): m / z 351.2 [M+H] + ,373.1[M+Na] + .

[0685] R f :0.42 (Hex:EtOAc 1:1).

[0686] Purification in an automated flash chromatography (SiO2) system afforded 68 (454 mg, 40% yield).

[0687] 1 H NMR (400MHz, CDCl3): δ7.04 (d, J=9.0Hz, 1H), 6.45 (dd, J=17.5, 10.8Hz, 1H), 6.26 (d, J=1. 3Hz, 1H), 6.04 (dd, J=1.5, 0.8Hz, 1H), 5.89 (dd, J=17.6, 0.8Hz, 1H), 5.61 (dd, J=10.8, 0.8 Hz, 1H), 4.84-4.68 (m, 1H), 3.62 (dd, J=11.9, 0.9Hz, 1H), 3.25 (dd, J=11.9, 0.9Hz, 1H), 2. 54(d, J=0.9Hz, 3H), 1.94-1.72(m, 2H), 1.54(s, 1H), 1.53-1.20(m, 2H), 0.99-0.80(m, 3H).

[0688] MS (ES+): m / z 363.2 [M+H] + ,385.1[M+Na] + .

[0689] R f :0.50 (Hex:EtOAc 1:1).

[0690] Compounds 69 and 69a

[0691]

[0692] To a solution of 58 (47 mg, 0.13 mmol) in ethanol (1.32 mL) and water (1.32 mL) was added NH2OH·HCl (61 mg, 0.95 mmol) and NaOAc (44 mg, 0.58 mmol). After stirring at 23°C for 24 h, the ethanol was evaporated in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by HPLC using XBridge C18 5μm H2O / CH3CN to afford 69a (1.6 mg) and 69 (16.7 mg, 35% yield).

[0693] Compound 69a

[0694] 1 H NMR (500MHz, CDCl3) δ6.96 (d, J=8.9Hz, 1H), 5.94 (dd, J=2.2, 0.6Hz, 1H), 5.43 (d, J=2.2Hz, 1H), 4.81 (td, J=8.7, 6.5Hz, 1H), 3.80 (d, J=0.7Hz, 3H ), 3.69 (dd, J=11.7, 0.7Hz, 1H), 3.22 (dd, J=11.7, 0.7Hz, 1H), 2.20 (d, J=0.7Hz, 3H), 1.82-1.51 (m, 3H), 1.63 (s, 3H), 0.96 (dd, J=8.4, 6.4Hz, 6H).

[0695] Compound 69

[0696] 1 H NMR (500MHz, CDCl3) δ8.70 (s, 1H), 7.08 (d, J = 8.8Hz, 1H), 5.93 (d, J = 2.2Hz, 1H), 5.43 (d, J = 2.2Hz, 1H), 4.81 (td, J = 8.7, 6.6Hz, 1H), 3 .79 (s, 3H), 3.54 (d, J = 11.6Hz, 1H), 3.24 (d, J = 11.6Hz, 1H), 2.23 (s, 3H), 1.84-1.56 (m, 3H), 1.52 (s, 3H), 0.97 (dd, J = 9.5, 6.5Hz, 6H).

[0697] Compound 70

[0698] The crude product was purified by HPLC using H2O / CH3CN to afford 70 (8 mg, 22% yield).

[0699] 1 H NMR (400MHz, CD3OD): δ6.02 (dd, J=2.2, 0.7Hz, 1H), 5.51 (d, J=2.2Hz, 1H), 4.74 (dd, J=9.1, 5.8Hz, 1H), 4.08 (q, J=7.0Hz, 2 H), 3.55 (d, J=11.5Hz, 1H), 3.17 (d, J=11.5Hz, 1H), 2.18 (s, 3H), 1.52 (s, 3H), 1.38 (t, J=7.0Hz, 3H), 0.98 (t, J=7.4Hz, 3H).

[0700] MS (ES+): m / z 396.2 [M+H] + ,418.2[M+Na] + .

[0701] R f :0.17 (Hex:EtOAc 6:4).

[0702] Compounds 71 and 71a

[0703]

[0704] To a solution of 60 (45 mg, 0.11 mmol) in ethanol (1.2 mL) and water (1.2 mL) was added NH2OH·HCl (56 mg, 0.81 mmol) and NaOAc (41 mg, 0.5 mmol). After stirring at 23°C for 24 h, the ethanol was evaporated in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by HPLC using an XBridge C18 5μm H2O / CH3CN to afford 71a (2.5 mg) and 71 (15.9 mg, 34% yield).

[0705] Compound 71

[0706] 1H NMR (400MHz, CD3OD): δ6.03 (d, J=2.2Hz, 1H), 5.52 (d, J=2.2Hz, 1H), 4.74 (dd, J=9.2, 5.7Hz, 1H), 4.02 (t, J=6.4Hz, 2H), 3.56 (d, J=1 1.5Hz, 1H), 3.17 (d, J=11.4Hz, 1H), 2.18 (d, J=0.7Hz, 3H), 1.92-1.70 (m, 4H), 1.53 (s, 3H), 1.49-1.35 (m, 3H), 0.98 (q, J=7.5Hz, 6H).

[0707] MS (ES+): m / z 424.3 [M+H] + ,446.1[M+Na] + .

[0708] R f :0.53 (Hex:EtOAc 6:4).

[0709] Compound 71a

[0710] 1 H NMR (500MHz, CDCl3) δ7.00 (d, J=8.9Hz, 1H), 5.91 (d, J=2.2Hz, 1H), 5.41 (d, J=2.2Hz, 1H), 4.80-4.59 (m, 1H), 3.94 (td, J=6.5, 1.1Hz, 2H), 3 .70 (d, J=11.7Hz, 1H), 3.23 (d, J=11.6Hz, 1H), 2.20 (s, 3H), 1.88-1.67 (m, 4H), 1.64 (s, 3H), 1.56-1.29 (m, 4H), 0.96 (dt, J=8.1, 7.4Hz, 6H).

[0711] Compounds 72 and 72a

[0712]

[0713] Compound 61 (0.131 mmol) was dissolved in ethanol (1.4 mL) before addition of water (1.4 mL), NH OH HCl (67 mg, 0.963 mmol) and NaOAc (48 mg, 0.591 mmol). The mixture was stirred for 16 hours and then the ethanol was evaporated. The aqueous residue was diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered and evaporated to dryness, and the crude product was chromatographed on a SiO column flash chromatography system eluting with a hexane / EtOAc mixture from 100: 0 to 60: 40 in 40 minutes. This purification allowed the separation of the two stereoisomers.

[0714] Compound 72

[0715] 1 H NMR (400MHz, CDCl3): δ9.31 (s, 1H), 7.16 (d, J=8.8Hz, 1H), 5.91 (d, J=2.2Hz, 1 H), 5.41 (d, J=2.1Hz, 1H), 4.73 (q, J=7.9Hz, 1H), 3.91 (t, J=6.5Hz, 2H), 3.51 (d , J=11.6Hz, 1H), 3.24 (dd, J=11.6, 0.5Hz, 1H), 2.22 (s, 3H), 1.95-1.66 (m, 4H), 1.51 (s, 3H), 1.45-1.17 (m, 10H), 0.95 (t, J = 7.3Hz, 3H), 0.88 (t, J = 6.8Hz, 3H).

[0716] 13 C NMR (100MHz, CDCl3): δ174.2, 170.4, 167.9, 164.5, 162.1, 153.0, 100.7, 88.9, 84.3 , 69.2, 51.0, 39.9, 34.7, 31.6, 28.8, 28.4, 25.7, 24.6, 22.5, 19.0, 14.0, 13.6, 11.2.

[0717] Compound 72a

[0718] 1H NMR (400MHz, CDCl3): δ7.05 (d, J=8.8Hz, 1H), 5.91 (d, J=2.2Hz, 1H), 5.40 (d, J=2.3Hz, 1H), 4.73 (q, J=7.9Hz, 1H), 3.91 (t, J=5.8Hz, 2H), 3.68 (d, J= 11.7Hz, 1H), 3.22 (d, J=11.6Hz, 1H), 2.19 (s, 3H), 1.89-1.66 (m, 4H), 1.63 (s, 3H), 1.43-1.17 (m, 10H), 0.94 (t, J=7.4Hz, 3H), 0.89 (t, J=6.8Hz, 3H).

[0719] 13 C NMR (100MHz, CD3OD): δ173.3, 172.4, 170.5, 164.7, 163.7, 162.1, 100.5, 88.9, 83.9 , 69.2, 51.1, 40.9, 35.1, 31.6, 28.8, 28.4, 25.7, 24.9, 22.5, 19.1, 14.0, 13.6, 11.8.

[0720] Compounds 73 and 73a

[0721]

[0722] At 23 ℃, to 62 crude products (7gmg, 0.134mmol) solution in EtOH (1.5mL) and H o (1.5mL) add NH OH HCl (69mg, 0.992mmol) and NaOAc (49mg, 0.603mmol).Reactant mixture is stirred at 23 ℃ and spent the night, then concentrated in vacuo.The residue obtained is diluted with a saturated aqueous solution of NaCl, and extracted with EtOAc (3x).The organic layer merged is through anhydrous Na sO dried, filtered and concentrated under vacuum.The crude product obtained is purified in a flash chromatography automatic system (SiO , Hex:EtOAc) to obtain 73 (33mg, two-step yield is 41%) and 73a (7mg, two-step yield is 8%).

[0723] Compound 73

[0724] 11H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 2.1 Hz, 1H), 5.40 (d, J = 2.2 Hz, 1H), 4.73 (q, J = 7.7 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.51 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 11.6 Hz, 1H), 2.22 (s, 3H), 1.95 - 1.66 (m, 4H), 1.51 (s, 3H), 1.46 - 1.15 (m, 30H), 0.95 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H).

[0725] 13 13C NMR (100 MHz, CDCl3): δ 174.2, 170.3, 167.9, 164.5, 162.0, 153.0, 100.7, 88.9, 84.3, 69.2, 51.0, 39.9, 34.8, 31.9, 29.7, 29.6, 29.5 (x2), 29.3, 29.2, 28.4, 25.8, 24.6, 22.7, 19.1, 14.1, 13.6, 11.2.

[0726] Compound 73a

[0727] 1 1H NMR (500 MHz, CDCl3): δ 8.29 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 5.39 (d, J = 2.2 Hz, 1H), 4.73 (q, J = 7.9 Hz, 1H), 3.91 (td, J = 6.6, 1.9 Hz, 2H), 3.55 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 11.6 Hz, 1H), 2.24 (s, 3H), 1.94 - 1.68 (m, 4H), 1.52 (s, 3H), 1.45 - 1.18 (m, 32H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H).

[0728] 13 13C NMR (125 MHz, CDCl3): δ 173.9, 170.3, 167.9, 164.4, 162.2, 153.4, 100.6, 88.9, 84.3, 69.2, 51.0, 39.9, 34.8, 31.9, 29.7, 29.6, 29.5 (x2), 29.3, 29.2, 28.4, 25.8, 24.7, 22.7, 19.1, 14.1, 13.6, 11.3.

[0729] Compounds 74 and 74a

[0730]

[0731] At 23 ℃, to the crude product 63 (700 mg, 1.78 mmol) solution in EtOH (20 mL) and H o (20 mL) add NH OH HCl (920 mg, 13.23 mmol) and NaOAc (660 mg, 8.04 mmol). The reaction mixture is stirred at 23 ℃ for 24 hours and concentrated under vacuum. The obtained residue is diluted with a saturated aqueous solution of NaCl and extracted with EtOAc (3x). The combined organic layer is dried over anhydrous Na sO , filtered and concentrated under vacuum. The crude product obtained is purified by flash chromatography on silica gel (CH Cl : EtOAc from 90: 10 to 70: 30) to obtain 74 (387 mg, 53% yield) and 74a (45 mg, 6% yield).

[0732] Compound 74

[0733] 1 H NMR (400MHz, CD3OD): δ6.06 (d, J=2.2Hz, 1H), 6.04-5.94 (m, 1H), 5.53 (d, J=2.2Hz, 1H), 5.43-5.29 (m, 2H), 4.74 (dd, J=9.1, 5.8Hz, 1H), 4.58 (td, J=5. 5, 1.5Hz, 2H), 3.55 (d, J = 11.5Hz, 1H), 3.17 (d, J = 11.5Hz, 1H), 2.17 (s, 3H) , 1.92-1.77(m, 2H), 1.52(s, 3H), 1.50-1.34(m, 2H), 0.98(t, J=7.3Hz, 3H).

[0734] 13 C NMR (100MHz, CDCl3): δ174.4, 169.8, 168.2, 164.4, 162.3, 152.9, 130.6, 119.5, 100.5, 89.5, 84.3, 69.6, 51.0, 39.9, 34.7, 24.6, 19.0, 13.6, 11.2.

[0735] MS (ES+): m / z 408.2 [M+H] + ,430.1[M+Na] + .

[0736] Optical rotation: [α D ]+53.7 (c 0.071, MeOH).

[0737] R f :0.29 (Hex:EtOAc 6:4).

[0738] Compound 74a

[0739] 1 H NMR (400MHz, CDCl3): δ10.44(br s, 1H), 7.07 (d, J=8.9Hz, 1H), 6.01-5.88 (m, 1H), 5.42 (dd, J=3.3, 1.7Hz , 1H), 5.39-5.31 (m, 2H), 4.73 (td, J=8.3, 6.7Hz, 1H), 4.48 (dt, J=5.5, 1. 5Hz, 2H), 3.65 (d, J=11.7Hz, 1H), 3.21 (d, J=11.7Hz, 1H), 2.19 (s, 3H), 1 .89-1.65 (m, 2H), 1.60 (s, 3H), 1.41-1.28 (m, 2H), 0.93 (t, J=7.4Hz, 3H).

[0740] 13 C NMR (100MHz, CDCl3): δ173.5, 169.9, 164.6, 164.5, 162.5, 147.2, 130.5, 119.6, 100.3, 89.4, 83.6, 69.6, 51.0, 40.8, 35.0, 24.7, 19.2, 19.0, 13.5.

[0741] Compounds 75 and 75a

[0742]

[0743] At 23 ℃, to the crude product 64 (3.0 g, 7.68 mmol) solution in EtOH (85 mL) and H2O (85 mL) was added NH2OH HCl (3.95 g, 56.86 mmol) and NaOAc (2.84 g, 34.58 mmol). The reaction mixture was stirred at 23 ℃ overnight and then concentrated in vacuo. The obtained residue was diluted with a saturated aqueous solution of NaCl and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product obtained was purified by flash chromatography on silica gel (hexane: EtOAc from 100: 0 to 40: 60) to give 75 (1.44 mg, 46% yield in 2 steps) and 75a (392 mg, 12% yield in 2 steps).

[0744] Compound 75

[0745] 1 1H NMR (400 MHz, CD3OD): δ 6.07 (d, J = 2.2 Hz, 1H), 5.64 (d, J = 2.3 Hz, 1H), 4.81 (d, J = 2.4 Hz, 2H), 4.78 - 4.69 (m, 1H), 3.54 (d, J = 11.5 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 3.15 - 3.13 (m, 1H), 2.18 (s, 3H), 1.92 - 1.76 (m, 2H), 1.52 (s, 3H), 1.49 - 1.35 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0746] 13 13C NMR (125 MHz, CDCl3): δ 174.3, 168.7, 168.0, 163.8, 162.7, 153.1, 100.1, 90.1, 84.3, 77.8, 75.6, 56.5, 51.0, 39.9, 34.8, 24.7, 19.0, 13.6, 11.3.

[0747] MS (ES+): m / z 406.1 [M + H]+ + .

[0748] R f : 0.29 (Hex∶EtOAc 6∶4).

[0749] Compound 75a

[0750] 1 1H NMR (400 MHz, CDCl3): δ 7.02 (d, J = 8.7 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 5.56 (dd, J = 2.3, 0.8 Hz, 1H), 4.74 (q, J = 8.1 Hz, 1H), 4.66 (dt, J = 2.4, 1.2 Hz, 2H), 3.69 (dd, J = 11.7, 0.8 Hz, 1H), 3.22 (dd, J = 11.7, 0.9 Hz, 1H), 2.63 (t, J = 2.4 Hz, 1H), 2.20 (s, 3H), 1.91 - 1.64 (m, 2H), 1.63 (s, 3H), 1.46 - 1.32 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0751] 13C NMR (100MHz, CDCl3): δ173.9, 168.7, 167.5, 163.7, 162.8, 153.3, 100.0, 90.1, 84.2, 77.7, 75.6, 56.5, 51.0, 39.9, 34.8, 24.7, 19.1, 13.6, 11.3.

[0752] Compound 141

[0753]

[0754] 1 H NMR (400MHz, CDCl3): δ8.71 (s, 1H), 7.13 (d, J=8.7Hz, 1H), 6.28 (s, 1H), 4.85 -4.71 (m, 2H), 3.57 (d, J = 11.6Hz, 1H), 3.33 (d, J = 2.7Hz, 2H), 3.24 (d, J = 11.6H z, 1H), 2.62 (t, J=2.4Hz, 1H), 2.23 (s, 3H), 1.99-1.72 (m, 2H), 1.54 (s, 3H), 1. 48-1.25(m, 1H), 1.29-1.23(m, 1H), 0.97(t, J=7.4Hz, 3H), 0.92-0.80(m, 1H).

[0755] 13 C NMR (125MHz, CDCl3): δ174.3, 168.6, 164.5, 162.5, 153.2, 102.9, 95.7, 84.4, 80.8, 77.9, 76.8, 67.6, 57.1, 51.6, 40.1, 34.9, 25.0, 19.2, 13.7, 13.3, 11.5.

[0756] MS (ES+): m / z 444.1 [M+H] + .

[0757] R f :0.29 (Hex:EtOAc 6:4).

[0758] Compounds 76 and 76a

[0759]

[0760] At 23 ° C, NH2OH·HCl (42 mg, 0.6 mmol) and NaOAc (30 mg, 0.36 mmol) were added to a solution of crude product 65 (33 mg, 0.08 mmol) in EtOH (0.9 mL) and H2O (0.9 mL). The reaction mixture was stirred at 23 ° C for 24 hours and concentrated under vacuum. The obtained residue was diluted with a saturated aqueous solution of NaCl and extracted with EtOAc (3x). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude product was purified by flash chromatography on silica gel (hexane: EtOAc from 100: 0 to 40: 60) to obtain 76 (15 mg, 44% yield) and 76a (3 mg, 9% yield).

[0761] Compound 76

[0762] 1 H NMR (400MHz, CD3OD): δ7.85 (d, J=8.6Hz, 1H), 6.05 (s, 1H), 5.48 (s, 1H), 4.74 (q, J=6. 8, 5.0Hz, 1H), 3.86 (d, J = 7.2Hz, 2H), 3.56 (d, J = 11.5Hz, 1H), 3.17 (d, J = 11.5Hz, 1H), 2.19 (s, 3H), 1.96-1.72 (m, 2H), 1.52 (s, 3H), 1.43 (ddd, J=29.8, 14.7, 7.4Hz, 4H), 1. 31-1.16 (m, 1H), 0.99 (t, J=7.4Hz, 3H), 0.63 (d, J=7.6Hz, 2H), 0.35 (d, J=5.0Hz, 2H).

[0763] 13 C NMR (100MHz, CD3OD): δ175.1, 171.2, 168.8, 165.3, 163.8, 151.5, 126.4, 99.7, 87.9, 84.2, 74.0, 50.7, 39.1, 33.9, 23.6, 18.8, 12.5, 9.6, 9.0, 2.3.

[0764] MS (ES+): m / z 422.1 [M+H] + ,444.2[M+Na] + .

[0765] Optical rotation: [α D ]+55 (c 0.022, MeOH).

[0766] R f :0.42 (hexanes ∶ EtOAc 1 ∶ 1).

[0767] Compound 76a

[0768] 1 H NMR (400MHz, CDCl3): δ8.32 (s, 1H), 7.19 (d, J=8.7Hz, 1H), 5.94 (t, J=2.1Hz, 1H), 5.41-5.33 (m, 1H), 4.73 (q, J=7.9Hz, 1H), 3.76 (dd, J=7.2, 2.1Hz, 3H), 3.57 (d, J=11.6Hz, 1H), 3.23 (dd, J=11.7, 1.9Hz, 1 H), 2.24(s, 3H), 2.20(s, 1H), 1.95-1.65(m, 2H), 1.64(s, 1H), 1.54(s, 2H), 1.45-1.31(m, 2H), 1.23( d, J=18.1Hz, 2H), 0.95 (q, J=7.4Hz, 3H), 0.83 (s, 1H), 0.67 (dd, J=7.9, 1.3Hz, 3H), 0.38-0.29 (m, 1H).

[0769] 13 C NMR (100MHz, CDCl3): δ173.8, 170.1, 168.4, 164.3, 162.3, 153.3, 100.5, 88.9, 84.2, 73.8, 51.1, 39.9, 34.8, 24.7, 19.1, 13.6, 11.3, 9.4, 3.4 (x2).

[0770] MS (ES+): m / z 422.1 [M+H] + .

[0771] Compound 77

[0772] The crude product was purified by HPLC with 5 μm H 2 O / CH 3 CN to afford 77 (2.9 mg, 12% yield).

[0773] 1H NMR (500MHz, CD3OD) δ6.10 (dd, J=2.4, 0.7Hz, 1H), 5.01 (d, J=2.4Hz, 1H), 4.75 (dt, J=9.3, 5.8Hz, 1H), 3.60 (d, J=11.5Hz, 1H), 3.43-3.34 (m .

[0774] MS (ES): m / z 423.2 [M+H] + ,445.2[M+Na] + .

[0775] The crude product was purified by HPLC to afford 78 (2.9 mg, 18% yield).

[0776] 1 H NMR (400MHz, CD3OD): δ7.81 (d, J=8.7Hz, 1H), 6.14 (d, J=1.5Hz, 1H), 6.02 (s, 1H), 4.75 (ddd, J=8.9, 5.9, 3.0Hz, 1H), 3.54 (d, J=11.5Hz, 1 H), 3.17 (d, J=11.5Hz, 1H), 2.18 (s, 3H), 2.15 (d, J=1.2Hz, 3H), 1.90-1.78 (m, 2H), 1.53 (s, 3H), 1.49-1.36 (m, 2H), 0.99 (t, J=7.4Hz, 3H).

[0777] MS (ES): m / z 366.2 [M+H] + ,388.1[M+Na] + .

[0778] R f :0.35 (hexanes ∶ EtOAc 6 ∶ 4).

