Synthetic method and intermediate for preparing therapeutic azaketolide

Abstract

The invention relates to a method for preparing a compound of formula I and / or formula I. The invention also relates to a method for selectively cleaving a main ring of a compound of formula IV to provide a starting material for the synthesis of a compound of formula I or formula I. The invention also relates to intermediates of the methods described herein.

Description

Technical Field

[0001] The present invention relates to a process for preparing compounds of formula I and / or formula I'. The present invention also relates to a process for selectively cleaving the main ring of a compound of formula IV to provide a starting material for the synthesis of a compound of formula I or formula I'. The present invention also relates to intermediates of the processes described herein. Background Art

[0002] A nonsense mutation is a mutation in which a stop codon (UAA, UAG or UGA) replaces a codon encoding an amino acid, resulting in premature termination of translation and ultimately producing a truncated inactive protein. The Human Gene Mutation Database reports the presence of thousands of pathogenic mutations, of which about 12% are single-point (nonsense) mutations that produce premature stop codons (Krawczak M et al., Hum Mutat. 2000, 15, 45-51.; Mort et al., M. Hum. Mutat. 2008, 29, 1037-47). Nonsense mutations that produce truncated proteins have been shown to cause many forms of genetic diseases, including cancer, hemophilia, Tay-Sachs disease, lysosomal storage diseases or mucopolysaccharidosis such as Hurler syndrome, Duchenne muscular dystrophy, ataxia-telangiectasia, Rett syndrome, various hereditary retinopathy, and cystic fibrosis.

[0003] Effective treatment of genetic diseases caused by nonsense mutations remains elusive. Therefore, the discovery and development of new compounds that are effective for nonsense and / or frameshift mutations that produce premature stop codons are still an ongoing unmet need, and are thus useful for the treatment of genetic diseases and disorders caused by nonsense mutations. Azaketolides, as disclosed in PCT / US2019 / 062030, PCT / US2019 / 062045, PCT / US2022 / 031565, PCT / US2023 / 023971, PCT / US2023 / 069034, are a class of recently discovered compounds that can be used to treat such conditions. There remains a need for methods for preparing such compounds. Summary of the invention

[0004] These needs and others are met by the present invention, which is directed to methods for preparing azaconolactones useful for treating genetic diseases caused by nonsense mutations.

[0005] In one aspect, the present invention includes a method for preparing a compound of Formula I or Formula I' or a pharmaceutically acceptable salt thereof:

[0006]

[0007] It includes:

[0008] (a1) Intramolecular cyclization of a compound of formula A, wherein O-LG is a leaving group and PG is a protecting group, to form a compound of formula I:

[0009]

[0010] (b1) Intramolecular cyclization of a compound of formula B, wherein PG is a protecting group, to form a compound of formula I':

[0011]

[0012] in:

[0013] R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0014] And R 2a and R 2b The other of which is selected from halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0015] R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group;

[0016] R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0017] R 6a is an optionally substituted C 1-10 alkyl;

[0018] R 6b is -H, optionally substituted C1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl;

[0019] R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0020] R 9a is selected from -H and optionally substituted C 1-10 alkyl;

[0021] R 12 C 1-6 alkyl; and

[0022] L is C 2-5 Optionally substituted alkylene.

[0023] In one aspect, the present invention includes a method for preparing a compound of formula B-9 from a compound of formula IV, comprising contacting a compound of formula IV with ozone, optionally in the presence of an acid, to form a compound of formula B-9:

[0024]

[0025] in:

[0026] R 10a and R 10b One is OH and the other is H or R 10a and R 10b Together they form C=O.

[0027] Also provided are compounds useful as intermediates in the methods described in the Schemes and Experimental Examples provided herein.

[0028] Also provided are the compounds described in Table 1.

[0029] The methods disclosed herein start from readily available naturally occurring macrocyclic lactones. Thus, the present invention relates to the chemical synthesis of azalactones starting from natural products and solves the problem of preparing new compounds with therapeutic activity in a minimum of controlled steps. DETAILED DESCRIPTION

[0030] definition

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods and embodiments are only illustrative and not intended to be limiting. All publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by reference, including US Patent Publication No. 2013 / 0090326. In the event of a conflict, this specification (including these definitions) shall prevail.

[0032] As used herein, the terms "a," "an," and "the" include not only aspects having one member, but also aspects having more than one member.

[0033] As used herein, the term "about" means "approximately" and is used to modify a numerical value, indicating a limited range around the value. If "X" is this value, then "about X" will generally indicate a value between 0.95X and 1.05X. Any reference to "about X" at least specifically indicates the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Therefore, "about X" is intended to teach and provide written description support for the required limitation of, for example, "0.98X". When the quantity "X" only includes integer values ​​(e.g., "X carbons"), "about X" indicates from (X-1) to (X+1). In this case, "about X" as used herein at least specifically indicates the values ​​X, X-1, and X+1.

[0034] "About" and "approximately" are used interchangeably. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5% to 20%" is equivalent to "about 5% to about 20%". When "about" is applied to the first value of a group of values, it applies to all values ​​in the group. Thus, "about 7%, 9% or 11%" is equivalent to "about 7%, about 9% or about 11%".

[0035] The following abbreviations and terms have the indicated meanings throughout the text:

[0036]

[0037]

[0038]

[0039] The symbol "-" represents a single bond, "=" represents a double bond, and "≡" represents a triple bond. Indicates a single bond or a double bond. Refers to a group on a double bond that occupies either of the two positions at the end of the double bond to which the symbol is attached; i.e., the geometry of the double bond (E or Z) is undefined. When depicting a group removed from its parent formula, the "~" symbol will be used at the end of the bond that would theoretically cleave in order to separate the group from its parent formula.

[0040] When depicting or illustrating chemical structures, unless otherwise explicitly stated, all carbons are considered to have hydrogen substitutions to comply with tetravalence. For example, nine hydrogens are implicit in the structure on the left side of the schematic diagram below. These nine hydrogens are depicted in the structure on the right. Sometimes specific atoms in a structure are described in the formula of the text as having one or more hydrogens (well-defined hydrogens) as substitutions, such as -CH2CH2-. Those of ordinary skill in the art understand that the above descriptive techniques are commonly used in the chemical field to make the description of otherwise complex structures simple and clear.

[0041]

[0042] If the group "R" is depicted as "floating" on the ring system, as for example in the following formula,

[0043]

[0044] Unless otherwise defined, substituents "R" may be placed on any atom of the ring system as long as a stable structure results, as represented by the replacement of a depicted, implied or explicitly defined hydrogen from a ring atom.

[0045] If the radical "R" is depicted as floating on a fused or bridged ring system, as for example in the following formula,

[0046]

[0047] Unless otherwise defined, substituents "R" may be located on any atom of a fused or bridged ring system, as long as a stable structure is formed, representing the replacement of a depicted hydrogen (e.g., -NH- in the above formula), an implicit hydrogen (e.g., as in the above formula, where hydrogen is not shown but is assumed to be present), or an explicitly defined hydrogen (e.g., in the above formula, "Z" is equivalent to =CH-) from a ring atom. In the depicted example, the "R" group may be located on either the 5-membered ring or the 6-membered ring of the fused or bridged ring system.

[0048] When the group "R" is depicted as being present on a ring system containing a saturated carbon, such as, for example, in the following formula,

[0049]

[0050] Wherein, in this example, if each replaces the hydrogen depicted, implied or explicitly defined on the ring, "y" can be greater than one; then unless otherwise defined, two "R" can be located on the same carbon if the resulting structure is stable. In another example, two "R" on the same carbon including the carbon can form a ring, thereby generating a spirocyclic ring structure, which has a ring as depicted in the following formula, for example.

[0051]

[0052] The term "acyl" as used herein includes alkanoyl, aroyl, heterocyclic acyl or heteroaroyl as defined herein. Examples of acyl include, but are not limited to, acetyl, benzoyl and nicotinoyl.

[0053] As used herein, the term "alkanoyl" includes alkyl-C(O)- groups, wherein alkyl is as defined herein. Examples of alkanoyl groups include, but are not limited to, acetyl and propionyl.

[0054] As used herein, the term "agent" includes a compound or mixture of compounds that, when added to a composition, tends to have a particular effect on the properties of the composition. For example, a composition comprising a thickening agent may be more viscous than an otherwise identical comparative composition lacking the thickening agent.

[0055] As used herein, the term "alkenyl" includes straight or branched chain hydrocarbons containing at least one carbon-carbon double bond. The chain may contain the indicated number of carbon atoms. For example, "C1-C 12 "Alkenyl" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one carbon-carbon double bond. When the number of carbon atoms indicated is 1, then C i Alkenyl is double bonded to carbon (i.e., the carbon equivalent to the oxo group). In some aspects, the chain comprises 1 to 12, about 2 to 15, about 2 to 12, about 2 to 8, or about 2 to 6 carbon atoms. Alkenyl may preferably be a stereoisomer (i.e., cis or trans). Examples of alkenyl may include, but are not limited to, ethenyl (i.e., vinyl (vinyl)), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, propadienyl, butadienyl, pentadienyl, 3-(1,4-pentadienyl) and hexadienyl.

[0056] Alkenyl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (such as 1 to 4, 1 to 2 or 1) of alkenyl can be independently selected from following part replacement: fluoro, hydroxyl, alkoxyl, amino, alkylamino, amido, sulfo and alkylthio, condition is that there is no hydrogen atom substituent on the carbon-carbon double bond to be replaced by hydroxyl, amino or sulfo group.In some respects, alkenyl is unsubstituted or not optionally substituted.

[0057] As used herein, "alkenylene" includes alkenyl groups substituted at two positions. Examples are but-2-enyl (-CH2CH=CHCH2-) and the like.

[0058] As used herein, the term "alkyl" includes aliphatic hydrocarbon chains which may be straight or branched. The chain may contain the indicated number of carbon atoms: for example, C1-C 10 Indicates that the group may have 1 to 10 (inclusive) carbon atoms therein. If not otherwise specified, the alkyl group contains 1 to about 20 carbon atoms. In some aspects, the alkyl group has 1 to about 10 carbon atoms. In some aspects, the alkyl group ("low alkyl group") has 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl, isobutyl (iBu), tert-butyl, amyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopentyl, or cyclohexyl.

[0059] Alkyl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2 or 1) of alkyl can be independently selected from following part replacement: fluoro, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio.In some respects, alkyl is unsubstituted or not optionally substituted.

[0060] As used herein, "alkylene" includes alkyl groups substituted at two positions. Examples are methylene (-CH2-), propylene (-CH2CH2CH2-), and the like.

[0061] As used herein, the term "alkoxy" includes a straight or branched chain saturated or unsaturated hydrocarbon containing at least one oxygen atom in an ether group (e.g., EtO-). The chain may contain the indicated number of carbon atoms. For example, "C1-C 12 "Alkoxy" indicates that the group may have 1 to 12 (inclusive) carbon atoms and at least one oxygen atom. 12 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.

[0062] Alkoxy can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of alkoxy can be independently selected from the following moieties: fluoro, hydroxy, alkoxy, amino, alkylamino, amido, thio and alkylthio, provided that there is no alpha hydrogen atom of ether oxygen replaced by hydroxy, amino or thio groups. In some respects, alkoxy is unsubstituted or not optionally substituted.

[0063] As used herein, the term "alkynyl" includes straight chain, branched or cyclic hydrocarbons containing at least one carbon-carbon triple bond. Examples may include, but are not limited to, ethynyl, propargyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl or decynyl.

[0064] As used herein, "alkynylene" includes alkynyl substituted at two positions. Examples are 2-butynylene (-CH2CCCH2-) and the like.

[0065] Alkynyl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2 or 1) of alkynyl can be independently selected from the following partial replacements: fluoro, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio, with the condition that there is no sp hybridized hydrogen atom substituent to be replaced by hydroxyl, amino or thio group.In some respects, alkynyl is unsubstituted or not optionally substituted.

[0066] As used herein, the term "aryl" includes cyclic aromatic carbocyclic ring systems containing from 6 to 18 carbons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, naphthacene, biphenyl, and phenanthryl.

[0067] Aryl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (e.g., 1 to 5, 1 to 2 or 1) of aryl can be independently selected from following part replacement: alkyl, cyano, acyl, halogen, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio.In some respects, alkoxy is unsubstituted or not optionally substituted.

[0068] As used herein, the term "arylalkyl" or "aralkyl" includes alkyl groups as defined herein in which at least one hydrogen substituent has been replaced by an aryl group as defined herein. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4-methylbenzyl, and 1,1-dimethyl-1-phenylmethyl.

[0069] Arylalkyl or aralkyl can be unsubstituted or optionally substituted according to its constituent groups. For example, but not limited to, the aryl group of arylalkyl can be substituted, such as in 4-methylbenzyl. In some aspects, the group is unsubstituted or not optionally substituted, especially if it includes a clear substituent such as hydroxyalkyl or alkylaminoalkoxy.

[0070] As used herein, the term "cycloalkyl" includes non-aromatic saturated monocyclic or polycyclic ring systems which may contain the indicated number of carbon atoms. 12Indicates that the group may have 3 to 12 (inclusive) carbon atoms therein. If not otherwise specified, the cycloalkyl contains about 3 to about 20 carbon atoms. In some aspects, the cycloalkyl has 3 to about 12 carbon atoms in the group. In some aspects, the cycloalkyl has 3 to about 7 carbon atoms in the group. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl and cycloheptyl.

[0071] Cycloalkyl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (such as 1 to 4, 1 to 2 or 1) of cycloalkyl can be independently selected from the following partial replacement: fluoro, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio.In some respects, the substituted cycloalkyl can include olefins (such as cyclohex-2-ene-1-yl) outside or inside the ring.In some respects, cycloalkyl is unsubstituted or is not optionally substituted.

[0072] As used herein, "fluoroalkyl" includes alkyl groups wherein the alkyl group contains one or more fluoro substituents. Examples include, but are not limited to, trifluoromethyl.

[0073] As used herein, "geminal" substitution includes two or more substituents directly attached to the same atom. An example is 3,3-dimethyl substitution on a cyclohexyl or spirocyclohexyl ring.

[0074] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo.

[0075] The term "heteroaryl" or "heterocyclic aromatic radical" includes monocyclic and bicyclic aromatic radicals of about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms) containing at least one heteroatom. The heteroatom used in the term heteroaryl refers to oxygen, sulfur, and nitrogen. The nitrogen atom of the heteroaryl is optionally oxidized to the corresponding N-oxide. Examples include, but are not limited to, pyrazinyl, furanyl, thienyl, pyridinyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolyl, benzazaindolyl, 1,2,4-triazinyl, and benzothiazolyl.