[0779] Compound 79

[0780]

[0781] 1H NMR (400MHz, CD3OD): δ6.58 (dd, J=17.5, 10.8Hz, 1H), 6.47 (d, J=1.5Hz, 1H), 6.11 (d, J=1.4Hz, 1H), 6.02 (d, J=17.5Hz, 1H), 5.66 (d, J=10.8Hz, 1H), 4.85-4.72 (m, 1H ), 3.62-3.46 (m, 1H), 3.37-3.22 (m, 1H), 3.18 (dd, J=11.5, 0.9Hz, 1H), 2.19 (s, 3H ), 1.90-1.69 (m, 2H), 1.56 (s, 3H), 1.57-1.33 (m, 2H), 0.99 (td, J=7.4, 2.9Hz, 3H).

[0782] 13 C NMR (100MHz, CD3OD): δ176.6, 170.3, 164.9, 164.5, 153.9, 152.9, 134.5, 124.0, 111.5, 100.5, 85.6, 52.3, 40.8, 35.4, 25.2, 20.2, 13.8, 11.0.

[0783] MS (ES+): m / z 378.2 [M+H] + ,400.1[M+Na] + .

[0784] R f :0.39 (hexanes ∶ EtOAc 1 ∶ 1).

[0785] Scheme 9 provides further examples of the synthesis of more compounds of formula I.

[0786]

[0787] Option 9

[0788] Compound 80

[0789]

[0790] 1H NMR (300MHz, CDCl3): δ7.66 (m, 4H), 7.52-7.29 (m, 6H), 5.86 (d, J=2.2Hz, 1H), 5.49 (d, J=2.2Hz, 1H), 4.79-4.62 (m, 1H), 3.58 (d, J=11. 8Hz, 1H), 3.14 (d, J=11.7Hz, 1H), 2.04 (d, J=0.6Hz, 3H), 1.65 (m, 2H), 1.44 (s, 3H), 1.34-1.07 (m, 2H), 1.07 (s, 9H), 0.93-0.74 (m, 3H).

[0791] MS (ES): m / z 590.5 [M+H] + .

[0792] Compound 81

[0793] The obtained crude product was purified by filtration with EtOAc 1 / 1) to afford 81 (32 mg, 46% yield).

[0794] 1 H NMR (300MHz, CDCl3): δ7.74-7.57 (m, 4H), 7.56-7.29 (m, 6H), 6.96 (d, J=9.0Hz, 1H), 5.87 (d, J=2.2Hz, 1H), 5.23 (d, J=2.2Hz, 1H), 4.67 (q, J=7.8H z, 1H), 3.56 (d, J = 12.0Hz, 1H), 3.26 (d, J = 11.9Hz, 1H), 2.53 (d, J = 0.5Hz, 3H), 1.91-1.64 (m, 2H), 1.52 (s, 3H), 1.07 (s, 9H), 0.93 (t, J=7.3Hz, 3H).

[0795] MS (ES): m / z 591.3 [M+H] + ,613.2[M+Na] + .

[0796] Compounds 82 and 82a

[0797]

[0798] To a solution of 80 (35 mg, 0.059 mmol) in ethanol (0.7 mL) and water (0.7 mL) was added NH2OH·HCl (30 mg, 0.45 mmol) and NaOAc (22 mg, 0.28 mmol). After stirring at 23°C for 24 h, the ethanol was evaporated in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by HPLC using an XBridge C18 5μm H2O / CH3CN to afford 82a (1.5 mg) and 82 (5.6 mg, 26% yield).

[0799] Compound 82

[0800] 1 H NMR (500MHz, CDCl3): δ5.87 (s, 1H), 5.28 (d, J=0.7Hz, 1H), 4.69 (t, J=7.6Hz, 1H), 3.55-3.44 (m, 1H), 3.14 (d, J=11.6Hz, 1 H), 2.12 (s, 3H), 1.77 (t, J=7.7Hz, 2H), 1.50 (d, J=1.5Hz, 3H), 1.35 (ddd, J=41.7, 14.0, 7.0Hz, 2H), 0.93 (t, J=7.3Hz, 3H).

[0801] Compound 82a

[0802] 1 H NMR (500MHz, CD3OD): δ6.01 (d, J=2.1Hz, 1H), 5.67 (d, J=2.2Hz, 1H), 4.69 (dd, J=8.6, 6.8Hz, 1H), 3.58 (d, J=11.5Hz, 1H), 3.18 (d, J=11.5Hz, 1H), 2.21 (s, 3H), 1.85-1.69 (m, 2H), 1.50 (s, 3H), 1.45-1.22 (m, 3H), 0.94 (t, J=7.4Hz, 3H).

[0803] Scheme 10 provides further examples of the synthesis of more compounds of formula I.

[0804]

[0805] Plan 10

[0806] Compound 83

[0807]

[0808] 1H NMR (300MHz, CDCl3): 67.03 (d, J=8.8Hz, 1H), 5.89 (d, J=2.2Hz, 1H), 5.37 (d, J=2. 2Hz, 1H), 4.84-4.75(m, 1H), 4.76-4.63(m, 1H), 4.10-4.01(m, 2H), 4.01-3.91(m, 1H), 3.86-3.76(m, 2H), 3.74-3.41(m, 11H), 3.15(d, J=11.7Hz, 1H), 1.93-1.61(m , 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.46-1.16 (m, 9H), 0.90 (dt, J=17.4, 7.2Hz, 3H).

[0809] MS (ES): m / z 609.3 [M+Na] + .

[0810]

[0811] The product was chromatographed on silica gel (CH2Cl2 / EtOAc 8 / 1) to afford 50 (18 mg, 55% yield).

[0812] Compound 84

[0813]

[0814] 1 H NMR (300MHz, CDCl3): δ7.70 (s, 1H), 7.56-7.45 (m, 1H), 7.03 (d, J=8.8Hz, 1H), 5.84 (d, J=2.1Hz, 1H), 5.36 (d, J=2.1Hz, 1H), 4.68 (dd, J=15.6, 7.8Hz, 2H), 4.40-4.22 (m, 1H), 3.96 (t, J=6.1Hz, 2 H), 3.68-3.36 (m, 5H), 3.24 (d, J=6.5Hz, 2H), 3.15 (d, J=11.8Hz, 1H), 2.79 (d, J=1.6Hz, 1H), 1.9 8-1.67 (m, 4H), 1.60 (s, 3H), 1.52 (s, 3H), 1.42 (s, 9H), 1.26-1.15 (m, 6H), 0.93 (1, J=7.3Hz, 3H).

[0815] MS (ES): m / z 539.2 [M+H] + ,606.2[M+Na] + .

[0816] Compound 85

[0817] =2.2Hz, 1H), 5.42 (d, J = 2.2Hz, 1H), 4.72 (m, 1H), 4.08 (m, 2H), 3.82 (m, 2H), 3.74-3.48 (m, 11H), 3.28 (d, J = 12.0Hz, 1H), 2.56 (s, 3H),

[0818] The crude product 86 (100%) was obtained and used in the next step without further purification.

[0819] MS (ES): m / z 410.1 [M+H] + ,433.3[M+Na] + .

[0820] Compound 87

[0821] yield).

[0822] 1 H NMR (300MHz, CDCl3): δ9.45 (s, 1H), 6.85 (d, J=9.0Hz, 1H), 5.81 (dd, J=2.3, 0.7 Hz, 1H), 5.38 (d, J=2.2Hz, 1H), 4.70 (m, 1H), 4.05 (m, 2H), 3.82 (m, 2H), 3.72-3.4 7 (m, 7H), 3.15 (d, J = 11.5Hz, 1H), 2.22 (d, J = 0.4Hz, 3H), 1.99-1.65 (m, 2H), 1.5 8 (s, 3H), 1.47-1.27 (m, 2H), 1.21 (td, J=7.0, 0.5Hz, 3H), 0.95 (t, J=7.3Hz, 3H).

[0823] MS (ES): m / z 528.3 [M+H] + ,550.3[M+Na] + .

[0824] Compound 74

[0825]

[0826] Compound 88

[0827]

[0828] 1H NMR (400MHz, CDCl3): 610.74 (s, 1H), 10.17 (s, 1H), 7.30 (d, J=10.4Hz, 1H), 6.17 (d, J=2.1Hz, 1H), 5.78 (d, J=2.1Hz, 1H), 4.80 (dt, J=10.2, 7.8Hz, 1H ), 3.47 (d, J=12.0Hz, 1H), 3.24 (d, J=11.9Hz, 1H), 2.22 (s, 3H), 1.83 (tt, J =15.1, 6.1Hz, 2H), 1.51 (s, 3H), 1.45-1.23 (m, 2H), 0.98 (t, J = 7.3Hz, 3H).

[0829] 13 C NMR (100MHz, CD3OD): 6175.9, 172.3, 169.5, 167.4, 162.1, 152.1, 103.2, 92.5, 84.1, 50.6, 40.3, 34.0, 24.6, 19.1, 13.5, 11.2.

[0830] MS(Es): m / z 368.1[M+H] + ,390.0[M+Na] + .

[0831] R f :0.12(CH2Cl2:CH3OH 9:1).

[0832] Compound 89

[0833] Purification by HPLC gave 89 (0.7 mg).

[0834] 1 H NMR (500MHz, CD3OD): δ6.06 (d, J=2.0Hz, 1H), 5.56 (d, J=2.0Hz, 1H), 4.74 (m, 1H), 4.14 (t, J=6.0Hz, 2H), 3.54 (d, J=11.5Hz, 1H), 3.18 ( d, J=11.5Hz, 1H), 3.01 (t, J=7.0Hz, 2H), 2.19 (s, 3H), 2.09 (m, 2H), 1.86 (m, 2H), 1.54 (s, 3H), 1.51-1.36 (m, 2H), 0.99 (t, J=7.0Hz, 3H).

[0835] MS (ES): m / z 425.1 [M+H] + ,447.2[M+Na] + .

[0836] Scheme 11 provides further examples of the synthesis of more compounds of formula I.

[0837]

[0838] Plan 11

[0839] Compound 90

[0840] Rate).

[0841] 1 H NMR (400MHz, CDCl3): δ6.96 (d, J=8.7Hz, 1H), 5.84 (t, J=1.9Hz, 1H), 5.37 (d, J=2.1Hz, 1H), 5.18-5.07 (m, 1H), 4.72 (td, J=8.4, 6.5 Hz, 1H), 3.75 (d, J=1.6Hz, 3H), 3.66-3.38 (m, 6H), 1.90-1.69 (m, 2H), 1.59 (d, J=1.7Hz, 3H), 1.39-1.29 (m, 2H), 1.27-1.12 (m, 6H).

[0842] 13 C NMR (75MHz, CDCl3): δ180.6, 172.1, 172.0, 165.2, 164.0, 101.6, 101.0, 89 .6, 80.2, 59.1, 57.2, 52.2, 39.8, 35.8, 35.5, 25.0, 20.3, 16.4, 16.4, 14.8.

[0843]

[0844] MS (ES+): m / z 353.1 [M+H] + .

[0845] Compound 92

[0846]

[0847] 1H NMR (500MHz, (CD3)2CO): δ11.25 (s, 1H), 7.64 (d, J=8.6Hz, 1H), 6.03 (dd, J=2.2, 0.7Hz, 1H), 5.43 (d , J=2.2Hz, 1H), 5.24 (t, J=9.2Hz, 1H), 4.75 (td, J=8.9, 5.5Hz, 1H), 3.84 (s, 3H), 3.50 (d, J=9.2Hz, 2 H), 2.15 (d, J=0.6Hz, 3H), 1.86 (ddt, J=13.6, 9.8, 6.2Hz, 1H), 1.76 (dtd, J=14.0, 9.4, 5.2Hz, 1H), 1 .49 (dddd, J=15.5, 7.9, 6.2, 4.0Hz, 1H), 1.40 (ddt, J=13.7, 9.8, 6.9Hz, 1H), 0.95 (t, J=7.3Hz, 3H).

[0848] 13 C NMR (100MHz, (CD3)2CO): δ171.8, 170.8, 170.2, 165.2, 163.7, 152.9, 99.7, 99.5, 88.5, 79.9, 56.6, 51.7, 35.2, 33.9, 19.9, 13.9, 11.1.

[0849] MS (ES+): m / z 368.1 [M+H] + .

[0850] Scheme 12 provides another example of the synthesis of some compounds of formula I.

[0851]

[0852] Plan 12

[0853] Compound 93

[0854]

[0855] 1H NMR (400MHz, CDCl3): δ7.08 (d, J=8.8Hz, 1H), 6.01 (dddd, J=17.3, 10.5, 6.1, 5.7Hz, 1H), 5.88 (dd , J=2.3, 0.5Hz, 1H), 5.41 (d, J=2.2Hz, 1H), 5.38-5.22 (m, 2H), 4.78-4.67 (m, 3H), 3.78 (s, 3H), 3.5 1(d, J=11.6Hz, 1H), 3.19 (dd, J=11.6, 0.4Hz, 1H), 2.20 (s, 3H), 1.89 (ddt, J=13.4, 9.5, 6.5Hz, 1H) , 1.76 (dddd, J=13.6, 9.7, 8.0, 5.6Hz, 1H), 1.51 (s, 3H), 1.47-1.22 (m, 2H), 0.96 (t, J=7.3Hz, 3H).

[0856] 13 C NMR (100MHz, CDCl3): δ174.1, 170.8, 167.8, 164.1, 162.4, 151.9, 133.3, 118 .4, 100.1, 88.5, 84.3, 76.3, 55.9, 50.9, 39.8, 34.7, 24.7, 19.0, 13.6, 12.0.

[0857] Compound 94

[0858] The obtained crude product was purified in a 5% CO 2 -HCl (98:2 to 50:50) to afford 94 (11.7 mg, 91% yield).

[0859] 1 H NMR (400MHz, CDCl3): δ7.06 (d, J=8.8Hz, 1H), 5.88 (d, J=2.2Hz, 1H), 5.41 (d, J=2. 5Hz, 1H), 4.81 (d, J=2.4Hz, 2H), 4.72 (q, J=7.9Hz, 1H), 3.78 (s, 3H), 3.52 (d, J=11 .7Hz, 1H), 3.21 (d, J=11.6Hz, 1H), 2.52 (t, J=2.5Hz, 1H), 2.21 (s, 3H), 1.95-1.82 (m, 1H), 1.81-1.68 (m, 1H), 1.50 (s, 3H), 1.46-1.28 (m, 2H), 0.95 (t, J=7.6Hz, 3H).

[0860] 13C NMR (100MHz, CD3OD): δ174.0, 170.8, 167.4, 164.0, 162.4, 153.0, 100.1, 88 .5, 84.3, 78.7, 75.2, 62.8, 55.9, 50.9, 39.9, 34.7, 24.7, 19.0, 13.6, 12.1.

[0861] Compound 95

[0862] The crude product was purified by HPLC using XBridge C18 5 μm H 2 O / CH 3 CN to give 95 (9 mg, 53% yield).

[0863] 1 H NMR (500MHz, CDCl3): δ7.02 (d, J=8.9Hz, 1H), 5.90 (m, 1H), 5.42 (d, J=2.2Hz, 1H), 4. 81-4.68(m, 1H), 4.44(s, 2H), 3.83-3.77(m, 5H), 3.75-3.70(m, 2H), 3.68-3.65(m, 2H ), 3.63 (d, J = 11.7Hz, 1H), 3.58-3.54 (m, 2H), 3.38 (s, 2H), 3.27 (d, J = 11.7Hz, 1H), 2. 36 (s, 3H), 1.93-1.71 (m, 2H), 1.53 (s, 3H), 1.46-1.28 (m, 2H), 0.96 (t, J=7.4Hz, 3H).

[0864] 13 C NMR (100MHz, CD3OD): δ176.6, 173.5, 170.3, 166.7, 165.2, 152.9, 100.8, 88.9, 85.6, 72.9, 71.8, 71 .6, 71.3, 69.1, 59.1, 57.0, 54.8, 52.1, 49.7, 40.6, 35.2, 34.8, 26.8, 26.1, 25.0, 20.2, 13.8, 11.0.

[0865] MS (ES): m / z 542.3 [M+H] + ,564.2[M+Na] + .

[0866] R f :0.25 (hexanes ∶ EtOAc 1 ∶ 1).

[0867] The crude product was chromatographed on silica gel (CH2Cl2 / EtOAc 1 / 1) to afford 96 (11 mg, 83% yield).

[0868] 1 H NMR (500MHz, CDCl3): δ7.07 (d, J=8.7Hz, 1H), 5.88 (d, J=2.2Hz, 1H), 5.41 (d, J=2.2Hz , 1H), 4.73 (td, J=8.4, 6.8Hz, 1H), 4.43-4.32 (m, 2H), 3.79 (s, 5H), 3.69-3.63 (m, 6H), 3.62-3.57(m, 2H), 3.56-3.47(m, 3H), 3.20(d, J=11.6Hz, 1H), 2.19(s, 3H), 1.95-1.73 (m, 2H), 1.51 (s, 3H), 1.44-1.28 (m, 2H), 1.21 (t, J=7.0Hz, 3H), 0.96 (t, J=7.3Hz, 3H).

[0869] MS (ES): m / z 542.3 [M+H] + ,564.3[M+Na] + .

[0870] Compound 97

[0871] The crude product was chromatographed on silica gel (CH2Cl2 / EtOAc 9 / 1) to afford 97 (22 mg, 100% yield).

[0872] 1 H NMR (500MHz, CDCl3): δ7.06 (d, J=8.8Hz, 1H), 5.88 (dd, J=2.3, 0.5Hz, 1H), 5.41 (d, J=2.2Hz, 1H), 4.83-4.58 (m, 1H), 4.28 (t, J=6.0Hz, 2H), 3.78 (s, 3H), 3.51(d, J=11.6Hz, 1H), 3.30-3.11(m, 3H), 2.17(s, 3H), 1.98-1.61(m , 4H), 1.50 (s, 3H), 1.43 (s, 9H), 1.41-1.15 (m, 2H), 0.95 (t, J=7.3Hz, 3H).

[0873] MS (ES): m / z 539.3 [M+H] + ,561.2[M+Na] + .

[0874] Compound 98

[0875]

[0876] 1 H NMR (500MHz, CDCl3): δ7.02 (d, J=8.8Hz, 1H), 5.96 (d, J=2.2Hz, 1H), 5.46 (d , J=2.2Hz, 1H), 4.69 (q, J=7.9Hz, 1H), 4.35 (dt, J=7.5, 4.9Hz, 2H), 3.80 (s, 3 H), 3.69 (d, J=11.6Hz, 1H), 3.24-3.01 (m, 3H), 2.21 (s, 3H), 2.18-2.08 (m, 2H ), 1.88-1.75 (m, 2H), 1.54 (s, 3H), 1.47-1.29 (m, 1H), 0.96 (t, J=7.4Hz, 3H).

[0877] MS (ES): m / z 439.2 [M+H] + ,461.1[M+Na] + .

[0878] Scheme 13 provides further examples of the synthesis of more compounds of formula I.

[0879]

[0880] Plan 13

[0881] Compound 99

[0882]

[0883] 1 H NMR (500MHz, CDCl3): δ7.14 (d, J=8.9Hz, 1H), 5.90 (m, 1H), 5.41 (d, J=2.2Hz, 1H), 4.82-4.62 (m, 1H), 3.79 (s, 3H), 3.50 (d, J=11. 6Hz, 1H), 3.17 (d, J=11.6Hz, 1H), 2.11 (s, 3H), 1.88 (m, 1H), 1.76 (m, 1H), 1.52 (s, 3H), 1.48-1.21 (m, 2H), 0.96 (t, J=7.3Hz, 3H).

[0884] MS (ES): m / z 381.2 [M+H] + ,403.1[M+Na] + .

[0885] Example 10: Synthesis of other compounds of formula I

[0886] Scheme 14 provides examples of the synthesis of other compounds of Formula 1.

[0887]

[0888] Plan 14

[0889] Compound 100

[0890] The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give 100 (3.1 g, 85% yield) as a colorless oil.

[0891] 1 H NMR (500MHz, CDCl3): δ7.65 (m, 4H), 7.40 (m, 6H), 4.32 (q, J=7.0Hz, 1H), 1.32 (d, J=7.0Hz, 3H), 1.11 (s, 9H).

[0892] 13 C NMR (125MHz, CDCl3): δ207.1, 135.7, 130.2, 130.1, 127.9, 127.8, 69.1, 30.9, 30.8, 26.8, 26.7, 21.0, 19.1.

[0893] MS (ES): m / z 351.2 [M+Na] + .

[0894] Compound 101

[0895] (0.06 mL). The crude mixture was stirred at 23 ° C for 18 h, diluted with CH2Cl2, acidified to pH ~ 2 with aqueous HCl (0.5 M), and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to afford 101 (170 mg; 92% yield), which was used without further purification as a mixture of two diastereomers.

[0896] 1 H NMR (300MHz, CDCl3) δ7.96 (s, 1H), 7.86 (s, 1H), 7.66 (m, 8H), 7.61 (m, 1H), 4.27 (m, 2H), 3.98 (dd, J=11. 4, 2.7Hz, 2H), 3.78 (d, J=11.4, 1.7Hz, 2H), 1.27 (d, J=7.2Hz, 3H), 1.25 (d, J=7.2Hz, 3H), 1.20 (s, 18H).

[0897] MS (ES): m / z 452.3 [M+Na] + .

[0898] Compound 102

[0899] To a stirred solution of 101 (170 mg, 0.40 mmol) in anhydrous CH2Cl2 (3 mL)

[0900] The mixture was washed with brine and finally dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product, which was purified by flash chromatography on silica gel (hexane / EtOAc) to give 102 (102 mg, 46% yield) as a mixture of two diastereomers.

[0901] 1 H NMR (300MHz, CDCl3): δ8.06 (d, J=8.3Hz, 2H), 7.82 (s, 2H), 7.66 (m, 8H), 7.40 (m, 12H), 5.88 (d, J=2.3 Hz, 1H), 5.85 (d, J=2.3Hz, 1H), 5.38 (d, J=2.2Hz, 1H), 5.36 (d, J=2.2Hz, 1H), 4.69 (m, 2H), 4.28 (m, 6H) , 4.0(t, J=10.5Hz, 2H), 3.76(s, 3H), 3.72(s, 3H), 1.89-1.62(m, 4H), 1.50(s, 3H), 1.43(s, 3H), 1.35( m, 4H), 1.30 (d, J=7.5Hz, 3H), 1.23 (d, J=7.5Hz, 3H), 1.12 (s, 9H), 1.09 (s, 9H), 0.92 (t, J=7.3Hz, 6H).

[0902] MS (ES): m / z 609.2 [M+H] + .