[0076] As used herein, the term "heteroarylene" or "heterocycloarylene" includes heteroaryl groups that are substituted in two places.

[0077] Heteroaryl can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (e.g., 1 to 5, 1 to 2 or 1) of heteroaryl can be independently selected from following part replacement: alkyl, cyano, acyl, halide, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio.In some respects, heteroaryl is unsubstituted or not optionally substituted.

[0078] As used herein, the term "heteroaroyl" includes heteroaryl-C(O)- groups, wherein heteroaryl is as defined herein. Heteroaroyl includes, but is not limited to, thenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, and picolinoyl.

[0079] The term "heterocycloalkyl" is used interchangeably herein and as used herein includes heterocyclyl-C(O)- groups, wherein heterocyclyl is as defined herein. Examples include, but are not limited to, N-methylprolyl and tetrahydrofuroyl.

[0080] As used herein, "heterocyclyl" (heterocyclyl (prefix), heterocyclic, heterocycloalkyl) includes non-aromatic saturated rings of about 3 to about 8 ring atoms (e.g., 5 to about 10 ring atoms or 3 to about 6 ring atoms), wherein one or more atoms in the ring system is one or more elements other than carbon, such as nitrogen, oxygen or sulfur. The heterocyclyl optionally contains at least one sp 2The heterocyclic ring is a heterocyclic ring having a heteroatom selected from the group consisting of a carbonyl, an endocyclic olefin, or an exocyclic olefin. In some embodiments, the nitrogen or sulfur atom of the heterocyclic ring is optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Monocyclic heterocyclic ring refers to a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from O, N, and S. The three- or four-membered ring contains zero or one double bond and one heteroatom selected from O, N, and S. The five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. The six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. The seven- and eight-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperidinyl, oxazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

[0081] As used herein, the term "heterocycloalkylene" includes heterocyclyl groups (heterocyclyl(prefix), heterocyclic) that are substituted in two places.

[0082] The term "heterocyclyl" also includes polycyclic rings, such as bicyclic heterocycles or tricyclic heterocycles, which may be in fused, bridged or spiro orientations. Bicyclic heterocycles are monocyclic heterocycles fused to phenyl, or monocyclic heterocycles fused to monocyclic cycloalkyl, or monocyclic heterocycles fused to monocyclic cycloalkenyl, or monocyclic heterocycles fused to monocyclic heterocycles, or bridged monocyclic heterocyclic ring systems, wherein two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3 or 4 carbon atoms or an alkenylene bridge of 2, 3 or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.2.0]heptane, (3aR,6aS)-hexahydro-1H-2λ2-cyclopenta[c]pyrrole, (3aR,7aS)-octahydro-2λ2-isoindole.

[0083] Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to phenyl, or bicyclic heterocycles fused to monocyclic cycloalkyl, or bicyclic heterocycles fused to monocyclic cycloalkenyl, or bicyclic heterocycles fused to monocyclic heterocycles, or bicyclic heterocycles wherein two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms.

[0084] Heterocyclic radical can be unsubstituted or optionally substituted.When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2 or 1) of the group can be independently selected from the following partial replacements: fluoro, hydroxyl, alkoxy, amino, alkylamino, amido, thio and alkylthio.In some respects, the substituted heterocyclic radical can include olefins (e.g., cyclohex-2-ene-1-yl) outside or inside the ring.In some respects, heterocyclic radical is unsubstituted or not optionally substituted.

[0085] The monocyclic, bicyclic and tricyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and may be unsubstituted or substituted.

[0086] As used herein, the term "hydrophilic moiety" or "hydrophilic group" includes moieties or functional groups that have a strong affinity for water. Examples may include, but are not limited to, charged moieties, such as cationic or anionic moieties, or polar uncharged moieties, such as alkoxy or amine groups.

[0087] As used herein, the term "hydroxyalkyl" includes an alkyl group in which at least one hydrogen substituent has been replaced by an alcohol (-OH) group. In some aspects, the hydroxyalkyl group has one alcohol group. In some aspects, the hydroxyalkyl group has one or two alcohol groups, each of which is located on a different carbon atom. In some aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0088] When any two substituents, or any two instances of the same substituent, are "independently" selected from a list of options, the groups may be the same or different. a and R b independently selected from the group consisting of alkyl, fluoro, amino and hydroxyalkyl, then two R a Group and two R b All groups of the molecule of the group may be alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a Can be an alkyl group, the second R a It can be a fluorine group, the first R b can be a hydroxyalkyl group, and the second R b It may be an amino group (or any other substituent selected from the group described). a and the first R bcan be fluorine, and the second R b It may be an alkyl group (ie, some pairs of substituents may be the same, while other pairs may be different).

[0089] "Protecting group" refers to an "amino protecting group", which is a protecting group suitable for preventing undesired reactions at the amino nitrogen. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl, such as acetyl; alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr) and 1,1-bis (4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); etc. Representative oxygen protecting groups include, but are not limited to, silyl, such as TMS and TBDMS; esters, such as formates, acetates and benzoates (Bz); ethers, such as methoxymethyl (MOM), tetrahydropyranyl (THP); and benzyl (Bn).

[0090] The "yield" for each reaction described herein is expressed as a percentage of the theoretical yield.

[0091] "Subject" and "patient" are used interchangeably. "Subject" or "patient" for the purposes of the present invention includes humans and other animals, especially mammals, as well as other organisms. The methods are therefore suitable for both human therapy and veterinary applications. In a specific embodiment the patient is a mammal, and in a more specific embodiment the patient is a human.

[0092] A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985 (which is incorporated herein by reference) or SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, both of which are incorporated herein by reference.

[0093] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, Ethylenesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthylbenzenesulfonic acid, 4-toluenesulfonic acid, camphorbenzenesulfonic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and p-toluenesulfonic acid, and salicylic acid, etc.

[0094] Examples of pharmaceutically acceptable base addition salts include those formed when an acid proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methyl-reduced glucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methyl-reduced glucosamine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine." Platinum" and "platinum-containing agents" include, for example, cisplatin, carboplatin and oxaliplatin.

[0095] A "therapeutically effective amount" is an amount of a compound of the invention that improves disease symptoms when administered to a patient. The amount of a compound of the invention that is considered a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art, given his or her knowledge and this disclosure.

[0096] As used herein, the phrase "genetic disease" refers to a genetic disorder, genetic disease, genetic condition, or genetic syndrome.

[0097] "Preventing" or "prevention" of a disease, disorder or syndrome encompasses inhibiting the occurrence of the disease in humans, even though clinical symptoms of the disease, disorder or syndrome do not develop in an animal that may be exposed to or susceptible to the disease, disorder or syndrome but does not yet experience or express symptoms of the disease, disorder or syndrome.

[0098] As used herein, "treating" or "treatment" of a disease, disorder, or syndrome includes (i) inhibiting the disease, disorder, or syndrome, i.e., preventing its development; and (ii) alleviating the disease, disorder, or syndrome, i.e., reversing the disease, disorder, or syndrome. As known in the art, adjustments for systemic or local delivery, age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the condition may be necessary and can be determined by one of ordinary skill in the art through routine experimentation.

[0099] As used herein, the term "oxidant" refers to a substance or agent that tends to cause oxidation by being reduced and giving up electrons. Examples of oxidizing agents are selected from, but are not limited to, oxygen (O2), ozone (O3), hydrogen peroxide (H2O2) and other inorganic peroxides, Fenton's reagent, fluorine (F2), chlorine (Cl2) and other halogens, nitric acid (HNO3) and nitrate compounds, sulfuric acid (H2SO4), peroxydisulfuric acid (H2S2O8), peroxymonosulfuric acid (H2SO5), chlorites, chlorates, perchlorates and other similar halogen compounds, hypochlorites and other hypohalite compounds (including household bleach (NaClO)), hexavalent chromium compounds such as chromic acid and dichromic acid and chromium trioxide, pyridinium chlorochromate (PCC) and chromic acid / dichromic acid compounds, permanganate compounds such as potassium permanganate, sodium perborate, nitrous oxide (N2O), nitrogen dioxide / nitrogen tetroxide (NO2 / N2O4), potassium nitrate (KNO3) (oxidizer in black powder), sodium bismuthate, and sodium periodate (NaIO4).

[0100] The types of CFTR modulators used herein are drugs or compounds that target the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The three types of modulators are enhancers, correctors, and amplifiers. [Accessed May 23, 2019, Cystic Fibrosis Foundation https: / / www.cff.org / Research / Developing-New-Treatments / CFTR-Modulator-Types / ].

[0101] Enhancers such as the drug ivacaftor It is effective against residual function and splicing mutations in which the normal CFTR protein is deficient by keeping the gate open so chloride can flow through.

[0102] The corrector encourages the CFTR protein with two copies of the F508del mutation to adopt the correct three-dimensional shape so that it can move (or traffic) to the cell surface.

[0103] Amplifiers increase the amount of CFTR protein that cells make. Many CFTR mutations result in insufficient CFTR protein. If cells produce more CFTR protein, enhancers and correctors will be able to allow more chloride to flow across the cell membrane.

[0104] Implementation

[0105] In one aspect, the present invention includes a method for preparing a compound of Formula I or Formula I' or a pharmaceutically acceptable salt thereof:

[0106]

[0107] It includes:

[0108] (a1) Intramolecular cyclization of a compound of formula A, wherein O-LG is a leaving group and PG is a protecting group, to form a compound of formula I:

[0109]

[0110] (b1) Intramolecular cyclization of a compound of formula B, wherein PG is a protecting group, to form a compound of formula I':

[0111]

[0112] in:

[0113] R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0114] And R 2a and R 2b The other of which is selected from halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0115] R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group;

[0116] R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0117] R 6a is an optionally substituted C 1-10 alkyl;

[0118] R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl;

[0119] R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0120] R 9a is selected from -H and optionally substituted C 1-10 alkyl;

[0121] R 12 C 1-6 alkyl; and

[0122] L is C 2-5 Optionally substituted alkylene.

[0123] In some embodiments, R3 is H or Wherein R3c is H or a protecting group. In other embodiments, R3 is H. In still other embodiments, R3 is Wherein R3c is H or a protecting group.

[0124] In one embodiment, the intramolecular cyclization of the compound of formula B is carried out in the presence of a solvent under neutral conditions.

[0125] In another embodiment, the intramolecular cyclization of the compound of formula B is carried out at a temperature above 120 °C.

[0126] In one embodiment, the intramolecular cyclization of the compound of Formula B is carried out at a temperature of about 50°C to about 175°C.

[0127] In another embodiment, the intramolecular cyclization of the compound of formula B is carried out in the presence of meta-xylene at a temperature of about 60°C to about 150°C.

[0128] In another embodiment, the intramolecular cyclization of the compound of formula B is carried out in the presence of meta-xylene at a temperature of about 100°C to about 150°C.

[0129] In yet another embodiment, the intramolecular cyclization of the compound of formula B is carried out in the presence of meta-xylene at a temperature of about 130°C to about 140°C.

[0130] In one embodiment, the intramolecular cyclization occurs in an aprotic solvent. Examples of aprotic solvents include, but are not limited to, DMF, DMSO, acetone, DCM, ethyl acetate, toluene, or ether. In another embodiment, the intramolecular cyclization occurs in the presence of 4-dimethylaminopyridine (DMAP). In yet another embodiment, the intramolecular cyclization occurs in the presence of a base. In yet another embodiment, the base is an organic base, such as trimethylamine, diisopropylethylamine, DBU, and other organic bases known to those skilled in the art.

[0131] In one embodiment, the method of the present invention comprises the step of converting a compound of formula A-1 to a compound of formula A:

[0132]

[0133] In one embodiment, LG is R'-(C=O)-.

[0134] In one embodiment, R' is optionally substituted phenyl.

[0135] In one embodiment, the method comprises a base.

[0136] In another embodiment, the base is an amine base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pentamethylpiperidine (PMP), tributylamine, triethylamine, diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine).

[0137] In another embodiment, the method further comprises treating a compound of formula A-2, wherein R xFor optionally C 1-4 Alkyl, hydroxyl, oxo, COOH, COO(C 1-6 alkyl), amino, alkylamino, halo or cyano substituted C 1-6 The steps of converting an alkyl group into a compound of formula A-1 are:

[0138]

[0139] In one embodiment, R x In another embodiment, R x is methyl, benzyl, pentyl substituted with one or more of oxo, hydroxyl and methyl. In yet another embodiment, R x In some other embodiments, R x It is pentan-3-yl-2-one, 2-hydroxy-2-methylpentanal-3-yl and 1,2-dihydroxy-2-methylpentan-3-yl.

[0140] In another embodiment, the method further comprises the step of converting the compound of formula A-3 into the compound of formula A-2:

[0141]

[0142] In another embodiment, the method further comprises the step of converting the compound of formula A-4 to a compound of formula A-3:

[0143]

[0144] In another embodiment, the method further comprises the step of converting the compound of formula A-4A to a compound of formula A-4 by contacting the compound of formula A-4A with an oxidizing agent:

[0145]

[0146] In another embodiment, the method further comprises the step of converting the compound of formula A-4A1 to the compound of formula A-4A:

[0147]

[0148]

[0149] In another embodiment, the method further comprises the step of converting the compound of formula A-4A2 to the compound of formula A-4A1:

[0150]

[0151] In another embodiment, the method further comprises the step of converting the compound of formula A-4A3 to the compound of formula A-4A2:

[0152]

[0153] In another embodiment, the method further comprises the step of converting the compound of formula II to a compound of formula A-4A3:

[0154]

[0155] In one embodiment, the method comprises the step of converting a compound of formula III to a compound of formula II:

[0156]

[0157] In another embodiment, the method further comprises the step of converting the compound of formula A-4B to the compound of formula A-4:

[0158]

[0159] In another embodiment, the method further comprises the step of converting the compound of formula A-4B1 to a compound of formula A-4B:

[0160]

[0161] In another embodiment, the method further comprises the step of converting the compound of formula A-4B2 to the compound of formula A-4B1:

[0162]

[0163] In another embodiment, the method further comprises the step of converting the compound of formula A-4B3 to a compound of formula A-4B2:

[0164]

[0165] In another embodiment, the method further comprises the step of converting the compound of formula II to a compound of formula A-4B3:

[0166]

[0167] In one embodiment, R3 is And the method also includes the step of converting the compound of formula I into the compound of formula IA:

[0168]

[0169] In another embodiment, the method further comprises the step of converting the compound of Formula IA to a compound of Formula I':

[0170]

[0171] In another embodiment, the method further comprises the step of converting the compound of formula I' to a compound of formula IC:

[0172]

[0173] In one embodiment, the method comprises the following steps:

[0174] (b1) intramolecular cyclization of a compound of formula B, wherein PG is a protecting group, followed by removal of the protecting group to form a compound of formula I:

[0175]

[0176] In another embodiment, the method further comprises the step of converting the compound of formula B-1 to a compound of formula B:

[0177]

[0178] In another embodiment, the method further comprises the step of converting the compound of formula B-2 to the compound of formula B-1:

[0179]

[0180] In another embodiment, the method further comprises the step of converting the compound of formula B-3 into the compound of formula B-2:

[0181]

[0182] In another embodiment, the method further comprises treating a compound of formula B-4, wherein R 3c for Steps for conversion to compounds of formula B-3:

[0183]

[0184] In another embodiment, the method further comprises the step of converting the compound of formula B-5 to the compound of formula B-4:

[0185]

[0186] In another embodiment, the method further comprises the step of converting the compound of formula B-6 to the compound of formula B-5:

[0187]

[0188] In another embodiment, the method further comprises the step of converting the compound of formula B-7 to the compound of formula B-6:

[0189]

[0190] In another embodiment, the method further comprises the step of converting the compound of formula B-8 to the compound of formula B-7:

[0191]

[0192] In another embodiment, the method further comprises treating a compound of formula B-7, wherein R 10a is OH and R 10b H or R 10a and R 10b Steps for forming C=O and converting into a compound of formula B-6:

[0193]

[0194] In another embodiment, the method further comprises treating a compound of formula IV, wherein R 10a is OH and R 10b H or R 10a and R 10b Steps for forming C=O and converting to a compound of formula B-9:

[0195]

[0196] In one embodiment, R 12 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. 12 In another embodiment, R 12 It is tert-butyl.

[0197] In one embodiment, R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0198] In another embodiment, R 8a and R 8b One is H and the other is methyl.

[0199] In one embodiment, R 6a Selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0200] In one embodiment, R 6bSelected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0201] In another embodiment, R 6a and R 6b Each is a methyl group.

[0202] In one embodiment, R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or And R 3c is H or benzoyl.

[0203] In one embodiment, R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0204] In another embodiment, R 4a and R 4b One is H and the other is methyl.

[0205] In one embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0206] And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0207] In another embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0208] And R2a and R 2b The other one is methyl.

[0209] In one embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0210] In another embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one of them is methyl, ethyl, propyl or isopropyl.

[0211] In another embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one is methyl.

[0212] In one aspect, the present invention includes a method for preparing a compound of formula B-9 from a compound of formula IV, comprising contacting a compound of formula IV with ozone (optionally in the presence of an acid) to form a compound of formula B-9:

[0213]

[0214] in:

[0215] R 10a and R 10b One is OH and the other is H or R 10a and R 10b Together they form C=O;

[0216] R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0217] And R 2a and R 2b The other of which is selected from halo, optionally substituted C1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0218] R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group;

[0219] R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0220] R 6a is an optionally substituted C 1-10 alkyl;

[0221] R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl;

[0222] R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl; and

[0223] PG is a suitable protecting group.

[0224] In one embodiment, the compound of formula IV is contacted with ozone in the presence of an acid to form a compound of formula B-9. In another embodiment, the acid is soluble in dichloromethane.

[0225] In yet another embodiment, the acid is trifluoroacetic acid.

[0226] In one embodiment, the contacting occurs in dichloromethane.

[0227] In another embodiment, R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0228] In another embodiment, R 8a and R 8b One is H and the other is methyl.

[0229] In one embodiment, R 6a Selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0230] In one embodiment, R 6b Selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0231] In another embodiment, R 6a and R 6b Each is a methyl group.

[0232] In one embodiment, R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or And R 3c is H or benzoyl.

[0233] In one embodiment, R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0234] In another embodiment, R 4a and R 4b One is H and the other is methyl.

[0235] In one embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0236] And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0237] In one embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0238] And R 2a and R 2b The other one is methyl.

[0239] In one embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0240] In another embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one of them is methyl, ethyl, propyl or isopropyl.

[0241] In yet another embodiment, R 2a and R 2b One of them is H and R 2a and R 2b The other one is methyl.

[0242] In one aspect, the present invention includes a method for preparing a compound of formula A-3 from a compound of formula A-4, comprising coupling a compound of formula A-4 with an amine having the formula NH2-L-OH under reductive amination conditions to form a compound of formula A-3:

[0243]

[0244] in:

[0245] R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0246] And R 2a and R 2b The other of which is selected from halo, optionally substituted C1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0247] R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group;

[0248] R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0249] R 6a is an optionally substituted C 1-10 alkyl;

[0250] R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl;

[0251] R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl;

[0252] PG is a suitable protecting group; and

[0253] L is an optionally substituted C 2-5 Alkylene.

[0254] In one embodiment, the coupling of the compound of formula A-4 with the amine having the formula NH2-L-OH is performed in the presence of a solvent.

[0255] In another embodiment, the solvent is dichloromethane.

[0256] In one embodiment, the coupling of the compound of formula A-4 with an amine having the formula NH2-L-OH is performed in the presence of NaB(OAc)3H and acetic acid.

[0257] In one embodiment, NaB(OAc)3H and acetic acid are each present in about 2 molar equivalents relative to the compound of Formula A-4.

[0258] In some embodiments, L is C 2-8In some embodiments, L is C 2-6 In some embodiments, L is C 2-5 In some embodiments, L is C 2-4 Optionally substituted alkylene. In one embodiment, L is ethylene, which is optionally trisubstituted with halo, CN, NO2, amino, amido, carboxyl, alkylcarbonyl, alkoxycarbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently and optionally substituted with halo or alkyl.

[0259] In one embodiment, L is ethylene, optionally substituted up to tri-substituted with halo, alkyl or alkoxy.

[0260] In one embodiment, NH2-L-OH is NH2-CH2-L1-OH, NH2-CH(C 1-6 alkyl)-L1-OH, NH2-L1-CH2-OH or NH2-L1-CH(C 1-6 Alkyl)-OH;

[0261] L1 is CR 14a R 14b ;

[0262] R 14b H or C 1-6 alkyl;

[0263] R 14a Selected from optionally substituted R 101 -CH2-、R 101 -CH2CH2-、R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 -CH2CH2CH-OMe-; or

[0264] R 14a is an optionally substituted saturated or partially unsaturated cycloalkyl group, an optionally substituted saturated or partially unsaturated heterocycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group containing at least one double bond, or

[0265] R 14a and R 14b Together with the carbon atoms to which they are attached, they form Wherein Q is a 3, 4, 5 or 6-membered cycloalkyl or heterocyclic ring, wherein Represents a connection point and R 11a and R 11bare each independently selected from H, halo and optionally substituted C 1-10 In one embodiment, NH2-L-OH is NH2-L1-CH2-OH.

[0266] In one embodiment, NH2-L-OH is NH2-L1-CH2-OH or NH2-L1-CH(C 1-6 Alkyl)-OH.

[0267] In one embodiment, NH2-L-OH is NH2-L1-CH2-OH.

[0268] In one embodiment, L1 is CR 14a R 14b , where R 14b H or C 1-6 Alkyl and R 14a Selected from optionally substituted R 101 -CH2-、R 101 -CH2CH2-、R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 -CH2CH2CH-OMe-. In this embodiment, R 101 Selected from

[0269]

[0270] in Represents a connection point.

[0271] In one embodiment, L1 is CR 14a R 14b , where R 14b H or C 1-6 Alkyl and R 14a is an optionally substituted saturated or partially unsaturated cycloalkyl group, an optionally substituted saturated or partially unsaturated heterocycloalkyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group containing at least one double bond. 14a for Pyridyl,

[0272]

[0273]

[0274]

[0275] in Represents a connection point.

[0276] In one embodiment, L1 is CR 14a R 14b , where R 14a and R 14b Together with the carbon atoms to which they are attached, they form Wherein Q is a 3, 4, 5 or 6-membered cycloalkyl or heterocyclic ring, wherein In one embodiment, each R q independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl,

[0277]

[0278]

[0279] or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

[0280] In one embodiment, for In one embodiment, for And each R q independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl,

[0281]

[0282]

[0283] or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

[0284] In one embodiment, for And R q is selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me,

[0285]

[0286] in Represents a connection point.

[0287] In one embodiment, L in the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and B-1 is CH2-CR 14a R 14b , where R 14a and R 14b As defined herein.

[0288] In one embodiment of the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and B-1, L is CH2CH-R 14a , where R 14a Selected from optionally substituted R 101 -CH2-、R 101 -CH2CH2-、R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 -CH2CH2CH-OMe-. In this embodiment, R 101 Selected from

[0289]

[0290] in Represents a connection point.

[0291] In one embodiment of the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and 14a , where R 14a are optionally substituted saturated or partially unsaturated cycloalkyl, optionally substituted saturated or partially unsaturated heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl containing at least one double bond.

[0292] In one embodiment, R 14a for Pyridyl,

[0293]

[0294]

[0295]

[0296] in Represents a connection point.

[0297] In one embodiment of the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and B-1, L is CH2CR 14a R 14b , where R 14a and R 14b Together with the carbon atoms to which they are attached, they form Wherein Q is a 3, 4, 5 or 6-membered cycloalkyl or heterocyclic ring, wherein Represents a connection point and R 11a and R 11b are each independently selected from H, halo and optionally substituted C 1-10 In one embodiment, each R q independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl,

[0298]

[0299]

[0300] or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

[0301] In one embodiment of the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and B-1, for In one embodiment, for And each R q are independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me,

[0302]

[0303] or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

[0304] In one embodiment of the compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B and B-1, for And R q is selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me,

[0305]

[0306]

[0307] in Represents a connection point.

[0308] In one embodiment, R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0309] In another embodiment, R 8a and R 8b One is H and the other is methyl.

[0310] In one embodiment, R 6a Selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0311] In one embodiment, R 6b Selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0312] In another embodiment, R 6a and R 6b Each is a methyl group.

[0313] In one embodiment, R 3c is a protecting group selected from benzoyl, p-nitrobenzoyl, TMS, TES, IPDMS, TBS or methoxymethyl. 3c It is benzoyl.

[0314] In one embodiment, R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

[0315] In another embodiment, R 4a and R 4b One is H and the other is methyl.

[0316] In one embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0317] And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0318] In one embodiment, R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;

[0319] And R 2a and R 2b The other one is methyl.

[0320] In one embodiment, R 2a and R 2b One of them is H, and R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

[0321] In another embodiment, R 2a and R 2b One of them is H, and R 2a and R 2bThe other one of them is methyl, ethyl, propyl or isopropyl.

[0322] In one embodiment, R 2a and R 2b One of them is H and R 2a and R 2b The other one is methyl.

[0323] In another aspect, the present invention relates to compounds of formula A, B, A-1, A-2, A-3 and B-1.

[0324] On the other hand, the present invention is directed to compounds of formula A-4, A-4A, A-4A1, A-4A2, A-4B, A-4B1, A-4B2, A-4B3, B-2, B-3, B-4, B-5, B-6, B-7, B-8 and B-9.

[0325] In another aspect, the invention relates to compounds depicted in Table 1.

[0326] Table 1

[0327]

[0328]

[0329]

[0330]

[0331] Example

[0332] In order to more fully understand the invention described herein, the following examples are listed.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting the scope thereof.

[0333] Ozonolysis and preparation of intermediates

[0334] Ozonolysis route 1

[0335] Scheme 1 depicts the ozonolysis products S1-5, S1-6 and S1-8 starting from S1-1, which are obtained through an intermediate optionally protected at the C-5 erythrodeoxysugaramine hydroxyl group. In this method, S1-1 is converted to S1-2 according to known methods (see, for example, WO 2009 / 053259). In one option, the C-5 erythrodeoxysugaramine hydroxyl group of S1-2 is then protected, for example, the C-5 erythrodeoxysugaramine hydroxyl group is converted to a benzoyl group according to known methods to obtain S1-3. S1-3 is then ozonolyzed in dichloromethane in the presence of an acid such as trifluoroacetic acid. Quenching with dimethyl sulfide gives the ozonated product S1-5. Alternatively, the C-9 ketone in S1-3 is reduced to the corresponding alcohol S1-4, which after the aforementioned ozonolysis gives S1-6. In another option, S1-2 is reduced to give the alcohol S1-7, which after subsequent ozonolysis gives S1-8.

[0336]

[0337]

[0338] (3R,4S,5S,6R,7R,9R,13S,14R,E)-6-(((3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-13-hydroxy-4-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyloxacyclotetradec-11-ene-2,10-dione (S1-2). S1-2 was synthesized by a known method (PCT Int. Appl., 2009053259, April 30, 2009).

[0339] 163.2 kg of clarithromycin and 180.4 kg of TEA were charged into a glass-lined reactor (1000 L). The temperature was adjusted to 75-95° C. (white suspension). The reaction mixture was stirred at 45-50° C. for about 10 to 20 minutes to obtain a white suspension. 111.6 kg of ethylene carbonate (5.78 equivalents) and 60.3 kg of TEA were then charged into the glass-lined reactor (1000 L). The temperature was adjusted to 85-95° C. and the mixture was stirred for about 20-22 hours. IPC: 9.2% residual clarithromycin. 53.8 kg of ethylene carbonate was charged into the glass-lined reactor (1000 L). The temperature was adjusted to 85-95° C. and the mixture was stirred for 7-9 hours. IPC: 1.8% residual clarithromycin. The reaction mixture was then stirred at 85-95° C. for another 4 hours. IPC: 0.91% residual clarithromycin. The temperature was then adjusted to 45-55° C. 122.9 kg H2O was then added dropwise to the reaction mixture at 45-55°C. The mixture was stirred at about 45 to 55°C for 1 hour. The temperature was adjusted to 15-25°C and stirred for 15-17 hours. The reaction mixture was then freed of liquid. The filter cake was washed with 163.3 kg H2O. The filter cake (light white solid) was sampled for IPC, S1-2: 96.0%. The cake was then dried at 45-55°C for 23-25 ​​hours.