[0903] Compound 103

[0904] Drying over Na2SO4, filtration and concentration gave 103 (96 mg; 100% yield), which was used without further purification as a mixture of two diastereomers.

[0905] 1H NMR (300MHz, CDCl3): δ7.66 (m, 8H), 7.38 (m, 12H), 6.87 (d, J=8.7Hz, 1H), 6.81 (d, J=8.7Hz, 1H), 5 .81 (d, J=2.3Hz, 1H), 5.78 (d, J=2.3Hz, 1H), 5.40 (d, J=2.2Hz, 1H), 5.37 (d, J=2.2Hz, 1H), 4.66 (m , 2H), 4.50-4.25 (m, 4H), 3.97 (d, J=9.3Hz, 1H), 3.90 (d, J=9.3Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 1.90-1.57(m, 4H), 1.40(s, 3H), 1.38(s, 3H), 1.28(m, 10H), 1.06(s, 18H), 0.92(t, J=7.3Hz, 6H).

[0906] MS (ES): m / z 591.2 [M+H] + .

[0907] Compound 104

[0908] It was further purified and used as a mixture of two diastereomers.

[0909] 1 H NMR (300MHz, CDCl3): δ7.05 (t, J=9.6Hz, 2H), 5.89 (d, J=2.3Hz, 1H), 5.87 (d, J=2.3Hz, 1H), 5.40 (d, J=2.2Hz, 2H), 4.67 (m, 2 H), 4.58-4.22 (m, 4H), 4.10 (m, 2H), 3.76 (s, 6H), 1.86-1.60 (m, 4H), 1.5 (s, 6H), 1.46-1.30 (m, 10H), 0.92 (t, J=7.3Hz, 6H).

[0910] MS (ES): m / z 353.1 [M+H] + .

[0911] Compound 105

[0912] The phase was dried over Na2SO4, filtered and concentrated in vacuo to give an oil, and the crude product was purified by flash chromatography on silica gel (hexanes / EtOAc) to give 105 (9 mg, 18% yield) as a white solid.

[0913] 1H NMR (300MHz, CDCl3): δ6.84 (d, J=9.3Hz, 1H), 5.87 (d, J=2.3Hz, 1H), 5.41 (d, J=2.3Hz, 1H), 4.70 (m, 1H), 4.63 (d, J=9.3Hz, 1H ), 4.23 (d, J=9.3Hz, 1H), 3.78 (s, 3H), 2.55 (s, 3H), 1.92-1.71 (m, 2H), 1.56 (s, 3H), 1.44-1.30 (m, 2H), 0.96 (t, J=7.2Hz, 3H).

[0914] Compound 106

[0915]

[0916] The crude product was purified by silica gel chromatography (CH2Cl2 / EtOAc 1 / 1) to afford 106 (1.6 mg, 23% yield).

[0917] 1 H NMR (300MHz, CDCl3): δ6.85 (d, J=9.3Hz, 1H), 5.81 (d, J=2.3Hz, 1H), 5.35 (d, J=2.3Hz, 1H), 4.63 (m, 1H), 4.14 (d, J=9.3Hz, 1H), 3.92 (d, J=9.3Hz, 1H), 3.72 (s, 3H), 2.14 (s, 3H), 1.82-1.67 (m, 2H), 1.48 (s, 3H), 1.30 (m, 2H), 0.89 (t, J=7.2Hz, 3H).

[0918] MS (ES): m / z 366.2 [M+H] + .

[0919] Example 11: Synthesis of other compounds of formula I

[0920] Scheme 15 provides an example of the synthesis of compounds of formula I.

[0921]

[0922] Plan 15

[0923] 74 (37 mg; 0.091 mmol), 2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl trichloroacetimidate (30 mg, 0.061 mmol) and freshly activated A mixture of MS (244 mg) was dissolved / suspended in CH2Cl2 (1.0 mL) and stirred at 23°C for 1 hour. The temperature was then lowered to -20°C and TMSOTf (12 μL; 0.064 mmol) was slowly added. The reaction was allowed to rise to 23°C. The mixture was then stirred overnight. Subsequently, Et3N was added to quench the reaction mixture, and the resulting suspension was filtered through a pad of diatomaceous earth (top) and Na2SO4 (bottom). The solid was thoroughly washed with CH2Cl2, and the entire filtrate was concentrated in vacuo to give a yellow-orange gel. The crude product was purified by flash chromatography on silica gel (hexane: EtOAc from 70: 30 to 0: 100) to give pure 107 (23 mg, 51% yield).

[0924] 1 H NMR (400MHz, CDCl3): δ7.08 (d, J=8.9Hz, 1H), 6.00 (d, J=5.6Hz, 1H), 5.98-5.92 (m, 1H), 5.41-5.36 (m, 3H), 5.15 (d d, J=2.8, 2.8Hz, 1H), 4.92 (dd, J=9.3, 2.8Hz, 1H), 4.73 (q, J=7.8, 1H), 4.65 (dd, J=5.6, 2.8Hz, 1H), 4.49 (dt, J=5.6 , 1.2Hz, 2H), 4.23 (dd, J=4.0, 2.7, 2H), 3.93 (ddd, J=8.8, 5.0, 3.4, 1H), 3.53 (d, J=11.6, 1H), 3.21 (d, J=11.6, 1H), 2.17 (s, 3H), 2.10 (bs, 9H), 1.92-1.70 (m, 2H), 1.86 (s, 3H), 1.50 (s, 3H), 1.49-1.28 (m, 2H), 0.96 (t, J=7.3Hz, 3H).

[0925] 13 C NMR (100MHz, CDCl3): δ173.9, 170.8, 169.8, 169.8, 169.3, 167.5, 164.1, 162.4, 153.4, 130.7, 123.4, 119.8, 100.6, 98 .7, 89.6, 84.88, 74.9, 70.2, 69.8, 67.9, 67.4, 63.3, 51.1, 40.0, 35.0, 24.9, 21.4, 21.0, 20.9, 20.9, 19.2, 13.7, 12.2.

[0926] MS (ES+): m / z 738 [M+H] + , 760[M+Na] + .

[0927] R f :0.21 (Hex:EtOAc 50:50).

[0928] Scheme 16 provides an example of the synthesis of compounds of formula 1.

[0929]

[0930] Plan 16

[0931] a) Synthesis of 109

[0932]

[0933] To a solution of 108 (570 mg, 2.190 mmol) [obtained as described in Bioorg. Med. Chem. 2013, 21, 4839-4845] in anhydrous CH2Cl2 (11 mL) was added CCl3CN (2.20 mL, 21.90 mmol) and DBU (66 μL, 0.44 mmol) dropwise at 23°C. The reaction was stirred for 1 h and then concentrated in vacuo. The resulting dark red crude product was chromatographed (SiO2, hexane + 1% Et3N: EtOAc + 1% Et3N from 80:20 to 50:50) to afford 109 (827 mg; 93% yield) as a white solid.

[0934] 1 H NMR (400MHz): δ8.59 (s, 1H), 6.26 (s, 1H), 4.92 (dd, J=5.9, 3.4Hz, 1H), 4.86 (d, J=5.8Hz, 1H), 4.43 (ddd, J=8.3, 6. 2, 4.2Hz, 1H), 4.14-4.09 (m, 2H), 4.03 (dd, J=8.9, 4.2Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H).

[0935] 13 C NMR (100MHz): δ160.8, 113.6, 109.6, 104.9, 84.9, 83.0, 79.4, 72.8, 67.2, 27.1, 26.1, 25.3, 24.9.

[0936] MS (ES): m / z 426-428 [M+Na] + .

[0937] R f :0.64 (Hex:EtOAc 2:1).

[0938] b) Synthesis 110

[0939] A freshly prepared stock solution of Pd(PhCN)(OTf) catalyst in CHCl (840 μL; 5% mol), prepared by stirring Pd(PhCN)Cl (10 mg; 0.026 mmol) and AgOTf (14 mg; 0.052) in CHCl for 5 minutes, was added to a solution of 109 (50 mg; 0.124 mmol) and 74 (61 mg; 0.161 mmol) in CHCl (700 μL) at 23°C. The reaction mixture was stirred at 23°C overnight, then treated with benzene (1 mL) and poured directly onto a chromatography column (SiO, CHCl to CHCl:MeOH 98.2:1.8). Following this procedure, compound 110 (27.5 mg, 34% yield) was obtained as a foamy white solid (primarily the α isomer).

[0940] 1 H NMR (400MHz, CDCl3): δ9.25 (s, 1H), 7.10 (d, J=8.9Hz, 1H), 6.00-5.91 (m, 1H), 5. 69 (bs, 1H), 5.42-5.30 (m, 3H), 4.93-4.91 (dd, J=6.0, 3.6Hz, 1H), 4.87 (d, J=6.0H z, 1H), 4.73 (q, J=7.9Hz, 1H), 4.49 (bd, J=6.6Hz, 2H), 4.38 (m, 1H), 4.22 (dd, J=7 .7, 3.9Hz, 1H), 4.08 (bd, J=5.2Hz, 2H), 3.52 (d, J=11.6Hz, 1H), 3.20 (d, J=11.6Hz 1H), 2.19 (s, 3H), 1.93-1.72 (m, 2H), 1.51 (s, 3H), 1.50 (s, 3H), 1.49-1.28 (m, 11H), 0.96 (t, J=7.4Hz, 3H).

[0941] 13 C NMR (100MHz, CDCl3): δ174.0, 169.8, 167.5, 164.1, 162.5, 153.8, 130.8, 119.8, 113.0, 109.3, 109.0, 100.6, 89 .6, 84.8, 84.7, 83.3, 80.0, 73.5, 69.7, 66.8, 51.1, 40.0, 35.0, 27.1, 26.1, 25.3, 24.9, 24.6, 19.2, 13.7, 12.2.

[0942] MS (ES+): m / z 650 [M+H] + ,672[M+Na] + .

[0943] R f :0.39(CH2Cl2:MeOH 50:1).

[0944] Scheme 17 provides an example of the synthesis of another compound of formula I.

[0945]

[0946] Plan 17

[0947] Compound 110 (31 mg, 0.048 mmol) was dissolved in an aqueous solution of AcOH (80%, 1.0 mL) and stirred at 65°C for 4 h. The solution was then diluted with toluene (1.5 mL) and the volatiles were evaporated in vacuo to yield an oily, beige crude product. The co-evaporation of the aqueous AcOH solution with toluene was repeated twice. The resulting crude product was purified by column chromatography (SiO2, CH2Cl2 to CH2Cl2:MeOH 10:1) to yield compound 111 (18 mg, 62% yield) as a waxy white solid.

[0948] 1 H NMR (500MHz, CDCl3): δ7.04 (d, J=8.9Hz, 1H), 5.99-5.92 (m, 1H), 5.72 (bs, 1H), 5.42-5.34 (m, 3H), 5.01 (dd, J=6.0, 4 .3Hz, 1H), 4.89 (d, J=6.0Hz, 1H), 4.72 (q, J=8.0Hz, 1H), 4.49 (bd, J=5.5Hz, 2H), 4.25 (dd, J=8.0, 4.3Hz, 1H), 3.97 (b d, J=8.3, 5.8, 3.4Hz, 1H), 3.86 (d, J=11.5, 3.4Hz, 1H), 3.74 (d, J=11.5, 5.8Hz, 1H), 3.54 (d, J=11.6Hz, 1H), 3.21 (d, J=11.6Hz, 1H), 2.19 (s, 3H), 1.90-1.72 (m, 2H), 1.52 (s, 6H), 1.37 (s, 3H), 1.42-1.31 (m, 2H), 0.96 (t, J=7.4Hz, 3H).

[0949] 13C NMR (125MHz, CDCl3): δ174.0, 169.9, 167.6, 164.2, 162.4, 153.9, 130.7, 119.8, 113.0, 108.7, 100.7, 89.6, 84.7, 84.6, 82.7, 80.7, 71.0, 69.8, 64.5, 51.2, 40.1, 35.0, 26.1, 25.0, 24.7, 19.2, 13.7, 12.2.

[0950] MS (ES+): m / z 610 [M+H] + ,632[M+Na] + .

[0951] R f :0.12(CH2Cl2:MeOH 50:1).

[0952] Scheme 18 provides an illustration of the synthesis of another compound of formula I.

[0953]

[0954] Plan 18

[0955] A solution of 111 (180 mg, 0.29 mmol) in an AcOH (80%, 10 mL) aqueous solution was heated at 100° C. for 4 h. The solution was then diluted with toluene (10 mL) and the volatiles were evaporated in vacuo to afford an oily, beige crude product. The co-evaporation of the AcOH aqueous solution with toluene was repeated (× 5) to afford a beige crude product which was purified by flash chromatography (SiO , CH Cl to CH Cl : MeOH 90: 10). On a C18 Symmetry preparative column, flow rate 15 mL / min, H O: CH CN mixture was finally purified by HPLC to afford compound 112 (60 mg, 36% yield).

[0956] 1H NMR (500MHz, CDCl3): δ7.07 (d, J=8.8Hz, 1H), 6.00-5.92 (m, 1H), 5.72 (d, J=2.5, 1H), 5.44-5.34 (m, 3H), 4.72 (q, J=8.0Hz, 1H), 4.61 (t, J=4.9Hz, 1H), 4.50 (bd, J=5.6, 2H), 4.41 (dd, J=5.3, 2.5Hz, 1H), 4.20 (dd, J=6.8, 4.5Hz, 1H) ), 4.09 (td, J=6.4, 3.5Hz, 1H), 3.87 (dd, J=11.6, 3.3Hz, 1H), 3.77 (dd, J=11.6, 6.0Hz, 1H), 3.55 (d, J=11.6Hz, 1H ), 3.20 (d, J=11.6Hz, 1H), 2.20 (s, 3H), 1.92-1.73 (m, 2H), 1.52 (s, 3H), 1.42-1.28 (m, 2H), 0.96 (t, J=7.4Hz, 3H).

[0957] 13 C NMR (100MHz, CDCl3): δ174.2, 170.1, 167.9, 164.6, 162.5, 154.0, 130.7, 119.8, 110.5, 100. 8, 89.6, 84.6, 80.8, 75.6, 71.9, 71.6, 69.9, 63.7, 51.2, 40.3, 34.9, 25.0, 19.2, 13.7, 12.5.

[0958] MS (ES+): m / z 570 [M+H] + , 592[M+Na] + .

[0959] Compound 113

[0960] Purification by flash column chromatography and eluting with hexanes / EtOAc from 100:0 to 0:100 over 30 minutes afforded compound 113 (108 mg, 56% yield).

[0961] 1H NMR (400MHz, CDCl3): δ7.75-7.66(m, 2H), 7.48-7.33(m, 8H), 7.14(d, J=8.7Hz, 1H), 6.03-5.87(m, 1H), 5.94(d, J=2.2Hz, 1H), 5.42 (d, J=2.3Hz, 1H), 5.43-5.36 (m, 1H), 5.34 (dq, J=10.5, 1.2Hz, 1H), 4.73 (q, J=8.0Hz, 1H), 4.4 8 (dt, J=5.6, 1.5Hz, 2H), 3.46 (d, J=11.6Hz, 1H), 3.15 (d, J=11.6Hz, 1H), 2.35 (s, 3H), 1.89 (dq, J=9.5, 6.8Hz, 1H ), 1.78 (dddd, J=13.6, 9.6, 7.9, 5.7Hz, 1H), 1.50 (s, 3H), 1.49-1.20 (m, 2H), 1.15 (s, 9H), 0.97 (t, J=7.3Hz, 3H).

[0962] 13 C NMR (100MHz, CDCl3): δ174.2, 169.7, 168.5, 164.1, 162.4, 157.2, 135.5, 132.8, 130.6, 129.9 , 127.6, 119.6, 100.4, 89.4, 84.3, 69.6, 51.0, 39.7, 34.7, 27.1, 24.8, 19.6, 19.1, 13.6, 11.8.

[0963] Scheme 19 provides an example of the synthesis of compounds of formula I.

[0964]

[0965] Plan 19

[0966] Compound 114

[0967] 71% yield).

[0968] 1H NMR (400MHz, CD3OD): δ7.85 (d, J=8.6Hz, 1H), 6.06 (d, J=2.2Hz, 1H), 6.05-5.92 (m, 1H), 5.53 (d, J=2.2Hz, 1H), 5. 46-5.27 (m, 2H), 4.75 (ddd, J=8.8, 7.3, 4.3Hz, 1H), 4.58 (dt, J=5.6, 1.5Hz, 2H), 4.22 (t, J=6.5Hz, 2H), 3.67 (t, J= 6.2Hz, 2H), 3.58 (dd, J=11.5, 5.8Hz, 1H), 3.19 (d, J=11.6Hz, 1H), 2.19 (d, J=2.2Hz, 3H), 1.97-1.70 (m, 4H), 1.60 ( dd, J=8.7, 6.1Hz, 2H), 1.52 (d, J=1.9Hz, 3H), 1.49-1.34 (m, 4H), 0.98 (t, J=7.3Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H).

[0969] 13 C NMR (100MHz, CD3OD): δ175.0, 170.7, 168.0, 165.1, 163.9, 151.4, 131.1, 118.0, 99.5, 88.4, 8 4.2, 74.9, 69.6, 62.5, 50.8, 39.3, 33.9, 28.8, 25.4, 25.0, 23.5, 18.8, 17.7, 12.5, 10.4, -6.5.

[0970] MS (ES+): m / z 594 [M+H] + ,616[M+Na] + .

[0971] Compound 115

[0972] The residue afforded 115 (40 mg, 71% yield).

[0973] 1H NMR (400MHz, CD3OD): δ6.06 (d, J=2.2Hz, 1H), 6.05-5.91 (m, 1H), 5.54 (d, J=2.2Hz, 1H), 5.46-5.29 (m, 2H), 4.74 (dd, J=9.1, 5.8Hz, 1H), 4.59 (dt, J=5.5, 1.6Hz, 2H), 4.23 (t, J= 6.5Hz, 2H), 3.63-3.50 (m, 3H), 3.1g (d, J=11.5Hz, 1H), 2.19 (s, 3H), 1.89-1.73 (m, 3H), 1.62 (dd, J=8.9, 6.2Hz, 2H), 1.52 (s, 3H), 1.45-1.32 (m, 1H), 0.99 (q, J=8.1, 7.4Hz, 3H).

[0974] 13 C NMR (100MHz, CD3OD): δ174.9, 170.7, 168.0, 165.1, 163.9, 151.5, 131.1, 118.0, 99.5 , 88.4, 84.2, 74.9, 69.6, 61.2, 50.7, 39.3, 33.8, 28.6, 25.3, 23.5, 18.8, 12.4, 10.3.

[0975] MS (ES-): m / z 478 [MH] - .

[0976] Scheme 20 provides an illustration of the synthesis of additional compounds of Formula I.

[0977]

[0978] Plan 20

[0979] Compound 116

[0980] To a solution of 65 (42 mg, 0.103 mmol) in anhydrous toluene (1 mL) was added N-Boc-1,3-propylenediamine (19 mg, 0.107 mmol), pTsOH (1 mg, 0.005 mmol) and sodium aluminosilicate and the mixture was refluxed for 2 hours. The reaction mixture was then filtered through celite and the filtrate evaporated. The resulting residue was purified by flash chromatography on SiO2 (from hexane + 1% Et3N to Hex:EtOAc:Et3N 1:1:0.01) to afford 116 (29 mg, 50% yield).

[0981] 1H NMR (500MHz, CDCl3): δ7.10 (d, J=8.9Hz, 1H), 5.92 (d, J=2.2Hz, 1H), 5.34 (d, J=2.2Hz, 1H), 5.22 (brs, 1H), 4.75-4.70 (m 1H), 3.76 (dd, J=7.1, 2.8Hz, 2H), 3.53 (t, J=6.6Hz, 2H), 3.50 (d, J=11.7Hz , 1H), 3.30-3.26 (m, 2H), 3.16 (d, J=11.7HZ, 1H), 2.20 (s, 3H), 1.914-1.84 (m, 3H), 1.80-1.73 (m, 1H), 1.52 (s, 3H), 1.42 (s, 9H), 1.45-1.33 (m, 1H), 1 .24-1.19(m, 1H), 0.98-0.94(m, 4H), 0.68-0.64(m, 2H), 0.34-0.31(m, 2H).

[0982] 13 C NMR (125MHz, CDCl3): δ174.1, 173.7, 170.1, 170.0, 164.1, 162.3, 156.0, 100.5, 88.9, 88. 8, 85.6, 73.8, 50.9, 30.6, 34.9, 30.1, 28.4, 28.3, 24.9, 19.0, 14.78, 13.6, 9.4, 3.4, 3.3.

[0983] MS (ES+): m / z 563 [M+H] + .

[0984] R f :0.55 (Hex ∶ EtOAc ∶ Et3N 9 ∶ 1 ∶ 0.01).

[0985] Scheme 21 provides an example of the synthesis of compounds of formula I.

[0986]

[0987] Plan 21

[0988] Compound 117

[0989] To 74 (50 mg, 0.123 mmol) solution in MeOH (1 mL) was added iron powder (14 mg, 0.24 mmol) and concentrated HCl, and the reaction mixture was stirred at 23 ° C for 3 hours. The reaction mixture was then quenched with saturated Na CO aqueous solution and extracted with 10% MeOH in CH Cl. The organic layer was separated, dried over anhydrous Na SO, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (CH Cl : MeOH) to give 117 (23 mg, 48% yield).

[0990] 1 H NMR (400MHz, CD3OD): δ6.32-5.91 (m, 1H), 5.64-5.50 (m, 1H), 5.49-5.25 (m, 1H), 4.73 (dt, J=9.0, 6.3 Hz, 1H), 3.90-3.36 (m, 2H), 1.89-1.76 (m, 2H), 1.59-1.33 (m, 5H), 0.96 (ddd, J=8.6, 5.7, 1.8Hz, 3H).

[0991] Example 12. Synthesis of other intermediates of general formula II

[0992] Scheme 22 provides further examples of the synthesis of intermediates of formula II

[0993]

[0994] Plan 22

[0995] Compound (R)-118

[0996] Purification by (hexanes / EtOAc) afforded (R)-118 (730 mg, 73% yield) as a light yellow oil.

[0997] 1 H NMR (400MHz, CDCl3): δ6.19 (d, J=2.2Hz, 1H), 6.15 (d, J=2.3Hz, 1H), 4.83 (d, J=8.3Hz, 1H), 4.46 (d, J=7.4Hz, 1H ), 1.83 (ddt, J=12.8, 9.6, 6.2Hz, 1H), 1.73-1.61 (m, 1H), 1.44 (s, 9H), 1.42-1.24 (m, 2H), 0.96 (t, J=7.3Hz, 3H).