[0340] 128.61 kg of off-white solid S1-2 was obtained, with a yield of 80.85%.

[0341]

[0342] (3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,13S,14R,E)-14-ethyl-13-hydroxy-4-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S1-3). Preparation method 1: S1-2 (3.8 g, 5.2 mmol), benzoic anhydride (2.35 g, 10.4 mmol) and DMAP (63.5 mg, 0.52 mmol) were dissolved in dichloromethane (DCM, 30 mL) and triethylamine (2.16 mL, 15.6 mmol) was added. The mixture was refluxed overnight. The solution was washed with NaHCO3 (saturated aqueous solution, 2 times), dried with Na2SO4, filtered and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 40% B) to obtain the target compound (3.9 g, 90%). MS (ESI+) m / z: 834.21 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ8.02-7.92(m,2H),7.57-7.48(m,1H),7.40(t,2H),6.47(d,1H),5.05(dd,1H),4.94(dd,1H) ,4.80(d,1H),4.64(d,1H),4.03(dq,1H),3.93(d,1H),3.64(d,1H),3.60-3.51(m,1H),3.40(s,3H),3.14(s,3H) ,3.03(q,1H),2.86-2.74(m,1H),2.68(p,1H),2.44-2.30(m,1H),2.26(s,7H),1.98(s,3H),1.92-1.83(m,2H),1 .81-1.72(m,3H),1.59(dd,1H),1.49-1.36(m,3H),1.35-1.22(m,16H),1.17(dd,6H),0.85(t,3H),0.73(d,3H).

[0343] Preparation method 2: To a solution of S1-2 (20 g, 27.3 mmol) in DCM (160 mL) was added triethylamine (5.68 mL, 40.9 mmol), and the mixture was cooled in an ice-water bath. Benzoyl chloride (4.1 mL, 34.1 mmol) was added dropwise. The solution was warmed to room temperature and stirred for 1 h. The mixture was then heated to reflux overnight. The solution was washed with NaHCO3 (saturated aqueous solution, 2 times), dried with Na2SO4, filtered, and concentrated. The residue was purified with ISCO (120 g silica gel column, A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 40% B) to obtain the target compound (22.7 g, 100%).

[0344]

[0345] (3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,10S,13S,14R,E)-14-ethyl-10,13-dihydroxy-4-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-4). NaBH4 (270 mg, 5.44 mmol) was added to a solution of S1-3 (2.27 g, 2.72 mmol) in EtOH (20 mL). After 1 h, the mixture was concentrated by rotary evaporation and diluted with EtOAc. The mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 50% B) gave the title compound (1.86 g, 82%). MS (ESI+) m / z: 836.23 [M+H] + ; 1H NMR (400MHz, chloroform-d) δ8.05-7.93(m,2H),7.54(t,1H),7.42(t,2H),5.78(s,1H),5.05(dd,1H),4.79(dd,1H),4.74(d,1 H),4.70(d,1H),4.01(dq,1H),3.94(s,1H),3.79-3.70(m,2H),3.56(dtd,1H),3.44(s,3H),3.17(s,3H),3.02(t,1H) ,2.88(s,1H),2.79(td,1H),2.67(p,1H),2.40(d,1H),2.27(s,6H),2.18(dd,2H),1.86(d,1H),1.78-1.72(m,1H),1. 69-1.55(m,5H),1.42(dd,2H),1.34(s,3H),1.29-1.24(m,12H),1.14(d,3H),1.10(d,3H),0.81(t,3H),0.73(d,3H).

[0346]

[0347] (3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4S,5R,6R,8R)-1-(((2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl)oxy)-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,9,10-trioxoundec-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-5). A solution of trifluoroacetic acid (2.28 g, 20 mmol) in DCM (8 mL) was slowly added to a solution of S1-3 (12.9 g, 15.4 mmol) in DCM (128 mL). The solution was cooled in a dry ice-acetone bath (internal temperature about -60 °C) and O3 was passed through the solution until a blue color was observed (about 10 min). Nitrogen was passed through the solution for 3 min until no blue color was observed. Me2S (3.39 mL) was added and the solution was stirred in a dry ice-acetone bath for 20 min. The solution was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to give crude S1-5. MS (ESI+) m / z: 866.29 [M+H] + .

[0348]

[0349] (3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4S,5R,6R,8R,9S)-9-hydroxy-1-(((2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl)oxy)-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,10-dioxoundec-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-6). Trifluoroacetic acid (161 mg, 1.42 mmol) was added to a solution of S1-4 (960 mg, 1.14 mmol) in DCM (11.3 mL), and the solution was cooled in a dry ice-acetone bath. O3 was passed through the solution until a blue color was observed. Nitrogen was passed through the solution until no blue color was observed. Me2S (0.67 mL) was added and the solution was stirred in a dry ice-acetone bath for 40 min. The solution was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to give crude S1-6. MS (ESI+) m / z: 868.25 [M+H] + .

[0350]

[0351] (3R, 4S, 5S, 6R, 7R, 9R, 10S, 13S, 14R, E) -6- (((3R, 4S, 6R) -4- (dimethylamino) -3-hydroxy-6-methyltetrahydro -2H- pyran -2- yl) oxy) -14-ethyl -10, 13- dihydroxy -4- (((4R, 5S, 6S) -5-hydroxy -4-methoxy -4, 6- dimethyltetrahydro -2H- pyran -2- yl) oxy) -7-methoxy -3, 5, 7, 9, 11, 13- hexamethyloxacyclotetradec- 11- en-2-one (S1-7). S1-2 (8 g, 10.9 mmol) was dissolved in THF (50 mL) and EtOH (10 mL) and NaBH4 (824 mg, 21.8 mmol) were added. The mixture was stirred overnight and then concentrated. The residue was triturated with DCM, the solid was removed by filtration, the filtrate was concentrated, and purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 100% B) to obtain the target compound (6.8 g, 85%). MS (ESI+) m / z: 732.4 [M+H] + .

[0352]

[0353] (2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl(2R,3S,4S,5R,6R,8R,9S)-5-(((3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-hydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-10-oxoundecanoic acid (S1-8). Trifluoroacetic acid (39 mg, 0.34 mmol) was added to a solution of S1-7 (200 mg, 0.27 mmol) in DCM (5 mL) and the solution was cooled in a dry ice-acetone bath. O3 was passed through the solution until a blue color was observed. Nitrogen was passed through the solution until no blue color was observed. Me2S (0.3 mL) was added and the solution was stirred in a dry ice-acetone bath for 1 h. The solution was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to give crude S1-8. MS (ESI+) m / z: 764.2 [M+H] + .

[0354] Ozonolysis route 2

[0355] Scheme 2 provides an ozonolysis route to obtain S2-3 by first protecting compound S1-2 with a Cbz protecting group instead of the aforementioned benzyl protecting group. According to Scheme 2, S1-2 (see Scheme 1) is protected with Cbz at the C-5 erythromycin deoxyglucosamine hydroxyl group to obtain S2-1. Reduction to S2-2 and subsequent ozonolysis to obtain S2-3.

[0356] Scheme 2. Ozonolysis route 2 (PG=Cbz).

[0357]

[0358] Benzyl((3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,13S,14R,E)-14-ethyl-13-hydroxy-4-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10- Dioxocycloheteracyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)carbonate (S2-1): To a solution of S1-2 (500 mg, 0.684 mmol) in THF / H2O (1:1, 6.8 mL) was added NaOH (20% aqueous solution, 409 mg, 2.05 mmol) and then benzyl chloroformate (0.24 mL, 1.7 mmol). After 30 min, the reaction mixture was extracted with DCM, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 40% B) gave the title compound (516 mg, 87%). MS (ESI+) m / z: 864.29 [M+H] + .

[0359]

[0360] Benzyl ((3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,10S,13S,14R,E)-14-ethyl-10,13-dihydroxy-4-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl) carbonate (S2-2): To a solution of S2-1 (500 mg, 0.578 mmol) in EtOH (5.8 mL) was added NaBH4 (43.5 mg, 1.15 mmol). After 1 h, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 50% B) gave the target compound (460 mg, 92%). MS (ESI+) m / z: 866.26 [M+H] + .

[0361]

[0362] (2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl(2R,3S,4S,5R,6R,8R,9S)-5-(((3R,4S,6R)-3-(((benzyloxy)carbonyl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-hydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-10-oxoundecanoic acid (S2-3). Trifluoroacetic acid (33 mg, 0.29 mmol) was added to a solution of S2-3 (200 mg, 0.23 mmol) in DCM (5 mL), and the solution was cooled in a dry ice-acetone bath. O3 was passed through the solution until a blue color was observed. Nitrogen was passed through the solution until no blue color was observed. Me2S (0.3 mL) was added and the solution was stirred in a dry ice-acetone bath for 30 min. The solution was washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to give crude S2-3. MS (ESI+) m / z: 898.25 [M+H] + .

[0363] Conversion of S1-5 or S1-6 (ozonolysis route 1, Scheme 1) to tert-butyl ester S3-6

[0364] The ozonolysis products S1-5 and S1-6 are easily converted to the azalactone building block S3-6 according to Scheme 3. According to Scheme 3, reduction of S1-5 or S1-6 followed by periodate oxidation of the resulting alcohol S3-1 affords the diketone S3-2. Reduction of S3-2 affords S3-3. Ester hydrolysis of S3-3 with LiOH affords S3-4, which is converted to the tert-butyl ester S3-5. Removal of the erythrosin residue at C-4 of S3-5 affords S3-6.

[0365]

[0366]

[0367] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R)-1-(((2S,3R)-1,2-dihydroxy-2-methylpentan-3-yl)oxy)-9,10-dihydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1-oxoundec-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-1a). A solution of S1-5 (12.9 g, 14.8 mmol) in EtOH (125 mL) was cooled to -25 °C for 10 min. Powdered NaBH4 (1.14 g, 30.3 mmol) was added in portions. Once the addition was complete, the reaction mixture was stirred at -10 to -20 °C for 1 h. NaHCO3 (saturated aqueous solution, 100 mL) was added to the solution and the mixture was extracted with isopropyl acetate (500 mL). The organic layer was separated, washed with water (3 x 200 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (12.9 g, 100% crude) as a white foam. MS (ESI+) m / z: 872.28 [M+H] + .

[0368] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R,9S)-1-(((2S,3R)-1,2-dihydroxy-2-methylpentan-3-yl)oxy)-9,10-dihydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1-oxoundec-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-1b) was synthesized under the same conditions as compound S3-1a described in detail above.

[0369]

[0370] (3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4S,5R,6R,8R)-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,9-dioxo-1-(((R)-2-oxopentan-3-yl)oxy)nonan-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-2). A solution of crude S3-1a / b (5 g, 5.73 mmol) in EtOAc (57.3 mL) and water (4.2 mL) was cooled in an ice-water bath. NaIO4 (4.4 g, 20.6 mmol) was added and the mixture was stirred at room temperature for 2 h. The solution was poured off, diluted with EtOAc, washed with 10% Na2S2O3, water and brine. The organics were dried over Na2SO4, filtered and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 30% B) to give the title compound (2.8 g, 62%) as a white foam. MS (ESI+) m / z: 794.15 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ9.27(d,1H),8.11-7.93(m,2H),7.58-7.49(m,1H),7.42(q,2H),5.07(dd,1H),4.9 1-4.82(m,1H),4.79(d,1H),4.71(d,1H),4.00(ddt,2H),3.71(d,1H),3.61(dtt,1H),3.36(s,3H),3.08 -2.98(m,4H),2.97-2.84(m,1H),2.72(qd,1H),2.44(dpd,1H),2.30(s,6H),2.17-2.07(m,4H),1.85-1. 69(m,4H),1.58-1.39(m,3H),1.33-1.20(m,14H),1.12(dd,3H),0.99(d,3H),0.92(t,3H),0.72(d,3H).

[0371]

[0372] (3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4S,5R,6R,8R)-9-hydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-1-(((3R)-2-hydroxypentan-3-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1-oxonan-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-3). To a solution of S3-2 (9.2 g, 11.5 mmol) in EtOH (100 mL) was added NaBH4 (870 mg, 23 mmol), and the mixture was stirred at room temperature for 1 h. The solution was concentrated and the residue was redissolved in EtOAc (200 mL), washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH, gradient elution from 0 to 80% B) to give the title compound (7.2 g, 78%) as a white foam. MS (ESI+) m / z: 798.25 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ8.11-7.91(m,2H),7.54(t,1H),7.42(t,2H),5.07(dt ,1H),4.82(ddt,1H),4.70(dtd,2H),4.35-4.07(m,1H),4.01(dtd,1H),3. 76-3.21(m,12H),2.86(dtd,1H),2.70-2.51(m,1H),2.39-2.09(m,8H),1. 95-1.72(m,2H),1.69-1.04(m,27H),1.02-0.80(m,6H),0.78-0.54(m,3H).

[0373]

[0374] (2R,3S,4S,5R,6R,8R)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-hydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethylnonanoic acid (S3-4). A solution of S3-3 (900 mg, 1.12 mmol) in H2O / THF (1:3, 19.3 mL) and LiOH (134 mg, 5.6 mmol) were stirred at room temperature for 60 h. Formic acid (257 mg, 5.6 mmol) was added and the mixture was extracted with EtOAc (2×30 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM, gradient elution from 0 to 100% B) to give the title compound (570 mg, 71.5%). S3-3 (240 mg, 26.7%) was also recovered. MS (ESI+) m / z: 794.15 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ7.99(d,2H),7.53(t,1H),7.40(t,2H),5.11(dd,1H),4.69(d,4H ),3.98(dt,1H),3.92(t,1H),3.75(d,1H),3.62(dp,1H),3.53(dd,1H),3.34(s,3H), 3.21(s,4H),3.01(d,2H),2.53-2.40(m,1H),2.32(s,7H),2.08(td,1H),1.95-1.71( m,2H),1.58-1.37(m,4H),1.36-1.12(m,13H),0.99(d,3H),0.86(d,3H),0.68(d,3H).

[0375]

[0376] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R)-1-(tert-butoxy)-9-hydroxy-3-(((4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1-oxononan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-5). A solution of S3-4 (160 mg, 0.224 mmol) in toluene (2.2 mL) and N,N-dimethylformamide di-tert-butyl acetal (225 mg, 1.11 mmol) were heated at 80 °C for 2 h. The reaction solution was used directly in the next step. S3-5 was observed as the major product by LCMS. MS (ESI+) m / z: 768.26 [M+H] + .

[0377]

[0378] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R)-1-(tert-butoxy)-3,9-dihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxonan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-6). The above reaction solution and HCl (4M in dioxane, 0.36 mL, 1.45 mmol) were stirred at room temperature for 15 min. The mixture was slowly quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated. The material was purified by HPLC (Atlantis T3 column; mobile phase: A: water / 0.1% formic acid, B: CH3CN / 0.1% formic acid, gradient elution from 2% to 40% to 90% B in 15 min) to give the title compound (83 mg, 61%) as a white foam. Formate. MS (ESI+) m / z: 610.2 [M+H] + ; 1HNMR (400MHz, chloroform-d) δ8.06-8.00 (m, 2H), 7.57 (t, 1H), 7.43 (t, 2H), 5.20 (dd, 1H), 4.97 (d, 1H), 3.87 (d, 1H), 3.73-3.53 (m, 2H), 3.52-3.42 (m, 2H), 3.18 (s, 4H), 2.57 (s, 6H), 2. 47-2.33(m,1H),2.23-2.02(m,2H),1.83(qd,1H),1.58-1.46(m,1H),1.46-1.40(m,1H) ,1.38(s,9H),1.34-1.21(m,8H),1.18(d,3H),1.14(dd,1H),0.81(d,3H),0.56(d,3H).

[0379] Alternative method for preparing S3-6 (Scheme 3) via ozonolysis route 3

[0380] An alternative method for preparing the azalactone building block S3-6 is shown in Scheme 4. According to Scheme 4, the C-4 erythromycin residue is first removed under acidic conditions to obtain S4-1. The C-5 erythromycin deoxyglycosamine hydroxyl group is protected and then the resulting compound S4-2 is reduced to obtain the ozonolysis substrate S4-3. S4-5 is prepared by ozonolysis and then reduction of S4-3 with and without isolation of intermediate S4-4. The transformation of S4-5 to S3-6 was achieved via several 4-step routes, including (i) hydrolysis, esterification, periodate oxidation and reduction (S4-5→S4-10→S4-11→S4-12→S3-6); (ii) periodate oxidation, hydrolysis, esterification, reduction (S4-5→S4-6→S4-9→S4-10→S3-6); and (iii) periodate oxidation, reduction, hydrolysis, esterification (S4-5→S4-6→S4-7→S4-8→S3-6).

[0381]

[0382]

[0383] (3R,4S,5S,6R,7R,9R,13S,14R,E)-6-(((3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxacyclotetradec-11-ene-2,10-dione (S4-1). To a 2L three-necked round bottom flask equipped with an overhead stirrer, temperature probe, nitrogen inlet and outlet was added S1-2 (97 g, 133 mmol) and then methanol (500 mL). The reaction mixture was stirred until a clear solution was formed. The solution was cooled in a water bath and 6N HCl (161 mL, 798 mmol, 6 equiv) was added over about 20 min while maintaining the internal temperature at 20-25 °C. After 2 h, UPLC-MS analysis showed >99% conversion. 28-30% NH4OH aqueous solution (200 mL) was added to adjust the pH to 9-10, and water (100 mL) was added. The reaction mixture was stirred for another 16 h. The resulting white solid was collected by filtration, washed with MeOH / H2O (2:3, 300 mL), and dried in a vacuum oven at 35--40°C for 72 h. The target compound (45 g, 59%) was obtained as a white solid. MS (ESI+) m / z: 572.27 [M+H] + .

[0384]

[0385] (3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,13S,14R,E)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-2). A 500 mL three-necked round-bottom flask equipped with a temperature probe, a stirrer, a nitrogen inlet and outlet was charged with S4-1 (26 g, 45.4 mmol) and then DCM (250 mL). The mixture was stirred at room temperature until a clear light brown solution was obtained. Triethylamine (18.8 mL, 136 mmol, 3 eq.) and benzoic anhydride (20.5 g, 90.8 mmol, 2 eq.) were loaded. The reaction mixture was heated at 40 °C for 24 h, at which time UPLC-MS showed >99% conversion. After cooling to room temperature, the reaction mixture was washed with 2N NaOH (50 mL×2) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0 to 100% 80% DCM / 20% MeOH / 0.5% NH4OH aqueous solution in DCM) to give the desired product (26 g, 85%) as a white foam. MS (ESI+) m / z: 676.27 [M+H].

[0386]

[0387] (3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,10S,13S,14R,E)-14-ethyl-4,10,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-3). A 1 L round bottom flask equipped with a temperature probe, a stir bar, a nitrogen inlet and outlet was charged with S4-2 (22 g, 32.5 mmol) and anhydrous EtOH (200 mL). The mixture was stirred at room temperature until a clear solution was obtained. NaBH4 (2.45 g, 65 mmol, 2 equiv) was added in one portion. The mixture was stirred at room temperature for 16 h, at which time UPLC-MS showed a conversion of >99%. Water (50 mL) and saturated NH4Cl aqueous solution (20 mL) were added to quench the reaction. The mixture was concentrated to remove most of the EtOH, diluted with EtOAc (250 mL), and the two layers were separated. The organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in MTBE (100 mL) at 40--50 ° C, and hexane (200 mL) was added at the same temperature. The mixture was cooled to room temperature and stirred overnight. The resulting white solid was collected by filtration and dried in a vacuum oven at 35-40 ° C for 72 h to obtain the target compound (12.7 g, 58%). MS (ESI+) m / z: 678.22 [M+H].

[0388]

[0389] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R,9S)-3,9-dihydroxy-1-(((2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,10-dioxonadecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-4). S4-3 (410 mg, 0.6 mmol) was added to a 100 mL round bottom flask, followed by DCM (10 mL) and TFA (103 mg, 1.5 equiv). The solution was cooled to -65°C to -75°C with a dry ice / acetone cold bath, and O3 was passed through the solution until the color turned blue (approximately 5 min). Nitrogen was then passed through the solution until the blue color disappeared. Dimethyl sulfide (0.3 mL, 6.7 eq.) was added and the reaction mixture was stirred for 1 h. Saturated NaHCO3 aqueous solution (5 mL) was added and separated into two layers. The DCM layer was dried over Na2SO4 and concentrated to give a white foam (490 mg), which was used in the next step without further purification. MS (ESI+) m / z: 710.15 [M+H].

[0390]

[0391] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R,9S)-1-(((2S,3R)-1,2-dihydroxy-2-methylpentan-3-yl)oxy)-3,9,10-trihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxoundec-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-5).

[0392] Method 1: Crude S4-4 (490 mg, 0.6 mmol) was added to a 100 mL round-bottom flask, and EtOH (5 mL) was added. NaBH4 (51 mg, 2 eq) was added at room temperature, and the reaction mixture was stirred overnight. Saturated NH4Cl aqueous solution (2 mL) was added, and the mixture was stirred for 1 h. Water (2 mL) was added, and the mixture was stirred for 1 h. The mixture was concentrated to remove most of the EtOH and extracted with EtOAc (15 mL×2). The combined extracts were dried and concentrated to give a white foam (470 mg), which was used in the next step without further purification. MS (ESI+) m / z: 714.10 [M+H].

[0393] Method 2: S4-3 (1.6 g, 2.4 mmol) was added to a 100 mL round bottom flask, followed by MeOH (8 mL), DCM (10 mL) and TFA (0.24 mL, 1.5 eq). The solution was cooled to -78°C to -45°C. O3 was passed through the solution for 20 min, at which time UPLC-MS showed that the starting material was consumed. NaBH4 (446 mg, 5 eq) was added, and the reaction mixture was stirred at room temperature for 5 h. Saturated aqueous NH4Cl solution (2 mL), water (10 mL) and EtOAc (20 mL) were added, and the mixture was stirred for 16 h. The organic phase was separated, concentrated, and the residue was purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM 0-100% gradient) to give the desired product (400 mg, 24%) as a white foam. MS (ESI+) m / z: 714.25 [M+H].

[0394]

[0395] (3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4S,5R,6R,8R)-3-hydroxy-6-methoxy-2,4,6,8-tetramethyl-1,9-dioxo-1-(((R)-2-oxopentan-3-yl)oxy)nonan-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-6). Crude S4-5 (470 mg, 0.6 mmol) was added to a 100 mL round bottom flask, followed by EtOAc (5 mL) and water (6 drops). NaIO4 (412 mg, 3 equiv) was added and the reaction mixture was stirred for 3 h. The mixture was diluted to 30 mL with EtOAc, washed with 13% NaCl solution (5 mL), dried, and concentrated to a viscous oil (410 mg). The material was used in the next step without further purification. MS (ESI+) m / z: 636.19 [M+H].

[0396]

[0397] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R)-3,9-dihydroxy-1-(((3R)-2-hydroxypentan-3-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1-oxononan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-7). Crude S4-6 (410 mg, 0.6 mmol) was added to a 100 mL round bottom flask and EtOH (5 mL) was added. NaBH4 (48 mg, 2 equiv) was added and the reaction mixture was stirred for 30 min. Water (2 mL) was added and the mixture was stirred for 30 min. Ethyl acetate (20 mL) was added and the two phases were separated. The organic phase was concentrated and the residue was purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% NH4OH in DCM, 0-100% gradient) to give the desired product as a white foam (180 mg, 44% compared to S3-3). MS (ESI+) m / z: 640.24 [M+H].

[0398]

[0399] (2R,3S,4S,5R,6R,8R)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,9-dihydroxy-6-methoxy-2,4,6,8-tetramethylnonanoic acid (S4-8). S4-7 (150 mg, 0.23 mmol) was added to a 50 mL round bottom flask, followed by THF (3 mL) and water (3 mL). LiOH (34 mg, 6 equiv) was added and the reaction mixture was stirred overnight. The reaction mixture was neutralized to pH about 5, extracted with EtOAc (3×5 mL), and concentrated to give the title compound (140 mg) as a white foam. MS (ESI+) m / z: 554.08 [M+H].

[0400]

[0401] (2R,3S,4S,5R,6R,8R)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-6-methoxy-2,4,6,8-tetramethyl-9-oxononanoic acid (S4-9). S4-6 (170 mg, 0.27 mmol) was added to a 50 mL round bottom flask, followed by MeCN (3 mL) and water (1 mL). LiOH (19 mg, 3 eq) was added and the reaction mixture was stirred for 1 h. The reaction mixture was neutralized to pH about 5 and solid NaCl was added to saturation. The mixture was extracted with EtOAc (3×5 mL) and the combined extracts were concentrated. The residue was purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM 0-100% gradient) to give the title compound (160 mg, 100%) as a white foam. MS (ESI+) m / z: 552.13 [M+H].

[0402]

[0403] (2R,3S,4S,5R,6R,8R)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-6-methoxy-2,4,6,8-tetramethyl-9-oxononanoic acid (S4-12). S4-9 (30 mg, 0.27 mmol) was added to a 50 mL round bottom flask, and THF / hexane (0.3 mL / 0.3 mL) was added. Under nitrogen, tert-butyl 2,2,2-trichloroethylimidate (24 mg, 2 equiv.) and BF3·Et2O complex (1 drop) were added. After 24 h, tert-butyl 2,2,2-trichloroethylimidate (2 equiv.) and anhydrous DMF (0.1 mL) were added, and the reaction mixture was stirred for 16 h. The mixture was purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM 0-100% gradient) to give the title compound (14 mg, 42%) as a white foam. MS (ESI+) m / z: 608.10 [M+H].

[0404]

[0405] (2R,3S,4S,5R,6R,8R,9S)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,9,10-trihydroxy-6-methoxy-2,4,6,8-tetramethylundecanoic acid (S4-10). S4-5 (1.9 g, 2.7 mmol) was added to a 100 mL round bottom flask, followed by CH3CN (25 mL) and water (10 mL). LiOH (96 mg, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove most of the ACN and 6N HCl was added dropwise until the solution reached pH about 6. EtOAc (30 mL) was added followed by solid NaCl until the aqueous phase was saturated. The organic phase was separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to afford the title compound (1.35 g, 85%) as a white foam, which was used in the next step without further purification. MS (ESI+) m / z: 598.16 [M+H].

[0406]

[0407] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R,9S)-1-(tert-butoxy)-3,9,10-trihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxoundec-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-11). S4-10 (1.35 g, 2.25 mmol) was added to a 100 mL round bottom flask and anhydrous DCM (15 mL) was added. Under nitrogen, tert-butyl 2,2,2-trichloroethylimidate (2 g, 4 equiv) and BF3·Et2O complex (160 mg, 0.5 equiv) were added and the reaction mixture was stirred at room temperature for 48 h. After concentration, the residue was purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% NH4OH in DCM, 0-100% gradient) to afford the title compound (1 g, 68%) as a white foam. MS (ESI+) m / z: 654.28 [M+H].

[0408]

[0409] (2R,3S,4S,5R,6R,8R)-5-(((3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-hydroxy-6-methoxy-2,4,6,8-tetramethyl-9-oxononanoic acid (S4-12). S4-11 (34 mg, 0.05 mmol) was added to a 2 mL vial and DCM (1 mL) was added. NaIO4 / SiO2 (226 mg, 3 eq., 14.6% w / w, prepared according to the published paper Zhong, YL and Shing, TKMJ Org. Chem., 1997, 62(8), 2622-2624) was added and the reaction mixture was stirred for 1 h. The reaction mixture was filtered and the solid was washed with EtOAc (20 mL×3). The filtrate was concentrated and purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% NH4OH aqueous solution in DCM 0-100% gradient) to give the title compound (21 mg, 68%) as a white foam. MS (ESI+) m / z: 608.15 [M+H]. 1H NMR (400 MHz, chloroform-d) δ9.15 (d, 1H), 7.98-7.96 (m, 2H), 7.49-7.45 (m, 1H), 7.37-7.34 (m, 2H), 5.01-4.97 (m, 1H), 4.74-4.72 (m, 1H), 3.70 (m, 1H), 3.52-3.44 (m, 2H), 3.41 (s, 1H), 3.14--3.03 (m, 1H), 2.96 (s, 3H), 2.89-2.83 (m, 1H), 2.34-2.29 (m, 1H), 2.22 (s, 6H), 2.12-2.05 (m, 1H), 1.75-1.69 (m, 2H), 1.62 -1.56(m,1H),1.44-1.36(m,1H),1.32(s,9H),1.20(d,3H),1.17(s,3H),1.08(d,3H),0.88(d,3H),0.59(d,3H).