[0998] 13C NMR (100MHz, CDCl3): δ167.7, 161.3, 161.0, 154.9, 118.5 (q, k=321.1Hz), 103.4, 98.6, 80.9, 53.0, 35.1, 31.1, 28.4, 19.2, 13.7.

[0999] MS (ES+): m / z 438.0 [M+Na] + .

[1000] R f :0.27 (Hex:EtOAc 9:1).

[1001] Compound (R)-119

[1002] Purification by 2% ethanol:EtOAc (4% ethanol:EtOAc) afforded (R)-119 (90 mg, 23% yield) as a colorless solid.

[1003] 1 H NMR (400MHz, CDCl3): δ7.32-7.26 (m, 1H), 6.20 (dd, J=9.4, 1.0Hz, 1H), 6.13 (d, J=6.5Hz, 1H), 4.90 (d, J=8.8Hz, 1H), 4.41 (q, J=7. 9Hz, 1H), 1.79 (ddt, J=13.3, 9.5, 6.5Hz, 1H), 1.66 (dq, J=13.9, 7.7Hz, 1H), 1.42 (s, 9H), 1.38-1.24 (m, 1H), 0.93 (t, J=7.4Hz, 3H).

[1004] 13 C NMR (100MHz, CDCl3): δ164.3, 162.3, 155.1, 143.7, 132.2, 129.7, 128.8, 12 8.6, 127.2, 123.5, 114.6, 102.7, 80.3, 52.8, 35.4, 29.8, 28.4, 19.2, 13.7.

[1005] MS (ES+): m / z 290.3 [M+Na] + .

[1006] R f :0.13 (Hex:EtOAc 4:1).

[1007]

[1008] 1H NMR (400MHz, CD3OD): δ7.51 (ddd, J=9.6, 6.5, 1.0Hz, 1H), 7.27-6.99 (m, 1H), 6.49 (dd, J=6.6, 1.0Hz, 1H), 6.35 (dt, J=9.4, 1.0Hz, 1H), 4.18 (dd, J=9.0, 6.1Hz, 1H), 2.08-1.72 (m, 2H), 1.49-1.17 (m, 3H), 1.02-0.88 (m, 3H).

[1009] 13 C NMR (100MHz, CD3OD): δ162.6, 159.2, 145.1, 129.9, 129.2, 126.3, 117.2, 107.1, 53.5, 34.3, 19.6, 13.7.

[1010] Example 13. Synthesis of Intermediate 125

[1011] Scheme 23 provides an example of the synthesis of intermediate 125

[1012]

[1013] Plan 23

[1014] To the product 121 (326 mg, 100% yield) was added NaCO (383 mg, 3.6 mmol) solution and Boc anhydride (276 mg, 1.2 mmol) dissolved in 1,4-dioxane (2.4 mL). The reaction mixture was stirred at 23 ° C for 5 hours, then diluted with EtOAc and washed twice (x2) with 0.5N HCl and once (x1) with a saturated NaCl aqueous solution. The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude product 121 (326 mg, 100% yield), which was used for the next step without further purification.

[1015] 1 H NMR (400MHz, CD3OD): 64.17 (dd, J=9.0, 4.9Hz, 1H), 2.36-2.14 (m, 2H), 2.08 (ddt, J=16.2, 10.8, 5.4Hz, 1H), 1.95-1.81 (m, 1H), 1.45 (s, 9H).

[1016] 13 C NMR (100MHz, CD3OD): δ174.9, 158.0, 129.8 (q, J C-F =275Hz, CF3), 80.7, 53.7, 31.2 (q, J C-F=29Hz, C H2CF3), 28.7, 25.4.

[1017] Compound 122

[1018] Solution. After stirring at the same temperature for 1 hour, ZnCl2 (488 mg, 3.6 mmol) was added at -78 ° C, and the reaction mixture was stirred at -78 ° C for 30 minutes. The first mixture was added through a cannula. The reaction was stirred at -78 ° C for 4 h and then quenched with a saturated NH4Cl aqueous solution. It was extracted with EtOAc, and the organic layer was dried over Na2SO4 to obtain a crude product, which was purified by flash chromatography on silica gel (hexane / EtOAc from 9 / 1 to 7 / 3) to obtain 122 (256 mg, 54% yield).

[1019] 1 H NMR (400MHz, CDCl3): δ5.41 (d, J=8.2Hz, 1H), 5.32 (s, 1H), 4.28 (t, J=7.2Hz, 1H), 3.45 (d, J=3.3Hz, 2H), 2.29-2.01 (m, 4H), 1.65 (s, 6H), 1.41 (s, 9H).

[1020] 13 C NMR (100MHz, CDCl3): δ201.7, 164.05, 160.6, 155.4, 126.6 (q, J C-F =276Hz, C F3), 107.3, 96.9, 80.7, 58.3, 43.6, 29.9 (q, J C-F =29Hz, C H2CF3), 28.1, 24.9, 24.7, 23.1.

[1021] Compound 123

[1022]

[1023] 1 H NMR (400MHz, CDCl3): δ6.05 (s, 1H), 5.51 (s, 1H), 5.30 (s, 1H), 5.22 (s, 1H), 2.30-1.75 (m, 4H), 1.36 (s, 9H).

[1024] Compound 124

[1025]

[1026] 1H NMR (400MHz, CDCl3): δ5.96 (d, J=2.2Hz, 1H), 5.44 (d, J=2.2Hz, 1H), 5.12 (d, J= 9.4Hz, 1H), 4.45 (q, J=8.5Hz, 1H), 3.79 (s, 3H), 2.24-1.79 (m, 4H), 1.41 (s, 9H).

[1027] 13 C NMR (100MHz, CDCl3): δ170.8, 163.8, 161.7, 154.8, 126.5 (q, J C-F =276Hz, C F3), 100.3, 88.7, 80.6, 56.0, 51.5, 30.5 (q, J C-F =29Hz, C H2CF3), 28.2, 25.8.

[1028] Compound 125

[1029] 4.96(s, 2H), 4.34-4.26(m, 1H), 3.89(s, 3H), 2.44-2.11(m, 4H).

[1030] 13 C NMR (100MHz, CD3OD): d 172.2, 165.1, 157.8, 127.9 (q, J C-F =275Hz, C F3), 105.3, 90.8, 57.3, 52.4, 30.5 (q, J C-F =30Hz, C H2CF3), 24.8 (q, J C-F =3.1Hz, C H2CH2CF3).

[1031] Example 14. Synthesis of other compounds of general formula I

[1032] Scheme 24 provides another example of the synthesis of other compounds of Formula I.

[1033]

[1034] Plan 24

[1035] Compound 126

[1036] The organic layer was washed with HCl and finally dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane / EtOAc 6 / 4) to afford 126 (100 mg, 77% yield).

[1037] 1 H NMR (400MHz, CDCl3): δ7.26-7.20 (m, 1H), 7.09 (d, J=8.8Hz, 1H), 6.16 (dd, J=9.4, 1.0Hz, 1H), 6.06 (dd, J=6.5, 1.1Hz, 1H), 4.75 (q, J=7.9Hz, 1H), 3.65-3.37 (m, 4H), 3.15 (dd, J=1 1.7, 1.0Hz, 1H), 1.92-1.79 (m, 1H), 1.81-1.67 (m, 1H), 1.60 (d, J=0.9Hz, 3H), 1.54 (d, J= 0.9Hz, 3H), 1.44-1.28 (m, 2H), 1.21 (qd, J=7.2, 1.0Hz, 6H), 0.93 (td, J=7.3, 0.9Hz, 3H).

[1038] 13 C NMR (100MHz, CDCl3): δ177.2, 174.4, 163.5, 161.5, 143.2, 114.7, 102.4, 10 0.2, 85.1, 57.8, 57.7, 51.0, 40.4, 34.8, 25.3, 23.7, 19.1, 15.2(x2), 13.5.

[1039] MS (ES+): m / z 433.3 [M+Na] + .

[1040] R f :0.33 (Hex:EtOAc 1:3).

[1041]

[1042] 1H NMR (400MHz, CDCl3): δ7.40-7.17 (m, 1H), 7.04 (d, J=9.0Hz, 1H), 6.30-6.07 (m, 2H), 4.79 (q, J=7.1, 6.0Hz, 1H), 3.63 (dd, J=12.1, 3.2Hz, 1H), 3.28 (dd, J=12.0, 3.1Hz, 1H), 2.56 (d, J=3.8Hz, 2H), 1.97-1.77 (m, 1H), 1.55 (d, J=3.6Hz, 2H), 1.46-1.17 (m, 2H), 0.97 (q, J=5.7, 4.2Hz, 3H).

[1043] 13 C NMR (100MHz, CDCl3): δ193.2, 173.2, 170.4, 162.7, 161.7, 143.4, 114.9, 103.0, 86.1, 51.1, 40.1, 35.0, 26.3, 24.6, 19.1, 13.6.

[1044] Compound 128

[1045] The crude product was purified by silica gel chromatography (CH2Cl2 / EtOAc from 95 / 5 to 8 / 2) to afford 128 (29 mg, 40% yield).

[1046] 1 H NMR (400MHz, CD3OD): δ7.84 (d, J=8.6Hz, 1H), 7.46 (dd, J=9.4, 6.6Hz, 1H), 6.31-6.16 (m, 2H), 4.77 (ddd, J=8.8, 7.3, 4.3Hz, 1H), 3.5 2 (d, J=11.5Hz, 1H), 3.18 (d, J=11.5Hz, 1H), 2.18 (s, 3H), 1.94-1.75 (m, 2H), 1.52 (s, 3H), 1.49-1.34 (m, 1H), 0.99 (t, J=7.4Hz, 3H).

[1047] MS (ES+): m / z 352.3 [M+H] + ,374.1[M+Na] + .

[1048] Scheme 25 provides further examples of the synthesis of compounds of formula I:

[1049]

[1050] Plan 25

[1051] Compound 129

[1052] The product was stirred for 2 hours at room temperature for 1 hour at 4 ℃ for 3 hours at 4 ℃ for 1 hour at 8 ℃ for 2 hours at 8 ℃ for 3 hours at 4 ℃ for 4 hours at 8 ℃ for 5 hours at 8 ℃ for 3 hours at 8 ℃ for 4 hours at 8 ℃ for 5 hours at 8 ℃ for 2 ...5 hours at 8 ℃ for 4 hours at 8 ℃ for 5 hours at 8 ℃ for 2 hours at 8 ℃ for 3 hours at 8 ℃ for

[1053] 1 H NMR (400MHz, CDCl3): δ7.02 (d, J=8.5Hz, 1H), 5.93 (m, 1H), 5.41 (d, J=2.2Hz, 1H), 4. 65 (td, J=8.4, 6.2Hz, 1H), 3.78 (d, J=0.7Hz, 3H), 3.60 (m, 1H), 3.52 (m, 4H), 3.15 (dd, J=11.7, 0.7Hz, 1H), 1.84 (ddd, J=13.4, 9.4, 6.7Hz, 1H), 1.64 (dd, J=8.9, 5.5Hz, 1H), 1.59 (d, J=0.7Hz, 3H), 1.48 (s, 3H), 1.29 (m, 1H), 1.21 (m, 6H), 0.89 (t, J=7.3Hz, 3H).

[1054] 13 C NMR (100MHz, CDCl3): δ177.7, 175.8, 172.2, 165.4, 164.2, 101.4, 101.0, 89.7 , 86.4, 58.9, 58.8, 57.2, 52.1, 41.6, 35.8, 26.3, 24.9, 20.2, 16.5(x2), 14.8.

[1055] MS (ES+): m / z 463.3 [M+Na] + .

[1056] Compound 130

[1057] Dried, filtered and evaporated to dryness.The crude residue was purified on a SiO2 column flash chromatography system eluting with a hexane / EtOAc mixture from 100:0 to 50:50 over 15 minutes to afford 130 (240 mg, 50% yield).

[1058] 1H NMR (400MHz, CDCl3): δ6.94 (dd, J=8.6, 3.3Hz, 1H), 5.80 (m, 2H), 5.22 (m, 3H), 4.51 (dq, J= 11.6, 5.4, 4.0Hz, 1H), 4.34 (d, J=4.4Hz, 2H), 3.38 (m, 5H), 2.99 (dd, J=11.7, 3.6Hz, 1H), 1. 68 (dtd, J=11.2, 8.0, 7.4, 3.9Hz, 1H), 1.50 (tq, J=8.4, 4.6, 3.9Hz, 1H), 1.42 (d, J=3.4Hz, 3 H), 1.31 (d, J=3.4Hz, 3H), 1.04 (ddt, J=11.0, 6.9, 3.0Hz, 6H), 0.73 (td, J=7.5, 3.3Hz, 3H).

[1059] 13 C NMR (100MHz, CDCl3): δ176.2, 174.3, 169.6, 163.8, 162.9, 130.6, 119.2, 100.0, 9 9.7, 89.1, 85.0, 69.4, 57.5, 57.4, 50.7, 40.2, 34.4, 24.9, 23.5, 18.8, 15.1, 13.4.

[1060] MS (ES+): m / z 489.2 [M+Na] + .

[1061] Compound 131

[1062] Evaporated to dryness.The crude residue was purified on a SiO2 column flash chromatography system eluting with a hexane / EtOAc mixture from 100:0 to 50:50 over 15 minutes to afford 131 (343 mg, 46% yield).

[1063] 1H NMR(400MHz,CDCl3):δ6.92(d,J=8.5Hz,1H),5.81(dt,J=2.2,0.7Hz,1H),5.21(dd,J=2.2,0.6Hz,1H),4.51(td,J=8.4,6.1Hz,1H),3.93(qd,J=7.2,0.6Hz,1H),3.62(m,2H),3.38(m,5H),3.00(dd,J=11.7,0.7Hz,1H),1.68(m,1H),1.49(m,1H),1.42(d,J=0.6Hz,3H),1.32(s,3H),1.14(m,2H),1.05(m,7H),0.74(t,J=7.3Hz,3H),0.49(m,2H),0.18(m,2H).

[1064] 13 C NMR(100MHz,CDCl3):δ176.1,174.3,170.0,163.9,162.7,100.0,99.8,88.5,85.0,73.6,57.5,57.3,50.7,40.2,34.4,24.9,23.5,18.8,15.1,13.4,9.3,3.2(x2).

[1065] MS(ES+):m / z 503.3[M+Na] + .

[1066]

[1067] 1 H NMR(400MHz,CDCl3):δ6.93(d,J=8.5Hz,1H),5.99(dd,J=2.4,1.1Hz,1H),5.45(dd,J=2.3,1.1Hz,1H),4.68(q,J=7.8Hz,1H),3.81(d,J=1.2Hz,3H),3.67(dd,J=12.0,1.3Hz,1H),3.28(dd,J=11.9,1.2Hz,1H),2.56(d,J=1.2Hz,2H),1.85(m,1H),1.72(m,1H),1.50(d,J=1.3Hz,3H),1.30(m,2H),0.92(td,J=7.3,1.2Hz,3H).

[1068] 1313C NMR (100 MHz, CDCl3): δ 194.4, 174.5, 172.2, 171.5, 165.5, 163.3, 101.8, 89.9, 87.4, 57.3, 52.4, 41.5, 35.8, 27.6, 25.7, 20.3, 14.8.

[1069] MS (ES+): m / z 367.3 [M+H] + .

[1070] Compound 133

[1071] 5.41 (m, 4H), 4.69 (q, J = 7.8 Hz, 1H), 4.51 (dq, J = 5.8, 1.4 Hz, 2H), 3.67 (dd, J = 12.0, 1.1 Hz, 1H), 3.28 (dd, J = 11.9, 1.2 Hz, 1H), 2.56 (d, J = 1.2 Hz, 3H), 1.86 (m, 1H), 1.72 (m, 1H), 1.50 (d, J = 1.2 Hz, 3H), 1.30 (tt, J = 14.3, 6.8 Hz, 3H), 0.92 (m, 3H).

[1072] 13 13C NMR (100 MHz, CDCl3): δ 194.4, 174.5, 171.0, 166.2, 163.4, 159.6, 131.8, 120.9, 102.0, 90.7, 87.4, 70.9, 52.4, 41.5, 35.8, 27.6, 25.7, 20.3, 14.8.

[1073] MS (ES+): m / z 393.2 [M+H] + .

[1074]

[1075] 1H NMR (400MHz, CDCl3): δ6.93 (d, J=8.6Hz, 1H), 6.01 (d, J=2.2Hz, 1H), 5.39 (d, J=2.3Hz, 1H) , 4.69 (q, J=7.8Hz, 1H), 3.79 (dd, J=7.1, 2.7Hz, 2H), 3.68 (d, J=11.9Hz, 1H), 3.28 (dd, J=1 1.9, 0.6Hz, 1H), 2.56 (d, J=0.6Hz, 3H), 1.86 (ddt, J=14.0, 9.1, 7.1Hz, 1H), 1.71 (m, 1H), 1 .51 (s, 3H), 1.29 (m, 2H), 0.93 (t, J=7.4Hz, 4H), 0.68 (m, 3H), 0.35 (dt, J=6.2, 4.9Hz, 3H).

[1076] 13 C NMR (100MHz, CDCl3): δ194.4, 174.5, 173.6, 171.4, 165.5, 163.2, 102.1, 9 0.1, 87.4, 75.1, 52.4, 41.5, 35.8, 27.6, 25.7, 20.3, 14.8, 10.6, 4.7, 4.6.

[1077] MS (ES+): m / z 407.1 [M+H] + .

[1078] Compound 135

[1079] 50:50) to afford 135 (231 mg, 57% yield).

[1080] 1 H NMR (400MHz, CDCl3): δ11.10 (s, 1H), 7.06 (d, J=8.5Hz, 1H), 5.92 (t, J=1.9Hz, 1H), 5.40 ( t, J=2.0Hz, 1H), 4.61 (qd, J=7.4, 6.7, 1.5Hz, 1H), 3.73 (d, J=1.7Hz, 3H), 3.45 (dd, J=11. 6, 1.8Hz, 1H), 3.12 (dd, J=11.6, 1.6Hz, 1H), 2.10 (m, 3H), 1.76 (m, 1H), 1.62 (dddt, J=13. 6, 9.6, 5.7, 2.0Hz, 1H), 1.40 (d, J=1.6Hz, 3H), 1.19 (m, 2H), 0.81 (td, J=7.3, 1.6Hz, 3H).

[1081] 13 C NMR (100MHz, CDCl3): δ174.4, 170.9, 168.4, 164.4, 162.3, 151.8, 100.0, 88.3, 84.0, 55.8, 50.7, 39.6, 34.2, 24.3, 18.7, 13.3, 10.8.

[1082] MS (ES+): m / z 382.3 [M+H] + .

[1083] The mixture was stirred for 2 hours at room temperature for 1 h. The mixture was stirred for 2 hours at room temperature for 3 hours. The mixture was stirred for 2 hours at room temperature for 3 hours. The mixture was stirred for 3 ...4 hours. The mixture was stirred for 5 hours. The mixture was stirred for 5 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours.

[1084] 1 H NMR (400MHz, CDCl3): δ10.14 (s, 1H), 7.12 (m, 1H), 6.01 (t, J=1.7Hz, 1H), 5.94 (dddd, J=16.0, 9.7, 6.3, 5. 1Hz, 1H), 5.46 (t, J=1.7Hz, 1H), 5.39 (dq, J=17.2, 1.5Hz, 1H), 5.33 (dp, J=10.5, 1.1Hz, 1H), 4.69 (q, J=7.7 Hz, 1H), 4.49 (dt, J=5.6, 1.5Hz, 2H), 3.54 (dt, J=11.6, 1.0Hz, 1H), 3.24 (dd, J=11.6, 1.3Hz, 1H), 2.19 (m, 3 H), 1.83 (dtd, J=9.8, 7.7, 6.1Hz, 1H), 1.70 (m, 1H), 1.47 (m, 3H), 1.25 (m, 3H), 0.88 (td, J=7.4, 1.2Hz, 3H).

[1085] 13 C NMR (100MHz, CDCl3): δ174.5, 169.9, 168.1, 164.6, 162.3, 152.6, 130.5, 119.6, 100.6, 89.4, 84.3, 69.6, 51.0, 40.0, 34.5, 24.4, 18.9, 13.5, 11.2.

[1086] MS (ES+): m / z 408.2 [M+H] + .

[1087] Compound 137

[1088] The crude product was purified by silica gel chromatography (hexane / EtOAc from 100:0 to 50:50) to afford 137 (178 mg, 50% yield).

[1089] 1 H NMR (400MHz, CDCl3): δ10.45 (s, 1H), 7.12 (d, J=8.6Hz, 1H), 6.00 (d, J=2.1Hz, 1H), 5 .40 (dd, J=2.2, 0.7Hz, 1H), 4.67 (q, J=7.7Hz, 1H), 3.76 (m, 2H), 3.51 (d, J=11.6Hz, 1H ), 3.22 (dd, J=11.5, 0.7Hz, 1H), 2.17 (d, J=0.7Hz, 3H), 1.82 (ddt, J=13.7, 9.2, 6.8Hz , 1H), 1.68(m, 1H), 1.45(s, 3H), 1.25(m, 2H), 0.86(m, 3H), 0.62(m, 2H), 0.30(m, 2H).

[1090] 13 C NMR (100MHz, CDCl3): δ174.5, 170.3, 168.2, 164.8, 162.2, 152.4, 100.6, 88.8, 84.2, 73.8, 50.9, 39.9, 34.4, 24.3, 18.9, 13.4, 11.1, 9.3, 3.3 (x2).

[1091] MS (ES+): m / z 422.1 [M+H] + .

[1092] Scheme 26 provides further examples of the synthesis of compounds of formula I:

[1093]

[1094] Plan 26

[1095] Compound 138

[1096] The product was dried over Na2SO4, filtered and evaporated to dryness. The crude residue was purified on a SiO2 column flash chromatography system by eluting with a hexane / EtOAc mixture from 80:20 to 50:50 over 30 minutes to afford 138 (47 mg, 31% yield). Compound epi-138 was also isolated in similar yield.

[1097] Compound 138

[1098] 1 H NMR (400MHz, CDCl3): δ7.18 (d, J=9.3Hz, 1H), 5.89 (d, J=2.2Hz, 1H), 5.42 (d, J=2.2Hz, 1H), 4.82 (td, J=9.0, 5.2Hz, 1H), 3.79 (s, 3H), 3.65-3.4 2(m, 5H), 3.17(d, J=11.7Hz, 1H), 2.24-2.07(m, 3H), 2.09-1.95(m, 1H), 1.60 (s, 3H), 1.54 (s, 3H), 1.22 (t, J = 7.1Hz, 3H), 1.21 (t, J = 7.0Hz, 3H).

[1099] 13 C NMR (100MHz, CDCl3): δ177.2, 174.7, 170.5, 163.2, 161.0, 126.4 (q, J C-F =276Hz, C F3), 100.3, 100.2, 88.8, 85.1, 57.8, 57.6, 56.0, 49.8, 40.2, 30.5 (q, J C-F =30Hz, C H2CF3), 25.5, 25.3, 23.7, 15.12.

[1100] Compound 139

[1101] 2.2Hz, 1H), 5.47 (d, J=2.2Hz, 1H), 4.83 (q, J=7.4, 6.7Hz, 1H), 3.81 (s, 3H), 3.62 (d, J=12.0Hz, 1H), 3.28(d, J=12.0Hz, 1H), 2.55(s, 3H), 2.23-2.04(m, 4H), 1.56(s, 3H).

[1102] 13 C NMR (100MHz, CDCl3): δ193.1, 173.6, 170.6, 163.5, 162.6, 160.0, 126.4 (q, J C-F =276Hz, C F3), 101.2, 89.1, 86.0, 56.2, 50.0, 40.0, 30.5 (q, J C-F =30Hz, C H2CF3), 26.3, 25.8, 24.6.

[1103] Compounds 140 and 140a

[1104]

[1105] A mixture of 139 (40 mg, 0.095 mmol), ethanol (1.0 mL), water (1.0 mL), hydroxylamine hydrochloride (49 mg, 0.7 mmol) and NaOAc (35 mg, 0.43 mmol) was stirred at 23° C. for 16 h. The ethanol was then concentrated under vacuum, saturated aqueous NaCl solution was added, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed on a SiO2 column flash chromatography system eluting with a hexane / EtOAc mixture from 100:0 to 50:50 over 50 minutes. This purification allowed the separation of two stereoisomers: 140 (21.8 mg, 53% yield over two steps) and 140a (4.8 mg, 12% yield). 140

[1107] 1 H NMR (400MHz, CDCl3): δ8.91 (s, 1H), 7.25 (d, J=9.3Hz, 1H), 5.95 (d, J=2.2Hz, 1H), 5.46 (d, J=2.3Hz, 1H), 4.82 (q, J=8 .1Hz, 1H), 3.80 (s, 3H), 3.53 (d, J=11.7Hz, 1H), 3.23 (d, J=11.6Hz, 1H), 2.22 (s, 3H), 2.22-2.02 (m, 4H), 1.53 (s, 3H).

[1108] 13 C NMR (100MHz, CDCl3): δ174.5, 170.6, 168.2, 163.7, 160.4, 153.2, 126.4 (q, J C-F =276Hz, C F3), 101.0, 89.1, 84.3, 56.1, 50.0, 39.8, 30.5 (q, J C-F =30Hz, C H2CF3), 25.7, 24.8, 11.2.

[1109] 140a

[1110] 1H NMR (400MHz, CDCl3): δ9.12 (s, 1H), 7.17 (d, J=8.8Hz, 1H), 6.03 (d, J=2.2Hz, 1H), 5.50 (d, J=2.2Hz, 1H), 4.80 (q, J=8 .1Hz, 1H), 3.83 (s, 3H), 3.56 (d, J=11.6Hz, 1H), 3.25 (d, J=11.5Hz, 1H), 2.22 (s, 3H), 2.20-1.96 (m, 4H), 1.48 (s, 3H).

[1111] 13 C NMR (100MHz, CDCl3): δ174.4, 170.7, 168.3, 163.9, 160.5, 153.1, 126.4 (q, J (C-F) =277Hz, C F3), 101.1, 93.3, 89.0, 84.3, 56.2, 50.1, 40.1, 30.5 (q, J (C-F) =30Hz, C H2CF3), 25.4, 24.4, 11.2.

[1112] Example 15. Synthesis of other intermediates of general formula II

[1113] Scheme 27 provides other examples of the synthesis of intermediates of formula II

[1114]

[1115] Plan 27

[1116] Synthesis of (R)-142

[1117] To the mixture was added allyl tributyltin (0.34 mL, 1.088 mmol). The reaction mixture was refluxed for 2 hours and concentrated under vacuum. A 2M KF aqueous solution was added to the crude product, and the mixture was stirred at 23 ° C for 30 minutes. Filtered through diatomaceous earth and washed with Et2O to obtain a crude product, which was purified in a flash chromatography (SiO2) automated system to obtain (R)-142 (46.8 mg, 24% yield).

[1118] 1H NMR (400MHz, CDCl3): δ6.48 (dq, J=15.7, 6.7Hz, 1H), 6.24 (s, 1H), 6.18 (dd, J=16.3, 1.8Hz, 1H), 5.94 (d, J=1.5Hz, 1H), 4.92 (m, 1H), 4.46-4.31 (m, 1H), 1.93 (dd, J=6.8, 1.6Hz, 2H), 1.86-1.63 (m, 2H), 1.39-1.23 (m, 2H), 0.98-0.86 (m, 3H).

[1119] MS (ES+): m / z 330.3 [M+Na] + .

[1120] Synthesis of (R)-143

[1121]

[1122] 1 H NMR (400MHz, CDCl3): δ8.24 (dd, J=12.9, 8.5Hz, 2H), 5.81 (td, J=17.3, 7.3Hz, 1H), 5.38 (d, J=10.1Hz, 1H) , 5.16 (d, J=17.1Hz, 1H), 3.88 (d, J=7.3Hz, 2H), 2.07-1.83 (m, 2H), 1.42-1.22 (m, 2H), 1.04-0.78 (m, 3H).

[1123] MS (ES+): m / z 230.3 [M+Na] + , 208.3[M+H] + .

[1124] Example 16. Synthesis of other compounds of general formula I

[1125] Scheme 28 provides further illustrations of the synthesis of compounds of formula I.

[1126]

[1127] Plan 28

[1128] Synthesis of 144

[1129] The resulting residue was purified by flash chromatography over SiO2 (from CH2Cl2 to CH2Cl2:EtOAc 4:4) to afford 144 (60 mg, 58% yield).

[1130] 11H NMR (400 MHz, CD3OD): δ 7.86 (d, J = 8.5 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H), 6.04 - 5.95 (m, 1H), 5.54 (d, J = 2.2 Hz, 1H), 5.48 - 5.23 (m, 2H), 4.75 (dt, J = 9.2, 5.8 Hz, 1H), 4.59 (d, J = 5.4 Hz, 2H), 4.33 (t, J = 4.7 Hz, 2H), 3.77 (t, J = 4.7 Hz, 2H), 3.67 - 3.58 (m, 7H), 3.59 - 3.50 (m, 4H), 3.20 (d, J = 11.5 Hz, 1H), 2.21 (s, 3H), 1.93 - 1.76 (m, 2H), 1.53 (s, 3H), 1.50 - 1.31 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H).

[1131] 13 13C NMR (100 MHz, CD3OD): δ 174.9, 170.7, 167.8, 165.1, 164.0, 152.1, 131.2, 118.0, 99.5, 88.4, 84.3, 74.3, 70.3, 70.2, 70.1, 69.6, 69.5, 69.0, 66.1, 50.8, 39.3, 33.8, 23.5, 18.8, 14.1, 12.5, 10.5.

[1132] MS (ES+): m / z 568.2 [M + H] + , 590.2 [M + Na] + .

[1133] Synthesis of 145

[1134]

[1135] 1H NMR (400MHz, CD3OD): δ7.86 (d, J=8.6Hz, 1H), 6.05 (d, J=2.2Hz, 1H), 5.48 (d, J=2.2Hz, 1H), 4.75 (td, J=8 .8, 5.8Hz, 1H), 4.33 (t, J=4.7Hz, 2H), 3.86 (d, J=7.2Hz, 2H), 3.77 (t, J=4.7Hz, 2H), 3.66-3.59 (m, 7H), 3 .59-3.44(m, 4H), 3.20(d, J=11.6Hz, 1H), 2.22(s, 3H), 1.90-0.76(m, 2H), 1.52(s, 3H), 1.49-1.34(m, 3H ), 1.25-1.21 (m, 1H), 1.17 (t, J=7.0Hz, 3H), 0.98 (t, J=7.4Hz, 3H), 0.67-0.57 (m, 2H), 0.37-0.33 (m, 2H).

[1136] 13 C NMR (100MHz, CD3OD): δ176.3, 176.2, 172.5, 169.1, 166.6, 165.2(x2), 153.5, 101.0, 89.3, 85.7(x2), 75.7, 7 5.3, 71.6(x2), 71.5, 70.9, 70.4, 67.5, 52.2, 52.1, 40.7, 35.3, 35.2, 24.9, 20.2, 15.5, 13.9, 11.9, 10.4, 3.7.

[1137] MS (ES+): m / z 582.2 [M+H] + ,604.2[M+Na] + .

[1138] R f :0.43(CH2Cl2:EtOAc 6:4).

[1139] Synthesis of 146

[1140] Purification by flash chromatography on silica gel (CH 2 Cl 2 :EtOAc) afforded 146 (100 mg, 30% yield).

[1141] 1H NMR (400MHz, CDCl3): δ7.07 (d, J=8.5Hz, 1H), 5.86 (t, J=2.5Hz, 1H), 5.39 (d, J=2.5Hz, 1H ), 4.70 (d, J=7.9Hz, 1H), 4.21 (t, J=6.2Hz, 2H), 3.76 (s, 3H), 3.62 (t, J=6.3Hz, 2H), 3.48 (dd, J=11.8, 3.1Hz, 1H), 3.18 (dd, J=14.5, 9.4Hz, 2H), 2.15 (d, J=2.5Hz, 3H), 1.96-1.50 (m, 6H), 1.48 (s, 3H), 1.42-1.26 (m, 2H), 0.94 (d, J=7.3Hz, 3H), 0.86 (s, 6H), 0.02 (s, 3H).

[1142] 13 C NMR (100MHz, CDCl3): δ174.2, 170.8, 167.9, 164.0, 162.5, 162.4, 151.4, 100.1, 100.0, 88.5, 84.3, 75.4, 74.1, 62.7, 55.9, 50.9, 39.8, 34.7, 30.0(x2), 29.1, 25.9, 25.6, 24.7, 19.0, 18.3, 13.6, 11.8, 6.3, -5.3.

[1143] Synthesis of 147

[1144] The crude product was purified by flash chromatography on silica gel (CH 2 Cl 2 :EtOAc) to afford 147 (54 mg, 37% yield).

[1145] 1 H NMR (400MHz, CDCl3): δ7.06 (d, J=8.8Hz, 1H), 5.87 (dd, J=2.2, 0.5Hz, 1H), 5.40 (d, J=2.3Hz , 1H), 4.71 (td, J=8.3, 6.8Hz, 1H), 4.25 (td, J=6.4, 1.0Hz, 2H), 3.77 (s, 3H), 3.68 (t, J=6.4 Hz, 2H), 3.51 (d, J=11.6Hz, 1H), 3.41-3.27 (m, 3H), 3.18 (d, J=11.6Hz, 1H), 2.17 (s, 3H), 1. 92-1.62 (m, 6H), 1.50 (s, 3H), 1.48-1.29 (m, 2H), 1.29-1.17 (m, 3H), 0.95 (t, J=7.3Hz, 3H).

[1146] 13 13C NMR (100 MHz, CDCl3): δ 174.1, 170.9, 167.9, 164.1, 162.4, 151.6, 100.1, 88.5, 84.3, 75.2, 62.5, 59.3, 55.9, 50.9, 39.9, 34.8, 29.7, 29.1, 25.6, 24.8, 24.3, 19.8, 19.0, 13.7, 13.6, 11.9.

[1147] Synthesis of 148

[1148]

[1149] 1 1H NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.6 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 5.48 (s, 1H), 4.74 (td, J = 8.8, 5.7 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.86 (d, J = 7.2 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 3.58 (dd, J = 11.5, 5.3 Hz, 1H), 3.19 (d, J = 11.5 Hz, 1H), 2.20 (s, 3H), 1.94 - 1.71 (m, 4H), 1.64 - 1.57 (m, 2H), 1.52 (s, 3H), 1.51 - 1.32 (m, 2H), 1.28 - 1.20 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.72 - 0.57 (m, 2H), 0.37 - 0.33 (m, 2H), 0.05 (s, 6H).

[1150] 13 13C NMR (100 MHz, CD3OD): δ 175.0, 171.2, 168.0, 165.3, 163.8, 151.5, 99.7, 87.9, 84.3, 74.9, 73.9, 62.5, 50.8, 39.2, 33.9, 28.8, 25.4, 25.0, 23.5, 18.8, 12.5, 10.4, 9.0, 2.3, -6.6.

[1151] MS (ES+): m / z 608.2 [M + H] + , 630.2 [M + Na] + .

[1152] R f : 0.53 (CH2Cl2∶EtOAc 9∶1).

[1153] Synthesis of 149

[1154] The residue was dried, filtered and evaporated. The resulting residue was purified by flash chromatography over SiO2 (from CH2Cl2 to CH2Cl2:EtOAc 1:1) to afford 149 (0.59 g, 77% yield).

[1155] 1 H NMR (400MHz, CD3OD): δ7.87 (d, J=8.6Hz, 1H), 6.05 (d, J=2.2Hz, 1H), 5.48 (d, J=2.2Hz, 1H), 4 .74 (td, J=8.9, 5.7Hz, 1H), 4.23 (t, J=6.5Hz, 2H), 3.86 (d, J=7.2Hz, 2H), 3.70-3.49 (m, 3H), 3 .19(d, J=11.5Hz, 1H), 2.20(s, 3H), 1.88-1.74(m, 4H), 1.68-1.57(m, 2H), 1.52(s, 3H), 1.50- 1.32 (m, 2H), 1.25-1.20 (m, 1H), 0.98 (t, J=7.4Hz, 3H), 0.70-0.54 (m, 2H), 0.37-0.33 (m, 2H).

[1156] 13 C NMR (100MHz, CD3OD): δ176.4, 172.6, 169.3, 166.7, 165.2, 152.9, 101.1, 89.2, 85.7 ,76.3, 75.3, 62.6, 52.2, 40.7, 35.2, 30.0, 26.8, 24.9, 20.3, 13.9, 11.8, 10.4, 3.7.

[1157] MS (ES+): m / z 494.2 [M+H] + ,516.2[M+Na] + .

[1158] R f :0.46(CH2Cl2:EtOAc 1:1).

[1159] Synthesis 150

[1160] The crude product was purified by flash chromatography on silica gel to afford 150 (15 mg, 19% yield).

[1161] 1H NMR (400MHz, CDCl3): δ7.08 (d, J=8.8Hz, 1H), 5.93-5.86 (m, 1H), 5.42 (d, J=2.2Hz, 1H) , 4.73 (q, J=7.9Hz, 1H), 4.33 (t, J=6.1Hz, 2H), 3.79 (s, 3H), 3.52 (d, J=11.6Hz, 1H), 3. 29 (1, J=6.7Hz, 1H), 3.21 (d, J=11.6Hz, 1H), 2.79 (td, J=7.0, 2.2Hz, 3H), 2.19 (d, J=0. 6Hz, 3H), 2.13 (p, J=6.7Hz, 2H), 1.95-1.70 (m, 2H), 1.52 (s, 3H), 0.97 (t, J=7.3Hz, 3H).

[1162] 13 c NMR (100MHz, CDCl3): δ174.1, 170.9, 167.7, 164.1, 162.4, 152.0, 100.2, 88.6, 84.4, 7 3.4, 56.0, 50.9, 39.9, 38.7, 35.1, 34.8, 32.3, 29.7, 28.8, 24.8, 19.1, 13.6, 12.0, 4.6.

[1163] Synthesis of 151

[1164] The organic layer was evaporated to give a crude product, which was purified by silica gel flash chromatography to afford 151 (7 mg, 26% yield).

[1165] 1 H NMR (400MHz, CDCl3): δ7.07 (d, J=8.8Hz, 1H), 5.89 (d, J=2.2Hz, 1H), 5.41 (d, J=2.2Hz, 1H), 4.79-4.63 (m, 1H), 4.32 (dt, J=10.3, 6.1Hz, 2H), 3.79 (s , 3H), 3.51 (d, J = 11.6Hz, 1H), 3.19 (d, J = 11.6Hz, 1H), 2.83-2.57 (m, 5H), 2.18(s, 3H), 2.08-1.66(m, 4H), 1.56-1.48(m, 2H), 0.96(t, J=7.4Hz, 3H).

[1166] Synthesis of 152

[1167] The crude residue was purified by flash chromatography system on silica gel eluting with a mixture of hexanes:EtOAc from 80:20 to 60:40 over 20 min to give pure 152 (1.47 g, 100% yield).

[1168] 1 H NMR (400MHz, CDCl3): δ7.06 (d, J=8.7Hz, 1H), 6.01-5.88 (m, 1H), 5.90 (d, J=2.1Hz, 1H), 5.42-5.30 (m, 3H), 4.78-4.65 (m, 2H), 4.47 (dt, J=5.6, 1.5Hz, 2H), 4.27 (t, J=6.0Hz, 2H) , 3.50 (d, J=11.6Hz, 1H), 3.22 (q, J=7.9, 6.9Hz, 2H), 3.18 (d, J=11.6Hz, 1H), 2.16 (s, 3H) , 1.94-1.68 (m, 4H), 1.49 (s, 3H), 1.42 (s, 9H), 1.39-1.29 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[1169] 13 C NMR (100MHz, CDCl3): 6174.0, 169.6, 167.7, 164.0, 162.4, 155.9, 151.8, 130.6, 119.5, 100. 3, 89.3, 84.3, 79.1, 73.0, 69.5, 50.9, 39.8, 37.6, 34.7, 29.4, 28.3, 24.7, 19.0, 13.5, 11.8.

[1170] MS (ES+): m / z 587.3 [M+Na] + , 565.3[M+H] + .

[1171] TFA (16 mL). After stirring for 2.5 hours, the reaction mixture was evaporated to dryness. The crude residue was purified by flash chromatography through a CH2Cl2:MeOH mixture from 100:0 to 90:10 over 20 minutes to afford pure 153 (1.4 g, 100% yield).

[1172] 11H NMR (400 MHz, CDCl3): δ 8.07 (s, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.95 (d, J = 2.2 Hz, 1H), 6.01 - 5.86 (m, 1H), 5.43 (d, J = 2.2 Hz, 1H), 5.41 - 5.28 (m, 2H), 4.69 (q, J = 7.9 Hz, 1H), 4.47 (dd, J = 5.6, 1.6 Hz, 2H), 4.28 (td, J = 8.1, 7.3, 4.0 Hz, 2H), 3.55 (d, J = 11.5 Hz, 1H), 3.14 (d, J = 11.6 Hz, 1H), 3.09 (s, 2H), 2.16 (s, 3H), 2.14 - 2.05 (m, 2H), 1.78 (m, 2H), 1.52 (s, 3H), 1.48 - 1.21 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[1173] 13 13C NMR (100 MHz, CDCl3): δ 174.0, 170.1, 167.7, 164.7, 162.4, 152.7, 130.5, 119.5, 100.7, 89.3, 84.3, 71.7, 69.7, 50.9, 40.1, 37.4, 34.6, 27.2, 24.7, 19.0, 13.5, 11.8.

[1174] MS (ES+): m / z 465.2 [M + H] + .

[1175] R f : 0.8 (CH2Cl2∶MeOH 9∶1).

[1176] Synthesis of 154

[1177]

[1178] 1 1H NMR (400 MHz, CD3OD): δ 6.10 (s, 1H), 6.01 (m, 1H), 5.43 (s, 1H), 5.34 (m, 1H), 4.75 (m, 1H), 4.61 (m, 2H), 4.33 (m, 2H), 3.61 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 11.6 Hz, 1H), 3.08 (m, 2H), 2.24 (s, 3H), 2.09 (m, 1H), 1.85 (m, 2H), 1.55 (m, 3H), 1.53 - 1.31 (m, 2H), 0.99 (m, 3H).

[1179] 13C NMR (100MHz, CD3OD): δ174.6, 170.8, 168.1, 165.2, 163.7, 152.5, 131.1, 118.0, 99.8 , 88.5, 88.4, 84.1, 71.6, 69.6, 50.8, 39.3, 36.8, 33.8, 27.1, 23.4, 18.8, 12.4, 10.4.

[1180] MS (ES+): m / z 465.2 [M+H] + .

[1181] Synthesis of 155

[1182] The EtOAc mixture was eluted for 20 min to afford pure 155 (67 mg, 91% yield).

[1183] 1 H NMR (400MHz, CDCl3): δ7.05 (d, J=8.7Hz, 1H), 5.89 (d, J=2.2Hz, 1H), 5.53 (d, J=2.2Hz, 1H), 4.76 (tt, J= 3.8, 2.0Hz, 1H), 4.71 (td, J=8.4, 6.8Hz, 1H), 4.64 (d, J=2.4Hz, 2H), 4.26 (t, J=6.1Hz, 2H), 3.49 (d, J=1 1.6Hz, 1H), 3.21 (q, J=9.6, 8.0Hz, 2H), 3.18 (d, J=11.6Hz, 1H), 2.62 (t, J=2.4Hz, 1H), 2.16 (s, 3H), 1.9 5-1.78 (m, 3H), 1.81-1.66 (m, 1H), 1.49 (s, 3H), 1.41 (s, 9H), 1.46-1.25 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[1184] 13 C NMR (100MHz, CDCl3): δ174.0, 168.6, 167.7, 163.6, 162.8, 155.9, 151.8, 99.9, 90.0, 84.3 ,79.1,77.7,75.6,73.0,56.4,50.9,39.8,37.6,34.7,29.4,28.3,24.7,19.0,13.5,11.8.

[1185] Synthesis of 156

[1186]

[1187] 11H NMR (400 MHz, CDCl3): δ 7.02 (d, J = 8.8 Hz, 1H), 5.97 (d, J = 2.2 Hz, 1H), 5.58 (d, J = 2.2 Hz, 1H), 4.72 (q, J = 7.9 Hz, 1H), 4.66 (d, J = 2.5 Hz, 2H), 4.37 - 4.23 (m, 2H), 3.56 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 11.6 Hz, 1H), 3.11 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 2.4 Hz, 1H), 2.16 (s, 3H), 2.13 - 2.05 (m, 2H), 1.90 - 1.67 (m, 2H), 1.53 (s, 3H), 1.4g - 1.26 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

[1188] 13 13C NMR (100 MHz, CDCl3): δ 174.2, 169.2, 167.8, 164.5, 162.8, 152.8, 100.5, 90.1, 84.3, 77.8, 75.6, 71.8, 56.6, 50.9, 40.1, 37.6, 34.6, 27.2, 24.7, 19.0, 13.5, 11.8.