[0410]

[0411] (3R,4S,6R)-2-(((2R,3S,4S,5R,6R,8R)-1-(tert-butoxy)-3,9-dihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxononan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-6). S4-12 (100 mg, 0.16 mmol) was added to a 20 mL vial and EtOH (1 mL) was added. NaBH4 (12.4 mg, 2 equiv) was added and the mixture was stirred for 15 min. The reaction mixture was concentrated and purified by silica gel column chromatography (80% DCM / 20% MeOH / 0.5% NH4OH in DCM 0-100% gradient) to give the title compound (88 mg, 88%) as a white foam. MS (ESI+) m / z: 610.30 [M+H].

[0412] Conversion of S1-2 to S5-7 using ozonolysis route 4

[0413] Another method for preparing the azalactone building block S5-7 via ozonolysis route 4 is shown in Scheme 5. Protection of S1-2 gives S5-1. Conversion of S5-1 to S5-7 is achieved via two routes. In the first, ozonolysis of S5-1, followed by reduction, hydrolysis, and esterification (protection) with benzyl bromide gives the ester S5-5. Periodic acid oxidation of S5-5, followed by reduction of S5-6, gives S5-7. Alternatively, reduction of S5-1, followed by ozonolysis, hydrolysis, and esterification (protection) with benzyl bromide gives S5-11. Periodic acid oxidation of S5-11 gives S5-6, followed by reduction to give S5-7.

[0414]

[0415]

[0416] (2S,3S,4R,6R)-6-(((3R,4S,5S,6R,7R,9R,13S,14R,E)-6-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradec-11-en-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-1). S1-2 (30 g, 41 mmol) was charged to a 500 mL three-necked round bottom flask equipped with a stir bar, temperature probe, nitrogen inlet and outlet, and then anhydrous DCM (150 mL). The solution was cooled with an ice-water bath, and DMAP (8.7 g, 71.2 mmol, 1.74 equiv) and triethylamine (6.22 g, 61.5 mmol, 1.5 equiv) were added. Benzoyl chloride (11.8 g, 108 mmol, 2.05 equiv) was added dropwise while maintaining the internal temperature below 25°C. The addition was completed in about 15 min. The reaction mixture was then stirred at room temperature for 16 h. The solution was concentrated, diluted with IPAc (300 mL), washed with H2O (50 mL), 50% saturated K2CO3 (50 mL), and 50% saturated NaH2PO4 (2×50 mL), dried over Na2SO4, and concentrated to a viscous oil. The product was crystallized from EtOH / H2O (2:1) to give the title compound as a white solid (29.5 g, 79%). MS (ESI+) m / z: 938.30 [M+H].

[0417] Large-scale process for preparing S5-1

[0418] Method 1. S1-2 (745 g, 1.02 mol) was charged into a 4 L three-necked jacketed reactor equipped with an overhead stirrer. Dichloromethane (2.5 L) was then added, cooled to 0°C, and the reactor was equipped with a thermometer and nitrogen flow. DMAP (124 g, 1.02 mol, 1 eq) was added to the orange solution followed by TEA (212 mL, 1.53 mol, 1.5 eq). BzCl (241 mL, 2.09 mol, 2.05 eq) was added slowly while keeping the internal temperature below 25°C. The reaction mixture was stirred at room temperature for 16 h. The solution was then washed with water (1.5 L) followed by NaH2PO4 (1.5 L) and then 50% brine (1 L). The washed solution was dried over Na2SO4, filtered, and concentrated to near dryness. The residue was crystallized from MTBE / heptane (5:1, 1.5 L / 0.3 L) to give the target compound (666.9 g, 70%).

[0419] Method 2. A 400 L jacketed reactor was equipped with an overhead stirrer, a thermometer, and a nitrogen inlet and outlet. S1-2 (7.5 kg) was charged, followed by dichloromethane (35 kg), TEA (2.9 kg), and DMAP (0.9 kg). The reaction mixture was cooled to 5-10° C. BzCl (4.5 kg) was slowly charged into the reactor over 1-1.5 h while maintaining the internal temperature below 15° C. The reaction mixture was stirred at 23-27° C. for 16-18 h, and then at 35-40° C. for 5 h. After cooling to 0-15° C., water (5.0 kg) was slowly poured into the mixture over 1-1.5 h while maintaining the internal temperature below 15° C. Stirring was continued at 0-15° C. for 30 min. 40% NaH2PO4 (12.5 kg) was slowly added while maintaining the internal temperature below 25° C. After stirring at 0-15° C. for 20-30 min, the mixture was allowed to stand until two clear layers were formed. The organic phase was separated and washed with 40% NaH2PO4 (12.5 kg). The resulting organic phase was washed twice with 25% K2CO3 (10.0 kg). The organic phase was then diluted with EtOH (18 kg) and concentrated to 3.5-4 volumes. The EtOH (18 kg) replacement was repeated. EtOH (12 kg) was then added to the organic phase and the solution was heated to 40-45°C. Water (45 kg) was slowly added to the mixture at this temperature over 1 hour while stirring and then stirred at 20-25°C for 2-3 hours. The white solid was filtered, washed with EtOH / water (1 / 4) and dried to constant weight (8.0 kg, 89%).

[0420] Method 3. 49.1 kg S1-2, 230.4 kg DCM, 21.8 kg TEA and 4.3 kg DMAP were charged into a glass-lined reactor. The temperature was adjusted to -5-5°C. 25.0 kg BzCl was slowly added dropwise to the reaction mixture at -5-5°C. The temperature was adjusted to 15-25°C and the mixture was stirred for 20-22 hours. 100.9 kg H2O was slowly added dropwise to the reaction mixture at about 0 to 10°C. NaH2PO4 (wt% = 20%, aqueous solution) was poured into the reaction mixture and stirred for 10-20 min. The aqueous phase was removed. NaH2PO4 (wt% = 20%, aqueous solution) was poured into the reaction mixture and stirred for 10-20 min. The aqueous phase was removed. 35.9 kg K2CO3 (wt% = 25%, aqueous solution) was poured into the reaction mixture and stirred for 10-20 min. The aqueous phase was removed. 35.9 kg K2CO3 (wt% = 25%, aqueous solution) was poured into the reaction mixture and stirred for 10-20 min. The aqueous phase was removed. 110 kg MTBE was poured into the organic phase. The organic phase was then concentrated to 5-6 volumes at 30-40°C under vacuum (about -60 kPa to -100 kPa). 109.7 kg MTBE was poured into the organic phase. The organic phase was then concentrated to 5-6 volumes at 30-40°C under vacuum (about -60 kPa to -100 kPa). 73.0 kg MTBE was added to the residue. The mixture was stirred at about 30 to 40°C for about 1-2 hours. 339.6 kg n-heptane was then slowly added dropwise to the reaction mixture, which was then stirred at 30-40°C for 1-2 hours and then centrifuged. The resulting centrifuge cake was then washed with a mixture of MTBE (109.6 kg) / n-heptane (101.4 kg) solution and dried at 45-50°C for 11-13 hours. 59.48 kg of white solid S5-1 was obtained, with a yield of 94.2%.

[0421]

[0422] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(((2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,9,10-trioxonadecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-2). Prepared from S5-1 (14.4 g, 15.3 mmol) according to the method of S4-4 to give the target compound (14.3 g) as a white foam, which was used in the next step without further purification. MS (ESI+) m / z: 970.39 [M+H] + .

[0423]

[0424] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(((2S,3R)-1,2-dihydroxy-2-methylpentan-3-yl)oxy)-9,10-dihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxonadecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-3). Prepared by NaBH4 reduction starting from S5-2 (15 g, 15.4 mmol) according to the method of S4-5 to give the target compound (14 g) as a white foam, which was used in the next step without further purification. MS (ESI+) m / z: 976.19 [M+H] + .

[0425]

[0426] (2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((2R,4R,5S,6S)-5-(benzoyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-9,10-dihydroxy-6-methoxy-2,4,6,8-tetramethylundecanoic acid (S5-4). Prepared from S5-3 (2.25 g, 2.3 mmol) according to the method of S4-10 to give the title compound (1.4 g, 71%) as a white foam. MS (ESI+) m / z: 860.15 [M+H] + .

[0427]

[0428] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(benzyloxy)-9,10-dihydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxoundec-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-5). S5-4 (8.7 g, 10.1 mmol) was dissolved in CH3CN (90 mL) in a 500 mL round-bottom flask. DBU (1.65 mL, 11.1 mmol, 1.1 equiv) and benzyl bromide (1.38 mL, 11.6 mmol, 1.15 equiv) were added and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was redissolved in IPAC (120 mL). It was washed with 13% NaCl (50 mL), dried over Na2SO4 and concentrated to give the title compound (8.8 g) as a white foam. MS (ESI+) m / z: 950.18 [M+H] + .

[0429]

[0430] (2S,3S,4R,6R)-6-(((3R,4S,5S,6R,7R,9R,10S,13S,14R,E)-6-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-10,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2-oxooxacyclotetradec-11-en-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-8). According to the method of S4-3, S5-1 (10.5 g, 12.2 mmol) was prepared in EtOH / THF (1 / 1) to obtain the target compound (11.5 g) as a white foam, which was used in the next step without further purification. MS (ESI+) m / z: 940.30 [M+H] + .

[0431] Large-scale process for preparing S5-8

[0432] Method 1. Under the protection of a nitrogen balloon, S5-1 (315.56 g) was added to a 5 L jacketed reactor equipped with a mechanical stirrer, and THF (1.39 L) and MeOH (1.39 L) were added. The mixture was stirred at about 0-3 ° C to form a yellow solution. CeCl3·7H2O (275.71 g, 2.2 eq.) was added to the solution while stirring until all solids were dissolved. NaBH4 (27.99 g, 2.2 eq.) was added in portions, and the mixture was stirred at about 2-5 ° C for 50 min, at which time HPLC showed a conversion of >99%. H2O (316 mL) was slowly added to the reaction mixture, and the pH of the mixture was adjusted to a pH of about 5-6 with 3N HCl with the appearance of some white solids. The mixture was concentrated to remove most of the THF and MeOH. DCM (1.35 L) was then added, and the reaction mixture was washed with water (315 mL×2). The aqueous phase was separated and the organic phase was concentrated to give a yellowish oily crude S5-8. MTBE (945 mL, 3 volumes) was added to the reaction mixture while stirring to form a white turbid mixture. Hexane (1.89 L, 6 volumes) was then slowly added and the mixture was stirred for 1 h. The white solid was filtered, washed with solvent (500 mL, MTBE / hexane (v / v) = 1 / 2), and then dried under high vacuum at 50 ° C for 16 h to give S5-8 (287 g, 90.6% yield).

[0433] Method 2. 65.0 kg S5-1, 578.6 kg THF and 1026.8 kg MeOH were loaded into a glass-lined reactor (3000 L). The mixture was stirred at 100 rpm for 10-20 minutes at 15-25°C. Then 57.0 kg CeCl3·7H2O was poured into the reaction mixture. The mixture was stirred at 15-25°C for 10-20 minutes. The temperature was then adjusted to 0-10°C. Then 6.3 kg NaBH4 was added to the reaction mixture in portions while the internal temperature was kept at 0-10°C. The temperature was adjusted to 15-25°C and the mixture was stirred for 1-2 hours. Then 130.0 kg H2O was slowly added to the reaction mixture while the internal temperature was kept at 0-10°C. The temperature was adjusted to 15-25°C and the mixture was stirred for 10-20 minutes. Then 23.9 kg HCl (wt% = 10.5%, aqueous solution) was added to the reaction mixture, which was stirred for 10-20 minutes and the pH was adjusted to 5-6. Then 325.0 kg H2O was poured into the reaction mixture. The mixture was then concentrated to 3-4 volumes at 35-45°C in vacuo to remove most of the THF and MeOH. Then 585.0 kg DCM was poured into the concentrated reaction mixture. The resulting mixture was stirred at 15-25°C for 20-40 minutes and then allowed to stand at 15-25°C for 20-40 minutes. The organic layer and the aqueous layer were separated. 429.1.0 kg DCM was poured into the aqueous layer. The mixture was stirred at 15-25°C for 20-40 minutes and then allowed to stand at 15-25°C for 20-40 minutes. The organic layer and the aqueous layer were separated. The organic layers were combined. 130.0 kg H2O was poured into the combined organic layers. The mixture was stirred at 15-25°C for 20-40 minutes. Separate the organic layer and discard the aqueous layer. Pour 429.0 kg of n-hexane into the organic layer. Then concentrate the mixture to 8-10 volumes at 20-30° C. in a vacuum. Pour 214.5 kg of n-hexane into the mixture. Then concentrate the mixture to 8-10 volumes at 20-30° C. in a vacuum to obtain a white suspension. Pour 215.5 kg of n-hexane into the mixture. Then concentrate the mixture (suspension) to 8-10 volumes at 20-30° C. in a vacuum to obtain a white suspension. Pour 48.1 kg of MTBE into the white suspension. Adjust the temperature to 20-30° C. and keep it for 2-3 hours. Then filter the white suspension to remove the organic layer. Then wash the resulting filter cake with 133.3 kg of n-hexane. Discard the filtrate. The filter cake was slurried with MeOH: 51.8 kg (0.796 w / w), MTBE: 167.2 kg (2.57 w / w) and n-hexane: 86.7 kg (1.33 w / w) at 35-45°C. The slurry was stirred at 35-45°C for 1-2 h and then at 0-10°C for 1-2 h. The white suspension was filtered to remove the organic layer. The resulting filter cake was washed with 115.2 kg n-hexane. The filter cake was then vacuum dried at 45-55°C for 15-17 hours.S5-8 was obtained as a white solid, 55.64 kg, with a yield of 85.42% and a purity of 92.3%.

[0434]

[0435] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R,9S)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-hydroxy-1-(((2R,3R)-2-hydroxy-2-methyl-1-oxopentan-3-yl)oxy)-6-methoxy-2,4,6,8-tetramethyl-1,10-dioxoundec-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-9). Prepared from S5-8 (11.4 g, 12.2 mmol) according to the method of S4-4 to give the target compound (12.2 g) as a white foam, which was used in the next step without further purification. MS (ESI+) m / z: 972.39 [M+H] + .