[1189] Synthesis of 157

[1190]

[1191] 1 1H NMR (400 MHz, CDCl3): δ 7.09 (t, J = 8.0 Hz, 1H), 5.92 (d, J = 2.2 Hz, 1H), 5.35 (t, J = 1.7 Hz, 1H), 4.79 - 4.68 (m, 1H), 4.64 (s, 1H), 4.28 (t, J = 6.0 Hz, 1H), 3.76 (dd, J = 7.1, 1.9 Hz, 2H), 3.52 (dd, J = 11.6, 8.6 Hz, 1H), 3.28 - 3.14 (m, 4H), 2.18 (s, 3H), 2.07 - 1.95 (m, 2H), 1.90 (dd, J = 8.0, 4.9 Hz, 1H), 1.69 (s, 2H), 1.51 (d, J = 2.9 Hz, 3H), 1.43 (s, 9H), 1.25 (d, J = 2.₂ Hz, 3H), 0.96 (td, J = 7.3, 1.5 Hz, 3H), 0.66 (q, J = 6.1 Hz, 1H), 0.33 (dt, J = 6.1, 4.7 Hz, 1H).

[1192] Synthesis of 158

[1193] TFA (0.1 mL) was added to the precipitate. After stirring for 30 minutes, the reaction mixture was evaporated to dryness. The crude residue was purified by flash chromatography using a mixture of CH2Cl2:MeOH from 100:0 to 85:15 to afford pure 158 (4.9 mg, 49% yield).

[1194] 1 H NMR (400MHz, CDCl3): δ7.85 (s, 1H), 7.03 (d, J=8.9Hz, 1H), 6.01 (d, J=2.1Hz, 1H), 5.44 (d, J=2.2Hz, 1H ), 4.72 (q, J=7.9Hz, 1H), 4.30 (dt, J=12.0, 5.9Hz, 2H), 3.76 (dd, J=7.2, 1.7Hz, 2H), 3.58 (d, J=11.6Hz , 1H), 3.15 (d, J=11.6Hz, 1H), 2.36 (s, 1H), 2.17 (s, 3H), 2.10 (q, J=5.3, 4.3Hz, 2H), 1.79 (m, 2H), 1.55 (s, 3H), 1.36 (m, 2H), 1.27-1.15 (m, 1H), 0.95 (t, J=7.3Hz, 3H), 0.70-0.60 (m, 2H), 0.38-0.25 (m, 2H).

[1195] 13 C NMR (100MHz, CDCl3): δ174.2, 170.9, 167.9, 165.6, 162.2, 152.9, 101.4, 89.0, 84. 3, 74.2, 72.0, 50.9, 40.2, 37.8, 34.5, 27.2, 24.7, 19.1, 13.5, 11.8, 9.3, 3.3 (x2).

[1196] Synthesis of 159

[1197] 159 (60 mg, g 1% yield).

[1198] 1H NMR (400MHz, CD3OD): δ77.85 (d, J=8.6Hz, 1H), 6.05s, 1H), 5.48 (s, 1H), 4.75 (td, J=8.6, 5.8Hz, 1H), 4.30 (t , J=6.3Hz, 2H), 4.21 (p, J=6.3Hz, 1H), 4.08 (dt, J=8.0, 4.8Hz, 1H), 3.86 (d, J=7.2Hz, 2H), 3.70-3.48 (m, 2H) , 3.20 (d, J=11.5Hz, 1H), 2.20 (s, 3H), 1.99-1.93 (m, 2H), 1.91-1.76 (m, 2H), 1.52 (s, 3H), 1.50-1.38 (m, 2H) , 1.37 (s, 3H), 1.31 (s, 3H), 1.28-1.14 (m, 1H), 0.98 (t, J=7.3Hz, 3H), 0.71-0.50 (m, 2H), 0.36-0.33 (m, 2H).

[1199] 13 c NMR (100MHz, CD3OD): δ174.9, 171.2, 167.8, 165.3, 163.8, 151.9, 108.5, 99.7, 87.9, 84.3, 7 3.9, 73.3, 71.9, 69.1, 50.8, 39.3, 33.9, 32.9, 25.9, 24.6, 23.5, 18.9, 12.5, 10.5, 8.98, 2.3.

[1200] MS (ES+): m / z 550.3 [M+H] + ,572.3[M+Na] + .

[1201] R f :0.5(CH2Cl2:EtOAc 8:2).

[1202] Example 17: Synthesis of other compounds of general formula I

[1203] Scheme 29 provides other examples of the synthesis of compounds of formula I

[1204]

[1205] Plan 29

[1206] Synthesis 160

[1207] MeOH) to afford 160 (28 mg, 48% yield) as a mixture of geometric stereoisomers at a ratio of ca. (50:50) as a light orange oil.

[1208] 1 H NMR (500MHz, CDCl3): δ7.08 (d, J=8.8Hz, 1H) 7.02 (d, J=8.5Hz, 1H), 5.99 (d, J=2.3Hz, 1H), 5.98-5.91 (m, 2H), 5.90 (d, J=2.2Hz, 1H), 5.43-5.38 (m, 6H), 4.71 (q, J=7.8, 6.9Hz, 1H), 4.67 (q, J=7.8, 6.9Hz, 1H), 4.49 (m, 4H), 4.23 (td, J=6.4, 5.3Hz, 4H), 3.71 (t, J=4.9Hz, 8H), 3.54 (d, J=11.6 Hz, 1H), 3.49 (d, J=11.6Hz, 1H), 3.20 (d, J=2.3Hz, 1H), 3.17 (d, J=2.3Hz , 1H), 2.45(bs, 8H), 2.39-2.36(m, 4H), 2.15(s, 6H), 1.92-1.80(m, 2H), 1.79-1.64(m, 6H), 1.59(pd, J=6.8, 6.1, 3.4Hz, 4H), 1.49(s, 3H), 1.46( s, 3H), 1.43-1.25 (m, 4H), 0.94 (t, J=7.4Hz, 3H), 0.90 (t, J=7.4Hz, 3H).

[1209] MS (Es+): m / z 571.3 [M+Na] + , 549.2[M+H] + .

[1210] R f :0.15 (EtOAc).

[1211] The brown thick residue was dried in a vacuum assisted oven overnight to afford 161 (146 mg, 85% yield) as a light brown solid as a mixture of approximately (50:50) geometric stereoisomers.

[1212] 1H NMR (400MHz, CDCl3): δ8.67 (brs, 1H), 8.58 (brs, 1H), 6.10-5.87 (m, 4H), 5.48-5.30 (m, 6H), 4.75-4.59 (m, 2H), 4.49 (brt, J=6.4Hz, 4H), 4.44- 3.40 (m, 16H), 2.38 (brs, 6H), 1.97-1.72 (m, 12H), 1.70-1.23 (m, 16H), 1.22 (s, 3H), 1.20 (s, 3H), 0.95 (t, J = 7.4Hz, 3H), 0.91 (t, J = 7.2Hz, 3H).

[1213] MS (ES+): m / z 549.3 [M+H] + .

[1214] Synthesis of 162

[1215] The mixture was treated with a buffer solution, stirred and extracted with CH Cl (4 x 25 mL). The combined organic layers were dried over anhydrous Na SO, filtered and concentrated in vacuo. The resulting crude brown oil was purified by chromatography (SiO, EtOAc: MeOH from 90: 0 to 0: 100) to afford 162 (42 mg, 97% yield) as a mixture of approximately (50: 50) geometric stereoisomers as a white solid.

[1216] 1H NMR (500MHz, (CD3)2SO): δ7.87 (m, 2H), 6.11 (d, J=2.1Hz, 1H), 6.01 (d, J=2.2Hz, 1H), 6.04-5.93 (m, 2H), 5.60 (d, J=2.2Hz, 1H), 5.57 (d, J=2.2H z, 1H), 5.42 (ddd, J=12.4, 1.6, 0.7Hz, 1H), 5.38 (ddd, J=12.3, 1.6, 0.7Hz, 1H), 5.36-5.25 (m, 2H), 4.62 (d, J=5.5Hz, 2H), 4.60 (d, J=5.6Hz, 2H) , 4.58-4.51 (m, 2H), 4.19 (td, J=6.4, 2.3Hz, 4H), 3.60-3.52 (ddd, J=11.4, 7.9, 0.7Hz, 2H), 3.19 (ddd, J=11.4, 7.9, 0.7Hz, 2H), 2.45-2.20 (m, 2 0H), 2.15(s, 6H), 2.13(s, 6H), 1.82-1.70(m, 10H), 1.45(s, 3H), 1.43(s , 3H), 1.42-1.16 (m, 16H), 0.89 (t, J=7.4Hz, 3H), 0.85 (t, J=7.4Hz, 3H).

[1217] MS (ES+): m / z 570.3 [M+Na] + , 548.2[M+H] + .

[1218] Synthesis of 163

[1219] A mixture of geometric stereoisomers.

[1220] 1 H NMR (400MHz, CDCl3): δ8.30-8.50 (m, 1H), 6.07-5.88 (m, 4H), 5.48-5.30 (m, 6H), 4.75-4.60 (m, 2H), 4.49 (brt, J=6.4Hz, 4H), 4.44-2.63 (m, 1 6H), 2.94 (brs, 6H), 2.51-2.15 (m, 3H), 2.33 (brs, 6H), 2.10-1.54 (m, 14H), 1.52-1.17 (m, 11H), 0.96 (t, J=7.4Hz, 3H), 0.91 (t, J=7.2Hz, 3H).

[1221] MS (ES+): m / z 548.2 [M+H] + .

[1222] Example 18: Synthesis of other compounds of general formula I

[1223] Scheme 30 provides other examples of the synthesis of compounds of formula I

[1224]

[1225] Plan 30

[1226] Synthesis of 164

[1227] The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product as an oil.

[1228] The crude product was purified by flash chromatography using a reverse phase column with a gradient of 10% CH 3 CN in 5 min; 50% CH 3 CN in 20 min and 50% CH 3 CN in 15 min to afford 164 (22 mg, 31% yield).

[1229] 1 H NMR (400MHz, CD3OD): δ8.10-8.03 (m, 1H), 6.74-6.67 (m, 1H), 6.13-5.95 (m, 2H), 5.55 (d, J=2.2Hz, 1H), 5.49 (d, J= 0.9Hz, 1H), 5.42 (dd, J=17.3, 1.6Hz, 1H), 5.33 (dt, J=10.5, 1.2Hz, 1H), 5.05 (s, 2H), 4.75 (dd, J=9.2, 5.7Hz, 1H), 4.63-4.56 (m, 2H), 3.69-3.51 (m, 4H), 3.40-3.28 (m, 11H), 3.18 (dd, J=11.5, 0.8Hz, 1H), 3.08 (d, J=0.8Hz, 3H), 2. 19 (d, J=0.8Hz, 3H), 1.94-1.75 (m, 1H), 1.53 (d, J=0.8Hz, 3H), 1.47-1.32 (m, 1H), 1.29 (s, 1H), 1.04-0.95 (m, 3H).

[1230] 13 C NMR (100MHz, CD3OD): δ152.9, 132.6, 119.4, 107.9, 100.9, 89.8, 85.6, 71.0, 52.2, 49.5, 49.0, 48.9, 40.6, 39.3, 35.2, 25.0, 20.3, 13.8, 11.0.

[1231] MS (ES+): m / z 590.2 [M+Na] +, 568.3[M+H] + .

[1232] R f :0.27 (CH2Cl2: EtOAc 6:4).

[1233] Synthesis of 165

[1234] (30 mg, 99% yield), which was used in the next step without further purification.

[1235] 1 H NMR (400MHz, (CD3)2CO): δ8.12 (d, J=5.7Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 6.56 (d, J=5.8Hz, 1H), 6.09-5.85 (m , 2H), 5.48-5.38 (m, 2H), 5.31 (d, J=10.5Hz, 1H), 4.89-4.68 (m, 1H), 4.61 (d, J=5.5Hz, 2H), 3.69 (d, J=11.6H z, 1H), 3.30 (d, J=11.6Hz, 1H), 3.08 (q, J=6.7Hz, 2H), 2.99 (s, 3H), 2.79 (s, 4H), 2.56 (t, J=7.4Hz, 2H), 2.34 (s, 3H), 1.90-1.62 (m, 4H), 1.55 (s, 4H), 1.39 (s, 9H), 1.12 (dd, J=21.1, 11.4Hz, 1H), 0.96 (t, J=7.4Hz, 3H).

[1236] MS (Es+): m / z 621.2 [M+H] + ,643.2[M+Na] + .

[1237] Synthesis of 166

[1238]

[1239] 1H NMR (400MHz, (CD3)2CO): δ8.17-8.00 (m, 1H), 7.49 (d, J=8.6Hz, 1H), 6.62-6.51 (m, 1H), 6.01 (d, J=2.3Hz, 1H), 5.94 (s, 1H ), 5.36 (d, J = 2.2Hz, 1H), 4.83-4.68 (m, 1H), 3.88 (dd, J = 7.1, 2.3Hz, 2H), 3.69 (d, J = 11.6Hz, 1H), 3.31 (d, J = 11.6Hz, 1H), 3 .07 (q, J=6.6Hz, 2H), 2.99 (s, 3H), 2.81 (d, J=12.4Hz, 4H), 2.56 (t, J=7.4Hz, 2H), 2.35 (s, 3H), 1.76 (m, 2H), 1.55 (s, 3H), 1.53-1.44 (m, 2H), 1.39 (s, 9H), 1.33-1.18 (m, 1H), 0.96 (t, J=7.3Hz, 3H), 0.64-0.56 (m, 2H), 0.36 (dt, J=6.1, 4.4Hz, 2H).

[1240] MS (ES+): m / z 657.2 [M+Na] + .

[1241] Synthesis of 167

[1242] The crude product 167 (76 mg, 99% yield) was obtained and used in the next step without further purification.

[1243] 1H NMR (400MHz, CD3OD): δ8.03 (d, J=6.3Hz, 1H), 7.76 (d, J=7.5Hz, 2H), 7.65 (d, J=7.5Hz, 2H), 7.35 (t, J=7.5Hz, 2H), 7.27 (t, J=7. 5Hz, 2H), 6.69 (d, J=6.3Hz, 1H), 6.05 (d, J=2.2Hz, 1H), 5.97-5.87 (m, 1H), 5.48 (d, J=2.2Hz, 1H), 5.39-5.18 (m, 2H), 4.75 (dd, J= 9.1, 5.9Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 4.41-4.32 (m, 2H), 4.27 (d, J=6.6Hz, 1H), 4.20 (t, J=6.9Hz, 1H), 3.67 (d, J=11.6Hz, 1H) , 3.27(d, J=11.5Hz, 1H), 2.34(s, 3H), 2.26-2.14(m, 1H), 1.91-1.75(m, 2H), 1.53(s, 3H), 1.51-1.17(m, 2H), 1.07-0.89(m, 9H).

[1244] 13 C NMR (100MHz, CD3OD): δ174.3, 170.7, 168.7, 165.1, 164.0, 163.4, 160.4, 157.4, 143.8, 141.2, 131.1, 127.2, 126.8, 124 .8, 119.6, 118.0, 99.6, 88.6, 84.5, 69.6, 66.6, 59.1, 50.8, 39.9, 35.5, 33.8, 30.3, 23.4, 18.9, 18.2, 17.3, 12.5, 12.3.

[1245] MS (ES+): m / z 729.2 [M+H] + ,751.2[M+Na] + .

[1246] Synthesis of 168

[1247]

[1248] The crude product 168 (69 mg, 99% yield) was obtained and used in the next step without further purification.

[1249] 1H NMR (400MHz, CD3OD): δ8.04-8.03 (m, 1H), 7.77 (d, J=7.5Hz, 2H), 7.65 (d, J=7.5Hz, 2H), 7.37 (t, J=7.5Hz, 2H), 7.29 (t, J= 7.4Hz, 2H), 6.85 (d, J=6.8Hz, 1H), 6.05 (d, J=2.2Hz, 1H), 5.98-5.91 (m, 1H), 5.50 (d, J=2.3Hz, 1H), 5.42-5.19 (m, 2H), 4. 75 (dd, J=9.2, 5.7Hz, 1H), 4.53 (d, J=5.8Hz, 2H), 4.35 (d, J=7.1Hz, 2H), 4.21 (t, J=7.2Hz, 1H), 4.13 (s, 2H), 3.68 (d, J=11 .6Hz, 1H), 3.27 (d, J=11.5Hz, 1H), 2.34 (s, 3H), 1.87-1.79 (m, 2H), 1.54 (s, 3H), 1.50-1.27 (m, 2H), 0.97 (t, J=7.3Hz, 3H).

[1250] 13 C NMR (100MHz, CD3OD): δ174.3, 170.7, 168.7, 165.1, 164.0, 163.4, 160.4, 157.3, 143.8, 141.2, 131.1, 127.4, 126.8 (x2), 1 24.8, 119.6, 118.0, 99.5, 88.5, 84.5, 69.6, 66.6, 59.1, 50.8, 39.9, 35.6, 33.8, 30.3, 23.4, 18.9, 18.2, 17.3, 12.5, 12.3.

[1251] MS (ES+): m / z 687.2 [M+H] + ,709.3[M+Na] + .

[1252] Synthesis of 169

[1253] Product 169 (35 mg, 99% yield) was used in the next step without further purification.

[1254] 1H NMR (400MHz, (CD3)2CO): δ8.24-8.09 (m, 1H), 7.54 (d, J=8.7Hz, 1H), 6.71-6.51 (m, 2H), 6.13-5.93 (m , 2H), 5.42 (dd, J=15.1, 2.0Hz, 2H), 5.36-5.24 (m, 1H), 4.75 (dt, J=8.9, 4.5Hz, 1H), 4.67-4.55 (m, 2H ), 4.10 (d, J = 6.0Hz, 2H), 3.75-3.64 (m, 1H), 3.31 (d, J = 11.6Hz, 1H), 3.06 (s, 3H), 2.35 (s, 3H), 1.96- 1.69 (m, 2H), 1.56 (s, 3H), 1.53-1.44 (m, 1H), 1.44 (s, 9H), 1.33-1.23 (m, 1H), 0.96 (t, J=7.4Hz, 3H).

[1255] 13 C NMR (100MHz, (CD3)2CO): δ172.9, 169.7, 167.5, 164.3, 162.7, 159.6, 147.2, 131.7, 118.3, 106. 6, 98.8, 88.5, 84.7, 78.7, 69.4, 50.8, 41.3, 40.1, 38.4, 34.2, 27.7 (×2), 24.0, 19.0, 13.0, 12.4.

[1256] MS (ES+): m / z 565.2 [M+H] + ,587.3[M+Na] + .

[1257] Synthesis of 170

[1258] The product was purified by HPLC to afford 170 (25 mg, 57% yield).

[1259] 1H NMR (500MHz, (CD3)2CO): δ7.51 (d, J=8.7Hz, 1H), 6.05-5.99 (m, 1H), 6.02 (s, 1H), 5.63 (d, J=5.1Hz, 1 H), 5.52-5.36 (m, 2H), 5.31 (d, J=10.5Hz, 1H), 4.85-4.67 (m, 4H), 4.61 (d, J=5.5Hz, 2H), 4.50 (dd, J=5 .1, 2.6Hz, 1H), 3.70 (d, J=11.6Hz, 1H), 3.33 (d, J=11.6Hz, 1H), 2.37 (s, 3H), 1.95-1.69 (m, 2H), 1.56- 1.29 (m, 2H), 1.56 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 0.97 (t, J=7.4Hz, 3H).

[1260] 13 C NMR (125MHz, (CD3)2CO): δ173.8, 170.6, 167.1, 165.2, 163.6, 161.1, 132.7, 119.2, 109.7, 99.8, 97.4, 89 .5, 85.7, 73.0, 71.9, 71.1, 70.3, 69.0, 51.8, 41.1, 35.2, 26.4, 26.2, 25.1, 25.0, 24.9, 20.0, 13.9, 13.5.

[1261] MS (Es+): m / z 664.2 [M+H] + ,686.3[M+Na] + .

[1262] Synthesis of 171

[1263] 99% yield) which was used in the next step without further purification.

[1264] 1H NMR (400MHz, (CD3)2CO): δ7.50 (d, J=8.7Hz, 1H), 6.08-5.98 (m, 1H), 6.02 (s, 1H), 5. 52-5.37 (m, 2H), 5.31 (d, J=10.6, 1H), 4.75 (td, J=8.9, 5.7Hz, 1H), 4.61 (dt, J=5.5, 1 .6Hz, 2H), 4.32 (q, J=7.1Hz, 2H), 3.70 (d, J=11.6Hz, 1H), 3.31 (d, J=11.6Hz, 1H), 2. 34(s, 3H), 1.96-1.68(m, 2H), 1.55(s, 3H), 1.68-1.16(m, 5H), 0.96(t, J=7.3Hz, 3H).

[1265] MS (Es+): m / z 480.3 [M+H] + ,502.2[M+Na] + .

[1266] Synthesis of 172

[1267] The reaction mixture was heated to 23°C and stirred for 1 hour. The reaction solution was diluted with saturated aqueous Na2S2O3 solution, extracted with EtOAc, and washed with saturated aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The resulting residue was purified by SiO2 flash chromatography (hexane:EtOAc from 100:0 to 50:50) to give 172 (26 mg, 32% yield).

[1268] 1 H NMR (400MHz, CD3OD): δ7.92 (d, J=8.6Hz, 1H), 7.40-7.32 (m, 10H), 6.07 (d, J=2.2Hz, 1H), 6.05-5.8 9 (m, 1H), 5.51 (d, J=2.2Hz, 1H), 5.38 (dd, J=17.3, 1.6Hz, 1H), 5.29 (dd, J=10.5, 1.5Hz, 1H), 5.21 (s , 2H), 5.19 (s, 2H), 4.80-4.74 (m, 1H), 4.54 (dt, J=5.6, 1.5Hz, 2H), 3.70 (d, J=11.6Hz, 1H), 3.36-3 .17 (m, 1H), 2.22 (s, 3H), 1.97-1.71 (m, 2H), 1.55 (s, 3H), 1.55-1.21 (m, 2H), 0.98 (t, J=7.4Hz, 3H).

[1269] 13 C NMR (125MHz, CD3OD): δ175.6, 172.1, 167.2, 166.0, 165.3, 162.9, 162.8, 136.8, 136.7, 132.5, 129.8, 129.7, 129.6 (x3), 129.7, 129.3(x3), 129.2, 119.5, 101.0, 89.8, 85.9, 72.1(x2), 72.0(x2), 71.0, 52.2, 41.2, 35.2, 24.7, 20.3, 13.8, 12.7.

[1270] MS (ES+): m / z 668.3 [M+H] + ,690.2[M+Na] + .

[1271] Example 19. Synthesis of other compounds of formula 1

[1272] Scheme 31 provides further examples of the synthesis of compounds of formula 1

[1273]

[1274] Plan 31

[1275] Synthesis of 173

[1276] The product was diluted with CH2Cl2 before washing twice with 0.5N HCl and once with a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified on a silica gel (Hex:EtOAc) flash chromatography system to give 173 (20 mg, 68% yield).

[1277] 1 H NMR (400MHz, CDCl3): δ7.12-7.04 (m, 1H), 6.45 (dq, J=15.8, 6.8Hz, 1H), 6.19 (d, J=1.5Hz, 1H), 6.18-6.10 (m, 1H), 5.92-5.88 (m, 1H), 4.75 (1d, J=8.5, 6.5Hz, 1H), 3.63 (d, J=11.7Hz , 1H), 3.60-3.44 (m, 4H), 3.15 (dd, J=11.7, 0.8Hz, 1H), 1.91 (dd, J=6.7, 1.6Hz, 2H), 1.89- 1.67(m, 2H), 1.60(s, 3H), 1.55(s, 3H), 1.46-1.27(m, 2H), 1.21(m, 6H), 0.96-0.90(m, 3H).

[1278] 13 C NMR (100MHz, CDCl3): δ178.3, 174.1, 162.9, 161.8, 151.8, 136.2, 128.1, 109.5, 100.4, 100.3, 85.0, 58.0, 57.9, 51.3, 40.6, 35.0, 28.0, 27.0, 25.5, 23.9, 19.3, 19.0, 18.9, 17.7, 15.4, 15.3, 13.7(x2).

[1279] MS (ES+): m / z 473.1 [M+Na] + .

[1280] Synthesis of 174

[1281] A mixture of 173 (20 mg, 0.044 mmol), pentane (1 mL) and formic acid (0.7 mL) was vigorously stirred for 2 hours and the volatiles were evaporated. The crude product was evaporated several times with a mixture of CH2Cl2 / toluene to remove the acid. The crude product was purified by silica gel chromatography.

[1282] (dd, J=6.7, 1.6Hz, 3H), 1.90-1.59 (m, 4H), 1.55 (s, 3H), 1.49-1.23 (m, 2H), 0.97 (t, J=7.4Hz, 3H).

[1283] MS (ES+): m / z 399.2 [M+Na] + , 377.1[M+H] + .

[1284] Synthesis of 175

[1285] The crude product was concentrated and chromatographed on silica gel (hex:EtOAc) to afford 175 (2 mg, 34% yield).

[1286] 1H NMR (400MHz, CD3OD): δ6.66-6.52 (m, 1H), 6.41 (s, 1H), 6.29 (d, J=15.8Hz, 1H), 5.98 (s, 1H), 4.80 (m, 1H), 3.61 (dd, J=11.5, 1.1Hz, 1H), 3.17 (dd , J=11.5, 1.1Hz, 1H), 2.20 (d, J=1.1Hz, 3H), 1.92 (dt, J=6.8, 1.4Hz, 3H) , 1.92-1.79 (m, 2H), 1.57 (s, 3H), 1.34-1.13 (m, 2H), 1.00 (t, J=7.4, 3H).

[1287] 13 C NMR (100MHz, CD3OD): δ176.5, 170.4, 165.3, 164.1, 154.5, 152.9, 138.4, 1 28.9, 109.5, 101.0, 85.7, 40.7, 35.4, 30.4, 25.3, 20.3, 19.0, 13.9, 11.0.

[1288] MS (ES+): m / z 399.2 [M+Na] + , 377.1[M+H] + .

[1289] Example 20. Synthesis of other compounds of formula I

[1290] Scheme 32 provides further examples of the synthesis of compounds of formula I

[1291]

[1292] Plan 32

[1293] Synthesis of 176

[1294] The product was diluted with CH2Cl2 before use. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified on a silica gel (CH2Cl2:EtOAc) flash chromatography system to give 176 (660 mg, 63% yield).

[1295] 1H NMR (400MHz, CDCl3): δ6.98 (d, J=8.8Hz, 1H), 5.90-5.73 (m, 1H), 5.28 (dd, J=2.2, 1.2Hz, 1H), 5.14 ( ddd, J=10.1, 8.4, 1.3Hz, 1H), 4.71 (td, J=8.4, 6.5Hz, 1H), 3.71 (ddd, J=7.2, 3.2, 1.1Hz, 2H), 3.61- 3.38(m, 5H), 1.89-1.75(m, 1H), 1.74-1.59(m, 1H), 1.57(d, J=1.5Hz, 3H), 1.42-1.25(m, 2H), 1.24- 1.11 (m, 6H), 0.89 (td, J=7.3, 1.3Hz, 3H), 0.61 (dt, J=8.0, 1.0Hz, 1H), 0.28 (dt, J=4.8, 1.2Hz, 2H).

[1296] 13 c NMR (100MHz, CDCl3): δ170.8, 170.0, 164.0, 162.7, 88.7, 78.8, 77.4, 77.1, 76 .8, 73.7, 57.8, 50.9, 34.6, 34.2, 23.8, 19.0, 15.2, 15.1, 13.5, 9.4, 3.3(x2).

[1297] MS (ES+): m / z 489.2 [M+Na] + .

[1298] Co-evaporated with toluene twice.The crude product was purified by flash chromatography on silica gel (CH2Cl2:EtOAc) to afford 177 (23 mg, 40% yield).

[1299] 1 H NMR (400MHz, CDCl3): δ6.99 (d, J=8.8Hz, 1H), 5.95 (d, J=2.2Hz, 1H), 5.35 (d, J=2 .2Hz, 1H), 5.24 (dd, J=10.9, 10.2Hz, 1H), 4.77 (q, J=7.7Hz, 1H), 3.77 (td, J=6.9, 1.8Hz, 2H), 3.68-3.48(m, 2H), 2.55(s, 3H), 1.95-1.69(m, 2H), 1.48-1.17(m, 2H) , 0.96 (t, J=7.3Hz, 3H), 0.66 (dd, J=8.0, 1.2Hz, 2H), 0.33 (td, J=4.7, 2.2Hz, 2H).

[1300] 13 C NMR (100MHz, CDCl3): δ192.9, 172.8, 170.1, 169.4, 164.1, 161.8, 100.8, 88.9, 80.1, 73.9, 51.3, 34.8, 34.2, 26.3, 19.1, 13.6, 9.4, 3.4 (x2).

[1301] MS (ES+): m / z 393.2 [M+H] + ,415.3[M+Na] + .

[1302] Synthesis of 178

[1303] Purification by flash chromatography on (CH 2 Cl 2 :EtOAc) afforded 178 (14 mg, 61% yield).

[1304] 1 H NMR (400MHz, CD3OD): δ6.17 (dd, J=2.2, 0.8Hz, 1H), 5.50 (d, J=2.2Hz, 1H), 5.17 (d, J=9.4Hz, 1H), 4.73 (dd, J=9.3, 5.5Hz, 1H), 3.88 (dd, J=8.4, 7.2Hz, 2 H), 3.54-3.35 (m, 2H), 2.16 (d, J=3.1Hz, 3H), 1.96-1.70 (m, 2H), 1.59-1.34 (m, 2H), 0.98 (dt, J=10.4, 7.3Hz, 3H), 0.71-0.60 (m, 2H), 0.44-0.30 (m, 2H).

[1305] 13 C NMR (100MHz, CD3OD): δ171.4, 171.3, 170.9, 165.5, 164.0, 151.5, 99.7, 87.7, 78.7, 74.0, 73.9, 50.9, 33.8, 32.7, 18.8, 12.4, 9.6, 9.0, 2.2.

[1306] MS (ES+): m / z 408.2 [M+H] + ,430.1[M+Na] + .

[1307] Example 21. Synthesis of other compounds of formula 1

[1308] Scheme 33 provides further examples of the synthesis of compounds of formula I

[1309]

[1310] Plan 33

[1311] Synthesis of 179

[1312] A freshly prepared stock solution of Pd(PhCN)(OTf) catalyst in CHCl (700 μL; 5% mol), prepared by stirring Pd(PhCN)Cl (9 mg; 0.024 mmol) and AgOTf (12 mg; 0.047 mmol) in CHCl for 5 minutes, was added to a solution of 109 (37 mg; 0.0091 mmol) and 74 (50 mg; 0.139 mmol) in CHCl (500 μL) at 23°C. The reaction mixture was stirred at 23°C overnight, then treated with benzene (1 mL) and poured directly onto a chromatography column (SiO, CHCl:MeOH from 10:0 to 98.2:1.8). Following this procedure, compound 179 (31 mg, 51% yield) was obtained as a foamy white solid (primarily the α-isomer).

[1313] 1 H NMR (400MHz, CDCl3): δ9.38 (s, 1H), 7.14 (dd, J=8.8, 2.9Hz, 1H), 5.93 (dd, J=4.3, 2.1Hz, 1H), 5.67 (s, 1H), 5.37 (t, J=2.2Hz, 1H), 4.91 (dd, J=6.0 , 3.9Hz, 1H), 4.87 (d, J=5.9Hz, 1H), 4.73 (q, J=8.5, 7.9Hz, 1H), 4.38 (dt, J=7.8, 5.2Hz, 1H), 4.22 (dd, J=7.7, 3.8Hz, 1H), 4.08 (brs, 1H), 4.07 (s, 1 H), 3.84-3.69 (m, 2H), 3.52 (d, J=11.6Hz, 1H), 3.22 (dd, J=11.6, 2.3Hz, 1H), 2.22(s, 3H), 2.19(s, 3H), 1.93-1.71(m, 2H), 1.51(s, 3H), 1.49(s, 3 H), 1.45(s, 3H), 1.37(s, 3H), 1.35(s, 3H), 1.45-1.30(m, 1H), 1.30-1.12 (m, 1H), 0.95 (t, J=7.3Hz, 3H), 0.66 (m, 2H), 0.33 (dt, J=6.0, 4.7Hz, 2H).

[1314] 13C NMR (100MHz, CDCl3): δ174.3, 174.1, 170.3, 170.2, 168.2, 167.5, 164.5, 164.4, 162.4, 162.2, 153.8, 153. 1, 112.9, 109.3, 109.0, 108.9, 100.9, 100.7(x2), 100.6, 89.1(x2), 89.0(x2), 84.8, 84.6(x2), 84.4, 83.3 , 83.2, 80.1, 79.8, 74.1, 74.0, 73.8, 73.5, 66.8, 51.2, 51.1, 40.0, 39.9(x2), 35.0, 34.9, 27.1, 27.0, 26.1 , 26.0, 25.3, 25.2, 24.9, 24.8, 24.7, 24.6, 24.5, 19.2, 13.7(x2), 12.2(x2), 11.4, 11.3, 9.6, 9.5, 3.5(x2).

[1315] MS (ES+): m / z 664.2 [M+H] + ,686.3[M+Na] + .

[1316] Scheme 34 provides an illustration of the synthesis of additional compounds of Formula I.

[1317]

[1318] Plan 34

[1319] Synthesis of 180

[1320] 179 (30 mg; 0.045 mmol) was dissolved in a mixture of TFA:CHCl:H2O (2.5:100:1, 1.1 mL) and stirred at 23°C for 5 hours. The solution was then diluted with toluene (1.5 mL) and the volatiles evaporated in vacuo to afford an oily, beige crude product. Purification by flash chromatography on silica gel (CH2Cl2:MeOH 100:0 to 90:10) afforded 180 (18 mg, 66% yield) as a waxy solid.

[1321] 1H NMR (500MHz, CDCl3): δ7.07 (d, J=8.7Hz, 1H), 5.94 (d, J=2.0Hz, 1H), 5.72 (s, 1H), 5.36 (d, J=2.1Hz, 1H), 5.01 ( dd, J=5.9, 4.2Hz, 1H), 4.89 (d, J=5.9Hz, 1H), 4.72 (m, 1H), 4.25 (dd, J=8.7, 4.2Hz, 1H), 3.97 (m, 1H), 3.86 (d, J =11.5, 3.4Hz, 1H), 3.75 (m, 3H), 3.54 (d, J = 11.6Hz, 1H), 3.21 (d, J = 11.6Hz, 1H), 2.20 (s, 3H), 1.90-1.72 (m, 2H ), 1.52(s, 6H), 1.37(s, 3H), 1.42-1.31(m, 2H), 1.22(m, 1H), 0.96(t, J=7.4Hz, 3H), 0.64(m, 2H), 0.34(m, 2H).

[1322] 13 C NMR (125MHz, CDCl3): δ173.8, 170.1, 167.5, 164.3, 162.1, 153.8, 112.8, 108.6, 100.7, 88.9, 84.5, 84.4 , 82.5, 80.5, 73.8, 70.7, 64.3, 51.0, 39.9, 34.8, 29.7, 25.9, 24.8, 24.5, 19.0, 13.6, 12.1, 9.4, 3.4 (x2).

[1323] MS (ES+): m / z 624.2 [M+H] + ,646.3[M+Na] + .

[1324] R f :0.39(CH2Cl2:MeOH 15:1).

[1325] Scheme 35 provides an illustration of the synthesis of additional compounds of Formula I.

[1326]

[1327] Plan 35

[1328] Synthesis of 181

[1329] A solution of 180 (17 mg; 0.027 mmol) in aqueous AcOH (80%, 1.0 mL) was heated at 80°C for 4.5 hours. The mixture was then cooled, diluted with toluene (1.5 mL), and the volatiles evaporated in vacuo to afford a beige crude oil. 181 (14.6 mg, 92% yield) was purified by flash chromatography on silica gel (CH2Cl2:MeOH from 100:0 to 90:10) to obtain a light yellow solid.

[1330] 1 H NMR (500MHz, (CD3)2SO): δ7.90 (d, J=8.5Hz, 1H), 6.03 (d, J=2.2Hz, 1H), 5.49 (d, J=2.2Hz, 1H), 5.46 (d, J=4.8Hz, 1H), 5.26 (bd, J=5.3Hz, OH), 4.98 (bs, OH), 4.65 (bs, OH), 4.60 (q, J=7.8Hz, 1H), 4.41 (bs, OH), 4.16 (m, 1H), 4.07 (bs, 1H), 3.92 (dd, J=8.3, 2.7Hz, 1H), 3.85 (m, 1H), 3.71 (bs, 1H), 3.57-3.49 (m, 2H), 3.21 (d, J=11.6Hz, 1H), 2.19 (s, 3H), 1.75 (q, J=7.6Hz, 2 H), 1.45 (s, 3H), 1.43-1.24 (m, 2H), 1.18 (m, 1H), 0.90 (t, J=7.4Hz, 3H), 0.57 (dt, J=9.7, 3.1Hz, 2H), 0.30 (dt, J=6.0, 4.2Hz 2H).

[1331] 13 C NMR (100MHz, (CD3)2SO): δ172.6, 170.0, 165.9, 164.7, 163.1, 153.2, 111.0, 98.6, 88.0, 84 .2, 81.0, 75.4, 73.5, 70.9, 69.1, 63.1, 50.3, 39.6, 33.5, 24.0, 18.8, 13.4, 12.3, 9.4, 3.1.

[1332] MS (ES+): m / z 584.2 [M+H] + ,606.3[M+Na] + .

[1333] R f :0.16(CH2Cl2:MeOH 15:1).

[1334] Example 22. Synthesis of other compounds of formula I

[1335] Scheme 36 provides further examples of the synthesis of compounds of formula I

[1336]

[1337] Plan 36

[1338] To a solution of methyltriphenylphosphonium bromide (58 mg, 0.28 mmol) in THF (0.7 mL) was added nBuLi (0.175 mL, 1.6 M, 0.28 mmol) at 23 ° C. The yellow suspension was stirred for 2.5 hours and a solution of 65 (55 mg, 0.14 mmol) in THF (0.4 mL) was added. After 2 h, the reactants were refluxed for 3 h and then left overnight at 23 ° C. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The crude product was purified by flash chromatography on silica gel (CH2Cl2: EtOAc) to obtain a fraction (7 mg) containing 182. The fraction was then purified by flash chromatography on silica gel (hexane: EtOAc) to obtain 182 (4 mg, 7% yield).

[1339] 1 H NMR (400MHz, CDCl3): δ7.12 (d, J=8.6Hz, 1H), 5.91 (dt, J=2.2, 0.5Hz, 1H), 5.65 (d, J=1.4Hz, 1 H), 5.56 (d, J=1.6Hz, 1H), 5.34 (d, J=2.2Hz, 1H), 4.71 (q, J=7.8Hz, 1H), 3.83-3.68 (m, 2H), 3. 64-3.53 (m, 1H), 3.24 (dd, J=11.5, 0.6Hz, 1H), 2.09 (dt, J=1.5, 0.7Hz, 3H), 1.95-1.66 (m, 2H) , 1.51 (s, 3H), 1.44-1.18 (m, 3H), 1.00-0.90 (m, 3H), 0.73-0.57 (m, 2H), 0.33 (q, J=5.2Hz, 2H).

[1340] MS (ES+): m / z 405.2 [M+H] + ,427.3[M+Na] + .

[1341] Scheme 37 provides another example of synthesizing compounds of formula I

[1342]

[1343] Plan 37

[1344] To a solution of 76 (80 mg, 0.19 mmol) in DMF (0.2 mL) was slowly added CITBDPS (52 μL, 0.199 mmol) at 23° C., followed by the addition of DMAP crystals. The reaction mixture was stirred at 23° C. overnight. It was then diluted with CH 2 Cl 2 and washed with 0.5 M HCl and a saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (CH 2 Cl 2 : EtOAc) to afford 183 (119 mg, 91% yield).

[1345] 1 H NMR (400MHz, CD3OD): δ7.73-7.64 (m, 4H), 7.46-7.30 (m, 6H), 6.06 (dd, J=2.2, 0.7Hz, 1H) , 5.46 (d, J = 2.2Hz, 1H), 4.80-4.70 (m, 1H), 3.80 (dd, J = 7.2, 3.0Hz, 2H), 3.57 (d, J = 11.6Hz , 1H), 3.15 (d, J=11.5Hz, 1H), 2.40 (s, 3H), 1.90-1.75 (m, 2H), 1.53 (s, 3H), 1.51-1.16 (m , 2H), 1.12 (s, 9H), 0.97 (t, J=7.4Hz, 3H), 0.72-0.39 (m, 2H), 0.30 (dt, J=4.7, 1.3Hz, 2H).

[1346] 13 C NMR (100MHz, CD3OD): δ176.2, 172.6, 166.7, 165.3, 159.1, 136.5, 134.1, 131.1, 128.8, 101.1, 89.3, 85.8, 75.3, 61.5, 52.3, 40.7, 35.3, 27.6, 25.0, 20.4, 20.3, 14.5, 13.9, 12.0, 10.4, 3.7.

[1347] MS (ES+): m / z 660.3 [M+H] + ,682.3[M+Na] + .

[1348] Scheme 38 provides another example of synthesizing compounds of formula I

[1349]

[1350] Plan 38

[1351] To a solution of 113 (106 mg) in CH Cl (4.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (9 mg), acetic acid (47 μL) and tributyltin hydride (265 μL). The reaction mixture was stirred for 30 minutes and poured onto a silica gel column for purification. Elution with hexane:EtOAc from 100:0 to 0:100 afforded 184 (>100% yield).

[1352] 1 H NMR (400MHz, CDCl3): δ7.76-7.67 (m, 4H), 7.45-7.32 (m, 6H), 6.13 (d, J=2.1Hz, 1H), 5.59 (d, J=2.1Hz, 1H), 4.70 (q, J=7.9Hz, 1H), 3.37 (d, J =11.6Hz, 1H), 3.15 (d, J = 11.6Hz, 1H), 2.35 (s, 3H), 1.99-1.77 (m, 2H), 1.49 (s, 3H), 1.45-1.27 (m, 2H), 1.15 (s, 9H), 0.96 (t, J = 7.3Hz, 3H).

[1353] 13 C NMR (100MHz, CD3OD): δ175.4, 170.5, 169.1, 165.7, 162.5, 157.1, 135.5, 132.8, 132.7, 12 9.9, 127.6(x2), 101.4, 91.3, 83.9, 51.6, 39.5, 34.3, 27.1, 24.5, 19.5, 19.1, 13.6, 11.8.

[1354] Example 23. Synthesis of other compounds of formula I

[1355] Scheme 39 provides further examples of the synthesis of compounds of formula I

[1356]

[1357] Plan 39

[1358] Synthesis of 185

[1359] A mixture of 52 (138 mg, 0.29 mmol) and HCl in 1,4-dioxane (4 mL, 4 M, 16 mmol) was stirred at 23° C. for 60 min, and the volatiles were evaporated to dryness. The crude product was co-evaporated with toluene several times to remove the acid. The resulting residue was purified by preparative HPLC to afford 65 (30 mg, 25%) and 185 (15 mg, 12%), while recovering 50 mg of starting material.

[1360] 1 H NMR (500MHz, CDCl3): δ7.07 (d, J=8.7Hz, 1H), 5.91 (d, J=2.2Hz, 1H), 5.35 (d, J=2.2Hz, 1H), 5.10 (d, J=2.9H z, 1H), 4.72 (td, J=8.4, 6.6Hz, 1H), 4.45 (d, J=2.9Hz, 1H), 3.90 (q, J=7.0Hz, 2H), 3.83-3.69 (m, 2H), 3.60 (d , J=11.6Hz, 1H), 3.22 (d, J=11.6Hz, 1H), 1.92-1.87 (m, 1H), 1.76-1.71 (m, 1H), 1.54 (s, 3H), 1.40 (t, J=7.0 Hz, 3H), 1.45-1.30 (m, 2H), 1.27-1.19 (m, 1H), 0.95 (t, J=7.4Hz, 3H), 0.75-0.51 (m, 2H), 0.37-0.22 (m, 2H).

[1361] 13 C NMR (125MHz, CDCl3): δ174.4170.1, 167.2, 164.3, 162.8, 153.5, 100.2, 90.4, 8 8.8, 84.8, 73.7, 64.5, 51.0, 40.7, 34.6, 29.7, 24.6, 19.0, 14.7, 13.6, 9.4, 3.4.