[0436] Prepared from S5-8 (30.0 g, 32.0 mmol) according to the method of S4-4, using 3.6 equivalents of TFA and replacing Me2S with triphenylphosphine (1.2 equivalents), the crude target compound (45 g) was obtained as a white foam, which was used in the next step without further purification.

[0437] Prepared from S5-8 (0.5-30 g) according to the method of S4-4, using 2.4-4.8 equivalents of TFA and quenching the reaction with a reducing agent such as triphenylphosphine, HOAc / Zn, trimethoxyphosphine, triethoxyphosphine, etc. The crude target compound was used in the next step without further purification.

[0438]

[0439] (2R,3S,4S,5R,6R,8R,9S)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((2R,4R,5S,6S)-5-(benzoyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-9-hydroxy-6-methoxy-2,4,6,8-tetramethyl-10-oxoundecanoic acid (S5-10). Prepared from S5-9 (11.8 g, 12.2 mmol) according to the method of S4-10 to give the title compound (11.5 g) as a white foam. MS (ESI+) m / z: 858.15 [M+H]+ ; 1 H NMR (400 MHz, chloroform-d) δ 8.06-8.02 (m, 4H), 7.64-7.54 (m, 2H), 7.50-7.43 (m, 4H), 5.79 (s, 1H), 5.13-5.08 (m, 1H), 4.95-4.90 (m, 2H), 4.85-4.81 (m, 1H), 4.55-4.47 (m, 1H), 3.96-3.89 (m, 1 H),3.77(d,1H),3.72(d,1H),3.55(s,3H),3.17(s,3H),3.07-2.94(m,1H),2.81-2.77(m,1 H),2.54-2.50(m,1H),2.35(s,6H),2.28-2.24(m,1H),1.82(s,3H),1.76-1.71(m,2H),1.65 -1.60(m,2H),1.36(s,3H),1.27(m,4H),1.22(s,3H),1.17(d,3H),1.15(d,3H),0.98(d,3H),0.84(t,3H),0.75(d,3H).

[0440] Method 2. S5-9 (100 g) was stirred in CH3CN (500 mL) at 25-26°C until all solids dissolved. H2O (500 mL) was added to the reaction mixture. LiOH·H2O (4.82 g, 1.1 eq) was added to the mixture at 0-3°C and stirred at 14-17°C for 2 h. The reaction mixture was concentrated to remove most of the CH3CN. MTBE (50 mL) was added and stirred for 10 min and the two phases were separated. The MTBE extraction was repeated. The aqueous phase was separated and concentrated to remove most of the MTBE soluble in water. A 3N HCl aqueous solution was added to the aqueous phase by adjusting the pH to 6-7 until the phase turned turbid. The white solid was filtered and dried under high vacuum at 45-46°C for 16 h to obtain the target compound (57.18 g, 64.4% yield).

[0441] Method 3. S5-9 (41.2 g) was dissolved in CH3CN (200 mL) and water (136 mL) was added. The mixture was cooled to 0-5°C. Aqueous NaOH solution (1N, 64 mL) was added and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to remove most of the CH3CN (about 200 mL), leaving a viscous residue (about 240 g). Water (100 mL) was added and the diluted mixture was extracted with MTBE (200 mL). The aqueous phase was neutralized to a pH of about 5-7 with 3N HCl (about 22 mL) and extracted with DCM (250 mL). The aqueous phase was extracted again with DCM (100 mL) and the combined organic phases were concentrated. The residue was dissolved in EtOH (160 mL) at 65-75°C and heptane (200 mL) was added. The solution was stirred at ambient temperature for 16 h. The white solid was collected by filtration and dried under high vacuum at 35-45 °C for 16 h to give the title compound (28.6 g, 78.8%).

[0442] Large-scale process for preparing S5-10

[0443] Method 4. 5279.2 kg of S5-9 in DCM solution (source: 98.0 kg S5-8) was charged into a glass-lined reactor (3000 L). The solution was concentrated to 3-6 volumes at 15-25°C under vacuum. 363.0 kg of ACN was charged into the reactor. The mixture was concentrated to 3-6 volumes at 15-25°C under vacuum. 160.2 kg of ACN was charged into the reactor. The mixture was concentrated to 4-6 volumes at 15-25°C under vacuum. 121.3 kg of ACN was charged into the reactor. The mixture was concentrated to 3-6 volumes at 15-25°C under vacuum, from which 425.7 kg of S5-9 in ACN was obtained. 509.6 kg of H2O was poured into the solution. The internal temperature was adjusted to 5-15°C, and 125.3 kg of NaOH (wt%=3.85%, aqueous solution) was slowly added while maintaining the internal temperature at 5-15°C. The mixture was stirred at 15-25°C for 2-4 hours and then concentrated under vacuum to 5-7 volumes at 20-30°C to remove most of the ACN. Then 305.6 kg H2O and 454.5 kg MTBE were charged to the reactor. The mixture was stirred for 15-25 minutes and then allowed to stand at 10-20°C for 25-35 minutes. The organic layer and the aqueous layer were separated. The organic layer was discarded. Then 34.3 kg HCl (wt% = 9.75%, aqueous solution) was slowly added to the aqueous layer and the pH was adjusted to 5-7 at 10-20°C. 944.2 kg DCM was poured into the quenched solution and then stirred at 10-20°C for 25-35 minutes. The mixture was then allowed to stand for 25-35 minutes. The organic layer and the aqueous layer were separated. 405.7 kg DCM was poured into the aqueous layer and the resulting solution was stirred at 10-20°C for 25-35 minutes and then allowed to stand at 10-20°C for 25-35 minutes. Separate the organic layer and the aqueous layer. The combined organic layer is concentrated to 2-4 volumes at 25-35°C in a reactor (3000L). 241.5kg EtOH is loaded into the reactor. The mixture is concentrated to 2-4 volumes at 25-35°C in a vacuum to obtain a white suspension. 161.4kg EtOH is added to the mixture. The mixture is concentrated to 2-4 volumes at 25-35°C in a vacuum to obtain a white suspension. 40.6kg EtOH is poured into the suspension and stirred at 55-65°C for 10-40 minutes. Then 349.2kg n-hexane is poured into the white suspension. The temperature is adjusted to 55-65°C and maintained for 2-3 hours. The internal temperature is adjusted to 5-15°C and the mixture is stirred for 2-3 hours. The white suspension is filtered to obtain a wet cake. The cake is washed with 349.5kg n-hexane. The filtrate is discarded. The cake was dried under vacuum at 35-45°C for 15-24 hours to obtain S5-10 as a white solid, 54.05 kg.

[0444]

[0445] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R,9S)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(benzyloxy)-9-hydroxy-6-methoxy-2,4,6,8-tetramethyl-1,10-dioxoundec-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-11). Prepared from S5-10 (1.6 g, 1.9 mmol) according to the method of S5-5. Purification by silica gel column (80% DCM / 20% MeOH / 0.5% NH4OH aqueous solution in DCM 0-100% gradient) gave the title compound (1.0 g, 57%) as a white foam. MS (ESI+) m / z: 948.23 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.07-8.02 (m, 2H), 8.02-7.95 (m, 2H), 7.65-7.56 (m, 1H), 7.52 (td, 1H), 7.46 (t, 2H), 7.40 (t, 2H), 7.34 (s, 5H), 5.18-4.96 (m, 3H), 4.91 (d, 1H), 4.86-4.77 (m, 2H), 4.47 (dq, Hz, 1H), 4.08 (d, 1H), 3.94 (t, 1H), 3.78 (t, 1H), 3.75-3.69 (m, 1 H),3.67(d,1H),3.38(d,3H),3.09(s,3H),2.99-2.85(m,1H),2.75(qd,1H),2.32(s,6H),2.14(s,3H),2.05(dd,1H),1.70(dd,3 H),1.49-1.40(m,1H),1.37(d,1H),1.31(dd,1H),1.26(s,3H),1.18(d,4H),1.12(d,6H),1.01(d,3H),0.96(d,3H),0.67(d,3H).

[0446] S5-10 (24.5 g, 28.5 mmol) was dissolved in DMF (anhydrous, 100 mL) and K2CO3 (4.72 g, 34.2 mmol) and BnCl (3.92 mL, 34.2 mmol) were added. The mixture was heated at 40°C for 16 h under nitrogen. In another flask, 75 mL of brine was diluted with 425 mL of deionized water. The DMF solution was slowly added to the aqueous solution at room temperature while stirring vigorously. The resulting mixture was stirred for another 16 h. The white solid was collected by filtration and dried under high vacuum at 35-45°C for 16 h to obtain the target compound (26.5 g, 98.1%).

[0447] S5-10 (65 g) was dissolved in DCM (650 ml) in a 5 L jacketed reactor and stirred at 24-25 °C under nitrogen. Et3N (15.33 g), BnOH (9.01 g) and 2,4,6-trichlorobenzoyl chloride (22.17 g) were added and the resulting mixture was stirred at 24-25 °C for 30 min. DMAP (1.30 g) was added and the resulting reaction mixture was stirred at 24-25 °C for 1 h. The reaction mixture was concentrated to remove most of the DCM and diluted with MTBE (975 mL). The organic phase was washed with aqueous NaOH (1 N, 2×264 mL), aqueous NaH2PO4 (50%, 325 mL) and 13% aqueous NaCl (325 mL). The organic phase was concentrated under reduced pressure at 35-36 °C to give the target compound (75.7 g) as a white foam, which was used in the next step without further purification.

[0448] Large-scale process for preparing S5-1

[0449] 53.5 kg S5-10, 201.9 kg DMF and 11.3 kg K2CO3 were loaded into a glass-lined reactor (1000 L). 9.2 kg BnCl was slowly added dropwise to the reaction mixture while maintaining the internal temperature at 25-35 ° C. The internal temperature was adjusted to 30-45 ° C. The mixture was stirred for 17-19 hours. Then 540.0 kg H2O was slowly added dropwise to the mixture, which was then stirred at 15-25 ° C for 5-7 hours to obtain a white suspension. The white suspension was filtered to remove the organic layer. The cake was washed with 1080.0 kg H2O in batches. The filtrate was discarded. The filtrate was dried with a filter dryer at 0-5 ° C. 44.0 kg S5-11 was obtained as a white solid, which contained about 7% DMF. 44.0 kg S5-11 and 220 kg H2O were loaded into a glass-lined reactor (300 L). The mixture was stirred at 0-5 ° C for 15-25 ° C. The mixture was filtered to remove the water layer. The cake was washed with 1080.0 kg of H2O in portions. The solid was dried in a filter dryer at 0-5°C under vacuum with nitrogen flow for 98 h to obtain 41.3 kg of S5-11 as a white solid.

[0450]

[0451] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(benzyloxy)-6-methoxy-2,4,6,8-tetramethyl-1,9-dioxonan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-6). Prepared according to the method of S4-12 starting from S5-5 or S5-11, the title compound was obtained as a white foam. MS (ESI+) m / z: 904.11 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ9.27 (d, 1H), 8.08-8.01 (m, 4H), 7.62-7.51 (m, 3H), 7.48-7.41 (m, 4H), 7.38-7.34 (m, 4H), 5.13 (s, 2H), 5.11-5.08 (m, 2H), 5.03-4.99 (m, 1H), 4.94-4.88 (m, 1H), 4.72-4.66 (m, 1H) ,3.96-3.94(m,1H),3.67(d,1H),3.38(s,3H),3.32-3.28(m,1H),3.15-3.09(m,1H),3.00(s,3H),2 .90-2.78(m,1H),2.34(s,6H),2.19-2.18(m,3H),2.12(s,3H),2.03(s,3H),1.99-1.94(m,2H),1.68 -1.51(m,4H),1.26(s,3H),1.24(s,3H),1.20(d,3H),1.13(t,3H),1.00(d,3H),0.98(d,3H),0.73(d,3H).

[0452] S5-11 (75.70 g) was dissolved in toluene (1.51 L) in a 5 L jacketed reaction flask and stirred at 24-25°C. NaIO4 / SiO2 was added and the resulting reaction mixture was stirred at 24-25°C for 1 h. The reaction mixture was filtered through a silica gel plug (SiO2, 100 g) and eluted with EtOAc (227 mL). The organic phase was washed with Na2SO3 (60.33 g, 6.0 equiv., dissolved in 200 mL water) and aqueous NaCl solution (150 mL, wt=13% in H2O). Na2SO4 (45 g) was added to the organic phase. After one hour, the organic phase was separated and concentrated under reduced pressure below 30°C to a slightly yellow liquid. The slightly yellow liquid was dissolved in DCM (4×50 mL), concentrated under reduced pressure 4 times, and dried under high vacuum at room temperature for 4 h to obtain the target compound (72.3 g) as a white foam, which was used in the next step without further purification.

[0453]

[0454] (2S,3S,4R,6R)-6-(((2R,3S,4S,5R,6R,8R)-5-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1-(benzyloxy)-9-hydroxy-6-methoxy-2,4,6,8-tetramethyl-1-oxononan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-ylbenzoate (S5-7). Prepared from S5-6 (7.3 g, 8.1 mmol) according to the method of S3-6 (derived from S4-12 in Scheme 4) to give the title compound (7.1 g) as a white foam. MS (ESI+) m / z: 906.13 [M+H] + .

[0455] S5-3 (72.01 g, 10.55 mmol) was dissolved in THF (720 mL) and cooled to 0-5°C. NMM (4.83 g, 0.6 eq.) and isobutyl chloroformate (5.44 g, 0.5 eq.) were added and stirred at 0-3°C for 30 min. MeOH (360 mL) was added to the reaction mixture at 0-3°C. NaBH4 (6.03 g, 2.0 eq.) was then added slowly at 0-10°C over 30 min. 3N HCl aqueous solution was slowly added to the reaction mixture to adjust the pH to about 5-6 at 0-3°C. The solution was concentrated to remove most of the MeOH and THF, and water (144 mL) was added. The solution was extracted with EtOAc (720 mL) and washed with 13% NaCl aqueous solution (144 mL). Na2SO4 (40.0 g) was added to the organic phase. After two hours, the organic phase was separated and concentrated under reduced pressure at 30°C to obtain an oily substance, which was dried under high vacuum at room temperature to obtain 73.12 g of a white foam. The product was further purified by column chromatography (silica gel, 813 g, 200-300 mesh) with EtOAc / n-hexane / Et3N (1 / 2 / 0.03) as the eluent to obtain the desired product (44.31 g, yield 61%).