[1362] MS (ES+): m / z 435.2 [M+H] + ,457.3[M+Na] + .

[1363] Example 24. Synthesis of other intermediates of general formula II

[1364] Scheme 40 provides another example of the synthesis of the intermediate of formula II

[1365]

[1366] Plan 40

[1367] Synthesis of (R)-186

[1368]

[1369] 1H NMR (400MHz, CD3OD): δ7.16 (d, J=8.2Hz, 1H), 6.10-5.95 (m, 2H), 5.78 (d, J=2.4Hz, 1H), 5.41 (dq, J=17.3, 1.7Hz, 1H), 5.30 (dq, J=10.5, 1.4Hz, 1H) , 5.04-4.94 (m, 2H), 4.56 (dt, J=5.5, 1.6Hz, 1H), 4.39 (s, 1H), 1.62 (tt, J =13.7, 6.2Hz, 2H), 1.44 (s, 9H), 1.32-1.20 (m, 2H), 0.95 (t, J = 7.4Hz, 3H).

[1370] 13 C NMR (10MHz, CD3OD): δ170.9, 167.9, 152.9, 136.6, 133.3, 118.6, 99.0, 96.6, 80.8, 70.2, 53.4, 37.7, 28.7, 20.5, 13.9.

[1371] MS (ES+): m / z 323.3 [M+H] + .

[1372] R f :0.18 (EtOAc).

[1373] Synthesis of (R)-187

[1374]

[1375] 1 H NMR (400MHz, CD3OD): δ6.53 (s, 1H), 6.27 (d, J=1.9Hz, 1H), 6.11-5.93 (m, 3H), 5.48-5. 37(m, 2H), 5.36-5.26(m, 2H), 5.04-4.91(m, 1H), 4.68(d, J=4.9Hz, 1H), 4.64-4.56(m, 3H), 4.16 (dt, J=14.6, 7.3Hz, 2H), 3.37-3.25 (m, 7H), 1.97-1.82 (m, 4H), 1.43 (dd, J=1 3.9, 7.1Hz, 1H), 1.41-1.28 (m, 1H), 1.29 (s, 1H), 1.25-1.13 (m, 0H), 1.05-0.84 (m, 7H).

[1376] Example 25. Synthesis of other compounds of formula I

[1377] Scheme 41 provides another example of synthesizing compounds of formula I

[1378]

[1379] Plan 41

[1380] Synthesis of 188

[1381] The residue was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (CH2Cl2:EtOAc) to give 188 (517 mg, 64% yield).

[1382] 1 H NMR (400MHz, CD3OD): δ6.09 (dd, J=2.4, 0.5Hz, 1H), 6.08-5.96 (m, 1H), 5.79 (d , J=2.3Hz, 1H), 5.45-5.35 (m, 1H), 5.33-5.25 (m, 1H), 4.72-4.66 (m, 1H), 4.59 -4.55 (m, 2H), 3.69-3.46 (m, 4H), 3.23 (d, J=11.8, 1H), 1.84-1.67 (m, 2H), 1.6 0(s, 3H), 1.44(s, 3H), 1.48-1.32(m, 2H), 1.20(m, 6H), (0.94(t, J=7.4Hz, 3H).

[1383] Synthesis of 189

[1384]

[1385] 1 H NMR (400MHz, CD3OD): δ6.08-5.93(m, 2H), 5.77(d, J=2.4Hz, 1H), 5.45-5.34(m, 1H), 5.34-5.24(m, 1H), 4.78(m, 1H), 4.54(d t, J=5.5, 1.6Hz, 2H), 3.66-3.60 (m, 1H), 3.31-3.27 (m, 1H), 2.56 (m, 2H), 1.56 (s, 3H), 1.49-1.25 (m, 2H), 1.01-0.96 (m, 3H).

[1386] Synthesis of 190

[1387]

[1388] 1H NMR (400MHz, CD3OD): δ6.13-5.94 (m, 2H), 5.77 (dd, J=2.4, 1.1Hz, 1H), 5.39 (dp, J=17.2, 1.5Hz , 1H), 5.29 (dp, J=10.6, 1.4Hz, 1H), 4.76 (dd, J=9.0, 6.3Hz, 1H), 4.54 (dt, J=5.3, 1.5Hz, 2H), 3 .48(dd, J=11.5, 1.1Hz, 1H), 3.18(dd, J=11.5, 1.1Hz, 1H), 2.20(d, J=1.2Hz, 3H), 1.92-1.73(m , 2H), 1.52 (d, J=1.1Hz, 3H), 1.52-1.36 (m, 1H), 1.40-1.27 (m, 2H), 0.99 (td, J=7.4, 1.1Hz, 3H).

[1389] 13 C NMR (100MHz, CDCl3): δ176.7, 170.7, 170.5, 167.9, 152.9, 151.1, 133.3, 118.6, 99.9, 97.0, 85.5, 70.2, 52.3, 40.7, 36.7, 24.8, 20.5, 13.8, 11.0.

[1390] MS (ES+): m / z 407.1 [M+H] + .

[1391] R f :0.33(CH2Cl2:MeOH 9:1).

[1392] Scheme 42 provides further examples of the synthesis of compounds of formula I.

[1393]

[1394] Plan 42

[1395] Synthesis of 191

[1396] To anhydrous CH3CN (4.50mL) and anhydrous CH2Cl2 (4.50mL) solution of 149 (54mg, 0.110mmol) was added 1H-tetrazole (3mL, 1.317mmol) and (tBuO)2PNEt2 (0.150mL, 0.550mmol) at 23°C. The reaction mixture was stirred at 23°C for 1h, then 70% tBuOOH solution (2.20mL, 15.37mmol) was added, and the mixture was stirred at 23°C overnight. 10% NaHSO3 aqueous solution (5mL) was added and the mixture was stirred for 15 minutes. The mixture was extracted with CH2Cl2 (3x10mL) and washed with H2O (1x10mL). The organic extract was dried over anhydrous Na2SO4, filtered and evaporated. The resulting residue was purified by flash chromatography on SiO2 (from CH2Cl2 to CH2Cl2:EtOAc 1:1) to afford 191 (50 mg, 67% yield).

[1397] 1 H NMR (400MHz, CD3OD): δ6.06 (d, J=2.2Hz, 1H), 5.48 (d, J=2.2Hz, 1H), 4.74 (dd, J=9.1, 5. 9Hz, 1H), 4.25 (t, J=5.9Hz, 2H), 4.01 (q, J=6.2Hz, 2H), 3.86 (d, J=7.1Hz, 2H), 3.58 (d, J= 11.5Hz, 1H), 3.20 (d, J=11.6Hz, 1H), 2.20 (s, 3H), 1.88-1.75 (m, 6H), 1.52 (s, 3H), 1.47 ( s, 18H), 1.44-1.10 (m, 3H), 0.98 (t, J=7.4Hz, 3H), 0.76-0.50 (m, 2H), 0.44-0.27 (m, 2H).

[1398] 13 C NMR (100MHz, CD3OD): δ174.8, 171.2, 168.0, 165.3, 163.8, 151.6, 99.7, 87.9, 84.2, 82.8, 82.7, 74. 5, 73.9, 66.7, 66.7, 50.7, 39.2, 33.9, 28.8(x2), 26.5, 26.4, 25.3, 23.5, 18.9, 12.5, 10.4, 9.0, 2.3.

[1399] MS (ES+): m / z 686.2 [M+H] + .

[1400] Synthesis of 192

[1401] To a solution of 191 (150 mg, 0.219 mmol) in CH2Cl2 (13 mL) was added TFA (0.385 mL, 5.03 mmol). The reaction mixture was stirred at 23°C for 1 hour. The mixture was evaporated to dryness and co-evaporated several times with toluene. The resulting residue was purified by preparative HPLC (SunFire from 5% to 100% CH3CN + 0.04% TFA) to afford 192 (110 mg, 88% yield).

[1402] 1 H NMR (500MHz, CD3OD): δ7.87 (d, J=8.6Hz, 1H), 6.06 (d, J=2.2Hz, 1H), 5.50 (d, J=2.3Hz, 1H), 4.78 -4.68 (m, 1H), 4.26 (t, J=6.2Hz, 2H), 4.08-3.96 (m, 2H), 3.88 (d, J=7.1Hz, 2H), 3.59 (d, J=11.5Hz , 1H), 3.20 (d, J=11.5Hz, 1H), 2.22 (s, 3H), 1.94-1.71 (m, 6H), 1.54 (s, 3H), 1.52-1.46 (m, 1H), 1 .43-1.37(m1H), 1.28-1.21(m, 1H), 0.99(t, J=7.4Hz, 3H), 0.70-0.60(m, 2H), 0.41-0.32(m, 2H).

[1403] 13 C NMR (125MHz, CD3OD): δ174.9, 171.3, 168.0, 165.4, 163.8, 151.7, 99.7, 87.8, 84.3, 74. 5, 73.9, 65.9(x2), 50.7, 39.3, 33.8, 26.7, 26.6, 25.1, 23.5, 18.8, 12.4, 10.3, 8.9, 2.2.

[1404] MS (ES+): m / z 574.2 [M+H] + ,596.2[M+Na] + .

[1405] Example 26: Bioassay for detecting antitumor activity

[1406] The purpose of this assay is to evaluate the in vitro cytostatic (ability to delay or inhibit tumor cell growth) or cytotoxic (ability to kill tumor cells) activity of the test sample.

[1407] cell lines

[1408]

[1409] Reference 1 Yamada, T. et al. (1986) Establishment of a human pancreaticadenocarcinoma cell line (PSN-1) with amplifications of both c-myc and activated c-Ki-ras by a point mutation. Biochem. Biophys. Res. Commun. 140.167-173.

[1410] Assessment of cytotoxic activity using SRB colorimetric assay

[1411] A colorimetric assay using the sulforhodamine b (SRB) reaction has been employed to provide quantitative measurements of cell growth and viability (following the technique described by V. Vichai and K. Kirtikara (2006) Nature Protoc. 1, 1112-1116.)

[1412] This format of the assay utilizes 96-well cell culture microplates. Unless otherwise stated, all cell lines used in this study were obtained from the American Type Culture Collection (ATCC) and were derived from different types of human cancers.

[1413] Cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) (for A549, HT-29, and MDA-MB-231) or RPMI (for PSN-1) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U / mL penicillin, and 100 U / mL streptomycin at 37°C, 5% CO2, and 98% humidity. For experiments, cells were harvested from subconfluent cultures using trypsinization and resuspended in fresh medium before counting and plating.

[1414] Cells were seeded in 96-well microtiter plates at 150 μL aliquots of 5 × 103 cells per well and allowed to attach to the plate surface for 18 hours (overnight) in drug-free medium. Thereafter, one control (untreated) plate of each cell line was fixed (as described below) and used for time zero reference. The plates were then treated with the test compound (50 μL aliquots of a 4X concentrated compound stock solution prepared in complete medium) using 10 serial dilutions (concentrations ranging from 10 to 0.00262 μg / mL) and three replicate cultures (final DMSO concentration of 1%). After 72 hours of treatment, the anti-tumor effect was measured using the SRB method: Briefly, the cells were washed twice with PBS, fixed in a 1% glutaraldehyde solution for 15 minutes at room temperature, washed twice in PBS, and stained in a 0.4% SRB solution for 30 minutes at room temperature. The cells were then washed several times with a 1% acetic acid solution and air-dried at room temperature. SRB were then extracted in 10 mM Trizma base solution and the absorbance was measured at 490 nm in an automated spectrophotometric plate reader. Effects on cell growth and survival were assessed using the NCI algorithm (Boyd MR and Paull KD. Drug Dev. Res. 1995, 34, 91-104).

[1415] Dose-response curves were automatically generated using nonlinear regression analysis of 4-parameter logistic curves using triplicate mean ± SD. Three reference parameters were calculated by automatic interpolation (NCI algorithm): GI 50 = concentration of compound producing 50% cell growth inhibition compared to control cultures; TGI = total cell growth inhibition (cytostatic effect) compared to control cultures, and LC50 = concentration of compound producing 50% net cell killing (cytotoxic effect).

[1416] Table 3 shows the biological activities of the compounds of the present invention (GI 50 )Data(GI 50 value).

[1417] Table 3: Cytotoxicity test - activity data (GI 50 Moore

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof in: R1 is selected from hydrogen and unsubstituted C2-C 12 Alkynyl; R2 is selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, -OR a , and -NR c R d , wherein the optional substituents are one or more substituents R x ; R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, wherein the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; R4 is selected from hydrogen or methyl; R5 is selected from -C(OR e )2R g 、-CH(NR c R d )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=N-O-(C=O)R f )R g 、-(C=N-O-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)R g 、and -(C=CH2)OR a ; Y is -O-; Z is -S-; Each group R a are independently selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted phenyl and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ; Each group R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ; Each group R e is an unsubstituted C1-C 12 alkyl; Each group R f independently selected from substituted or unsubstituted C1-C 12 Alkyl, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x , and groups of the following formula: wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ; or two adjacent OR groups form an isopropylidene ketal; Each group R g is an unsubstituted C1-C 12 alkyl; Each group R h independently selected from hydrogen, tert-butyldiphenylsilyl protecting groups of OH, substituted or unsubstituted C1-C 12 Alkyl, unsubstituted C2-C 12 Alkenyl, unsubstituted C2-C 12 Alkynyl, -(CH2CH2O) p CH2CH3 wherein p is 1 to about 25, and is selected from 、 、 or A substituted or unsubstituted monosaccharide residue, wherein the optional substituent is one or more substituents R x ; Substituent R x Choose between OR y 、COR y SR y 、OP(=O)(OR y )2、NR y R z NR y C(=O)OR z and a group consisting of a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen or sulfur atom in the one or more rings, the heterocyclic group being optionally substituted with one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and Each R y and R z independently selected from hydrogen and C1-C 12 A group consisting of alkyl groups.

2. The compound according to claim 1, which also has the following general formula wherein R1, R2, R3, R4, R5, Y and Z are as defined in claim 1; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein R1 is selected from hydrogen and unsubstituted C2-C6 alkynyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which further has the general formula Ia: wherein R2, R3, R4, R5, Y and Z are as defined in claim 1; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, which further has the general formula Ib: wherein R2, R3, R4, R5, Y and Z are as defined in claim 1; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, -OR a , and -NR c R d , where R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkyl, -(CH2CH2O) p CH2CH3, wherein p is 1 to about 15; R c and R d are independently selected from substituted or unsubstituted C1-C6 alkyl, and wherein the optional substituents are one or more substituents R x ; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein R2 is selected from hydrogen, methyl, vinyl, allyl, NEt2, and OR a , where R a Selected from hydrogen, methyl, ethyl, n-butyl, n-heptyl, allyl, propargyl, cyclopropylmethyl, -(CH2)3NHBoc, -(CH2)3NH2, and -(CH2CH2O)3CH2CH3; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R3 is selected from halogen-substituted or unsubstituted C1-C6 alkyl, wherein the halogen substituent is one or more substituents independently selected from F, Cl, Br and I; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein R3 is selected from n-propyl, 3,3,3-trifluoropropyl and isobutyl; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein R5 is selected from -C(OR e )2R g 、-CH(NR c R d )R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=NO-(C=O)R f )R g 、-(C=NO-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)R g , and -(C=CH2)OR a ,in: R h a tert-butyldiphenylsilyl protecting group selected from hydrogen, OH, a substituted or unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, -(CH2CH2O) p CH2CH3 wherein p is 1 to about 15, and substituted or unsubstituted monosaccharide residues of the following general formula: 、 、 or ; R g is an unsubstituted C1-C6 alkyl group; R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ; R a is a substituted or unsubstituted C1-C6 alkyl group, wherein the optional substituent is one or more substituents R x ; R e is an unsubstituted C1-C6 alkyl group; and R f Selected from substituted or unsubstituted C1-C6 alkyl, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 15 and the optional substituents are one or more substituents R x , and groups of the following formula: wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ; or two adjacent OR groups form an isopropylidene ketal; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein R5 is selected from -CH(NH2)Me, -(C=O)Me, -(C=NR c )Me、-(C=N-OR h )Me、-(C=NO-(C=O)R f )Me, -(C=N-NH2)Me, -(C=NO-[(P=O)(OR a )2])Me, -(C=CH2)Me, or -(C=CH2)OR a , where R a is ethyl, R f is -(CH2)5-NHBoc, -CH2O(CH2CH2O)2Me, or a group of the following formula: And R h Selected from hydrogen, methyl, allyl, propargyl, -(CH2)3NHBoc, -(CH2)3NH2, -(CH2)3SH, -(CH2)4OH, -(CH2)4OP(=O)(OH)2, -(CH2)4OP(=O)(O t- Bu)2, -(CH2CH2O)3CH2CH3, and monosaccharide residues of the following general formula: 、 、 ,or ; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, which is selected from ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , as well as ; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, having the formula; ， or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, having the formula; ， or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, having the formula; ， or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, whose general formula is I, or a pharmaceutically acceptable salt thereof in: R1 is selected from hydrogen and unsubstituted C2-C 12 Alkynyl; R2 is selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, -OR a , and -NR c R d , wherein the optional substituents are one or more substituents R x ; R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, wherein the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; R4 is selected from hydrogen or methyl; R5 is selected from -C(OR e )2R g , -CH(NR c R d )R g , -(C=O)R g , -(C=NR c )R g , -(C=N-OR h )R g , -(C=N-O-(C=O)R f )R g , and -(C=N-NR c R d )R g ; Y is -O-; Z is -S-; Each group R a are independently selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted phenyl and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ; Each group R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ; Each group R e is an unsubstituted C1-C 12 alkyl; Each group R f independently selected from substituted or unsubstituted C1-C 12 Alkyl, and -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x ; Each group R g is an unsubstituted C1-C 12 alkyl; Each group R h independently selected from hydrogen, tert-butyldiphenylsilyl protecting groups of OH, substituted or unsubstituted C1-C 12 Alkyl, unsubstituted C2-C 12 Alkenyl, unsubstituted C2-C 12 Alkynyl, -(CH2CH2O) p CH2CH3 wherein p is 1 to about 25, and is selected from 、 、 or A substituted or unsubstituted monosaccharide residue, wherein the optional substituent is one or more substituents R x ; Substituent R x Choose between OR y 、COR y SR y NR y R z NR y C(=O)OR z , and a group consisting of a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen or sulfur atom in the one or more rings, the heterocyclic group being optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and Each R y and R z independently selected from hydrogen and C1-C 12 A group consisting of alkyl groups.

17. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A dosage form comprising the pharmaceutical composition according to claim 17.

19. Use of a compound as defined in any one of claims 1 to 16, or a pharmaceutical composition as defined in claim 17, or a dosage form as defined in claim 18, in the preparation of a medicament for treating a cancer selected from the group consisting of lung cancer, colon cancer, breast cancer and pancreatic cancer.

20. A method for obtaining a compound as defined in any one of claims 1 to 16, said method comprising coupling a compound of formula II with a compound of formula III according to Scheme 1 wherein R1 is as defined in the compound of formula I as described in claim 1 or 3 or is a suitably protected group as required, and R2, R3, R4, Y and Z are as defined in the compound of formula I as described in any one of claims 1 or 6 to 11; R5 is as defined in the compound of formula I as described in any one of claims 1 or 6 to 11 or is a tert-butyldiphenylsilyl protecting group for OH as required.

21. Intermediate compound of formula IIa in: R1 is selected from hydrogen and unsubstituted C2-C 12 Alkynyl; R2 is selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, -OR a , and -NR c R d , wherein the optional substituents are one or more substituents R x ; R3 is selected from halogen-substituted or unsubstituted C1-C 12 Alkyl, wherein the halogen substituents are one or more substituents independently selected from F, Cl, Br and I; R6 is selected from hydrogen and a carbamate protecting group of an amino group; Y is -O-; Ra is selected from hydrogen, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted phenyl and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ; Each group R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ; R f independently selected from substituted or unsubstituted C1-C 12 Alkyl, and -CH2O(CH2CH2O) p CH3, wherein p is 1 to about 25 and the optional substituents are one or more substituents R x ; Substituent R x Choose between OR y 、COR y SR y 、OP(=O)(OR y )2、NR y R z NR y C(=O)OR z , and a group consisting of a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen or sulfur atom in the one or more rings, the heterocyclic group being optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and Each R y and R z independently selected from hydrogen and C1-C 12 a group consisting of alkyl groups; or a salt thereof.

22. Intermediate compound of formula IIIa wherein R4 is methyl or hydrogen; R5 is selected from -C(OR e )2R g 、-(C=O)R g 、-(C=NR c )R g 、-(C=N-OR h )R g 、-(C=N-O-(C=O)R f )R g 、-(C=N-O-[(P=O)(OR a )2])R g 、-(C=N-NR c R d )R g 、-(C=CH2)R g 、and -(C=CH2)OR a ; Z is -S-; Each group R a are independently selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C 12 Alkyl, substituted or unsubstituted phenyl and -(CH2CH2O) p CH2CH3, wherein p is 1 to about 25, and the optional substituents are one or more substituents R x ; Each group R c and R d are independently selected from hydrogen and substituted or unsubstituted C1-C 12 Alkyl, wherein the optional substituents are one or more substituents R x ; Each group R e is an unsubstituted C1-C 12 alkyl; Each group R f independently selected from substituted or unsubstituted C1-C 12 Alkyl, -CH2O(CH2CH2O) p CH3 wherein p is 1 to about 25 and the optional substituents are one or more substituents R x , and groups of the following formula: wherein each R group is independently selected at each occurrence from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents R x ; or two adjacent OR groups form an isopropylidene ketal; Each group R g is an unsubstituted C1-C 12 alkyl; Each group R h independently selected from hydrogen, tert-butyldiphenylsilyl protecting groups of OH, substituted or unsubstituted C1-C 12 Alkyl, unsubstituted C2-C 12 Alkenyl, unsubstituted C2-C 12 Alkynyl, -(CH2CH2O) p CH2CH3 wherein p is 1 to about 25, and is selected from 、 、 or A substituted or unsubstituted monosaccharide residue, wherein the optional substituent is one or more substituents R x ; Substituent R x Choose between OR y 、COR y SR y 、OP(=O)(OR y )2、NR y R z NR y C(=O)OR z , and a group consisting of a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and including at least one oxygen, nitrogen or sulfur atom in the one or more rings, the heterocyclic group being optionally substituted by one or more substituents R y substituted, and where there is more than one optional substituent on any given group, the optional substituents R y may be the same or different; and Each R y and R z independently selected from hydrogen and C1-C 12 a group consisting of alkyl groups; or a salt thereof.

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