[0456] Synthesis of azalactones via S3-6 (Schemes 3 and 4)

[0457] Scheme 6 depicts a method for preparing aza lactones starting from S3-6. The method involves oxidation of S3-6 to give S6-1. Reductive amination of S6-1 and S6-2 followed by ring closure gives S6-3. Further elaboration of S6-3 includes: N-substitution of N-9a with R5-CHO or a similar ketone under reductive amination conditions, alkylation of C-2, and deprotection of the C-5 erythrodeoxyglycosamine hydroxyl group to give aza lactone S6-4, wherein R 9a is R5-CH2- and R 2b As defined for compounds of formula I.

[0458] Scheme 6. General synthesis of azalactones starting from S3-6

[0459]

[0460] A solution of compound S3-6 (20 mg, 32.7 μmol) in DCM (1 mL) and Dess-Martin reagent (34.6 mg, 81.7 μmol) were stirred at room temperature for 30 min. The mixture was diluted with MTBE (15 mL) and then Filter. Concentrate the filtrate and dry the residue in vacuo to obtain crude S6-1, which is used directly in the next step. MS (ESI+) m / z: 606.19 [M+H]+.

[0461]

[0462] To a solution of crude S6-1 (20 mg, 0.033 mmol) in DCM were added S6-2-1 (7 mg, 0.0395 mmol), AcOH (2 drops) and NaBH(OAc)3 (13.9 mg, 0.066 mmol). The mixture was stirred at room temperature for 30 min, and formaldehyde (27 mg, 37% in water, 0.12 mmol) and NaBH(OAc)3 (28 mg, 0.13 mmol) were added. After stirring for 40 min, the solution was diluted with DCM, washed with saturated NaHCO3 and water, and dried over Na2SO4. The solvent was removed and the residue was purified by ISCO to give S6-3-1a, 14 mg, 54%. MS (ESI+) m / z: 776.26 [M+H] + Compound S6-3-1a (10 mg, 0.0128 mmol) and anhydrous toluene (5 mL) were rotary evaporated and dried under vacuum. The residue was dissolved in m-xylene (5.5 mL) and N2 was introduced for 5 min. The solution was refluxed for 3 h to obtain S6-3-1. MS (ESI+) m / z: 702.22 [M+H] + Scheme 7 further illustrates an alternative general process. Starting from S4-6, S4-6 and S7-1 are coupled under reductive amination conditions to give S7-2. N-substitution of S7-2 at the N-9a position with an aldehyde R5-CHO or a similar ketone under reductive amination conditions gives S7-2, where R 9a S7-3 is converted to acid S7-4, which is then converted into a mixed anhydride and cyclized to give S7-5. S7-6 is obtained by removing the C-5 erythrosin from S7-5. S7-6 is oxidized to give S7-7. The last step of this method is C-2 alkylation, where R 2b Deprotection of the C-5 erythrodeoxyglycosamine as defined for compounds of formula I affords the azalide S7-8.

[0463]

[0464]

[0465] General procedure: A solution of S7-1 (1.2 eq) in DCM (0.2 M) was stirred with acetic acid (2 eq) and Na(OAc)3BH (2 eq) at 0°C for 10 min, and then S3-2 or S4-6 (1 eq) was added. The reaction mixture was warmed to room temperature and stirred until completion (30 min to overnight). The solution was used directly in the next step.

[0466]

[0467] A solution of compound S7-1-1 (377 mg, 2.19 mmol) in DCM (20 mL) was cooled in an acetone-dry ice bath to an internal temperature of -17 ° C. Acetic acid (0.436 mL, 7.64 mmol) was added under nitrogen, the temperature was raised to -13 ° C, and Na (OAc) 3 BH (606 mg, 2.86 mmol) was added once again. A solution of compound S3-2 (1.52 g, 1.91 mmol) in DCM (13 mL) was added while keeping the internal temperature below -10 ° C. The reaction mixture was slowly heated to 11 ° C in 2 h. Another portion of Na (OAc) 3 BH (606 mg, 2.86 mmol) was added at this temperature and stirred for 30 min, thereby completely converting to S7-2-1, MS (ESI +) m / z: 950.36 [M + H] + .

[0468]

[0469] General Procedure: To the above solution was added R5CHO (3 eq.) and Na(OAc)3BH (2 eq.). The resulting mixture was stirred for 30 min to overnight. The mixture was diluted with EtOAc (3 x DCM volume) and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The material was purified by ISCO (A: DCM, B: gradient of 20% MeOH in DCM containing 0.5% NH4OH) to afford the title compound.

[0470]

[0471] To S7-2-1 in the reaction mixture was added formaldehyde (37% in water, 0.62 mL, 8.29 mmol) and Na(OAc)3BH (606 mg, 2.86 mmol). The reaction mixture was stirred at room temperature for 1.5 h. After adding saturated NaHCO3 (30 mL), pH ~ 9, the reaction mixture was diluted with IPAc (120 mL) and the organic phase was separated. The aqueous layer was extracted with IPAc (2×40 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated. The crude material was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH) and the product came out at 100% B. 1.47 g (79.8%) of compound S7-3-1 was obtained as a white foam. MS (ESI+) m / z: 964.29 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ8.04-7.96 (m, 2H), 7.54 (t, 1H), 7.42 (t, 2H), 5.19-5.01 (m, 1H), 4.95-4.85 (m, 1H), 4.79 (d, 1H), 4.73 (d, 1H), 4.13-3.93 (m, 2H), 3.67 (d, 1H), 3.65-3.56 (m, 1H), 3.50 (dd, 1H), 3.38 (s, 3H), 3.34-3.20 (m, 2H), 3.18 (s, 3H), 3.05 (d, 1H), 2.94-2.83 (m,1H),2.78(qd,1H),2.65(tt,1H),2.53(s,4H),2.45(t,2H),2.40-2.27(m,8H),2.26(s,1H),2.21(s,4H),2.15(s,3H),2.13-2.04 (m,1H),1.88-1.67(m,8H),1.65-1.40(m,6H),1.32(d,3H),1.30-1.18(m,10H),1.15(d,3H),1.10(q,1H),0.93(t,6H),0.74(d,3H).

[0472]

[0473] General procedure: A solution of S7-3 (1 eq.) in THF / H2O (3:1, 0.1 M) and LiOH (5 eq.) were stirred at room temperature for 2 h. Water and formic acid (about 8 eq.) were added to adjust the pH to about 6. After the mixture was extracted twice with DCM, the aqueous layer was treated with excess saturated aqueous NaHCO3.

[0474] For water-soluble compounds, the aqueous solution was concentrated and the residue was dried under vacuum. The solid was triturated three times with DCM. The combined DCM solution was concentrated and the residue was dried under vacuum to give the target compound, S7-4.

[0475] For water-insoluble compounds, the aqueous layer was extracted three times with DCM. The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dried under vacuum to afford the target compound, S7-4.

[0476]

[0477] A solution of compound S7-3-1 (1.2 g, 1.24 mmol) in THF (9 mL) / H2O (3 mL) and LiOH (148 mg, 6.19 mmol) were stirred at room temperature for 2 h. The pH was adjusted to 8-9 by slowly adding HCl (6 mL, 1 M, 6 mmol). The mixture was concentrated to dryness in vacuo and the solid was extracted with DCM (3×15 mL). After removing DCM, compound S7-4-1 was obtained as a white foam, 1.02 g, 93%. MS (ESI+) m / z: 880.31 [M+H] +1 H NMR (400 MHz, chloroform-d) δ 8.06-7.92 (m, 2H), 7.52 (t, 1H), 7.40 (t, 2H), 5.10-4.95 (m, 1H), 4.88 (d, 1H), 4.69 (d, 1H), 4.06 (dt, 1H), 3.90 (d, 1H), 3.81-3.71 (m, 1H), 3.71-3.62 (m, 1H), 3.62-3.50 (m, 1H), 3.42 (s, 3 H),3.35-3.23(m,4H),3.01(t,2H),2.90-2.56(m,7H),2.48(dq,2H),2.37(d,3H),2.28(d,9H),1.89-1 .75(m,6H),1.67-1.49(m,5H),1.41(d,1H),1.35-1.20(m,17H),1.08(d,3H),0.98(d,3H),0.75(d,3H).

[0478]

[0479] General Procedure: To a solution of S7-4 (1 eq.) in dry DCM (38 V) was added Et3N (2 eq.) and 1,3,5-trichlorobenzoyl chloride (1.2 eq.). After 30 min, DMAP (0.02 eq.) was added. The mixture was stirred at room temperature for 30 min. The solution was washed with saturated aqueous NaHCO3 (3 times) and brine (1 time). The DCM layer was concentrated and the residue was dried under vacuum to give the title compound, S7-5.

[0480]

[0481] To a solution of compound S7-4-1 (500 mg, 0.568 mmol) in dry DCM (19 mL) was added Et3N (113 mg, 1.12 mmol), followed by a solution of 1,3,5-trichlorobenzoyl chloride (166 mg, 0.681 mmol) in DCM (0.6 mL). After stirring for 30 min, UPLC-MS showed a larger product peak (>90%) and a smaller SM (<5%). A solution of DMAP (1.38 mg, 0.0113 mmol) in DCM (0.6 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was washed with saturated NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. Concentrated and dried in vacuo to give a slightly yellowish foamy crude compound S7-5-1, about 530 mg, 108%. The main impurity was 1,3,5-trichlorobenzoic acid. The crude product was partially purified by HPLC to obtain the pure product. MS (ESI+) m / z: 862.29 [M+H] + . 1 H NMR (formate, 400 MHz, chloroform-d) δ 8.01-7.89 (m, 2H), 7.52-7.40 (m, 1H), 7.35 (t, 2H), 4.98 (dd, 1H), 4.72 (d, 1H), 4.58 (d, 1H), 4.33 (t, 1H), 4.05-3.82 (m, 2H), 3.60 (d, 1H), 3.53-3.39 (m, 2H), 3.30 (s, 3H), 3.13 (s, 3H), 3.02-2 .80(m,5H),2.79-2.58(m,4H),2.47(p,1H),2.31(dd,2H),2.19(s,7H),2.01(s,4H),1.92-1.75(m,6H),1.7 5-1.27(m,7H),1.27-1.13(m,12H),1.13-1.03(m,1H),1.00(d,3H),0.87(dd,1H),0.79(d,3H),0.70(d,3H).

[0482]

[0483] General Procedure: A solution of S7-5 (where R is erythrosin) (1 eq.) in DCM (0.12 M) and a solution of HCl in dioxane (4 M, 6 eq.) were stirred for 20 min. Water (same volume as DCM) was added. The DCM layer was separated and the aqueous layer was extracted with DCM (1 time). The aqueous layer was treated with saturated aqueous NaHCO3 and the aqueous solution was extracted with DCM (3 times). The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dried under vacuum to give the title compound, S7-6.

[0484]

[0485] A solution of crude compound S7-5-1 (300 mg, 0.347 mmol) in DCM (3 mL) and a solution of HCl in dioxane (4 M, 0.52 mL) were stirred together for 25 min. The reaction mixture turned dark blue. After dilution with water (10 mL), the aqueous layer was washed with DCM (2×10 mL). The aqueous layer was then slowly treated with saturated NaHCO3 until it was no longer bubbling (pH 8-9). The aqueous solution was extracted with DCM (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give compound S7-6-1, 223 mg (91%) as a white foam. MS (ESI+) m / z: 704.32 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ8.14-8.06 (m, 2H), 7.53 (t, 1H), 7.45 (t, 2H), 5.06-4.85 (m, 2H), 4.06 (t, 1H), 3.78 (d, 1H), 3.68-3.52 (m, 2H), 3.39 (d, 1H), 3.11 (s, 3H), 2.83-2.68 (m, 2H), 2. 56-2.40(m,7H),2.33(s,3H),2.30-2.28(m,1H),2.23(s,6H),1.86-1.74(m,6H),1.71(d ,1H),1.61-1.43(m,5H),1.35-1.24(m,9H),1.17-1.06(m,1H),0.89(d,6H),0.38(d,3H).

[0486]

[0487] General Procedure: A solution of N-succinimide (2 eq.) in anhydrous DCM (0.2 M) was stirred at -15 to -20 °C for 10 min. Dimethyl sulfide (2 eq.) was added to the solution. After stirring for 20 min, a solution of S7-6 (1 eq.) in DCM (0.2 M) was added dropwise to the suspension. The resulting mixture was stirred at -15 to -20 °C for 30 min, at which time triethylamine (2.5 eq.) was added. The mixture was stirred at -10 °C for 40 min. A saturated aqueous solution of NaHCO3 was added. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography.

[0488]

[0489] A solution of N-succinimide (300 mg, 0.226 mmol) in anhydrous DCM (1 mL) was stirred at -15 to -20 ° C for 10 min. Dimethyl sulfide (16.5 μL in 0.2 mL of DCM) was then added. After stirring for 20 min, a DCM solution (0.5 mL) of S7-6-1 (80 mg, 0.113 mmol) was added dropwise to the suspension at the same temperature within 5 min, and the resulting mixture was stirred for another 30 min at -15 to -20 ° C. TEA (39.2 μL) was added to the suspension, and the resulting mixture was stirred at -10 ° C for 30 min. The reaction was quenched by adding a saturated NaHCO3 aqueous solution, and the organic layer was separated and washed again with saturated NaHCO3 / H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by ISCO with 20% MeOH in DCM containing 0.5% NH4OH to afford compound S7-7-1 as a white foam, 52 mg (65.5%). MS (ESI+) m / z: 702.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.10-7.93(m,2H),7.58-7.47(m,1H),7.43(t,2H),5.03(dd,1H),4.54(d, 1H),4.41-4.18(m,1H),4.06(d,1H),3.65-3.50(m,3H),3.34-3.15(m,1H),2.86-2.69(m,4H),2 .58(t,4H),2.53-2.37(m,3H),2.25(d,6H),2.17(d,3H),1.98-1.68(m,7H),1.53(ttd,4H),1.4 2(td,1H),1.26(d,4H),1.21(d,3H),1.18(d,3H),1.15-1.08(m,1H),0.98(p,4H),0.83(d,3H).

[0490]

[0491] Compound S7-7-1 (370 mg, 0.527 mmol) was dissolved in dry THF (2.65 mL) and DME (2.65 mL), then evacuated and filled with N2, and then the solution was cooled to -72 °C (inside) in a dry ice / acetone bath. After stirring for 15 min, KHMDS (0.685 mL, 1 M, 0.685 mmol) was added dropwise (temperature <-68°C), the mixture was stirred at -72°C for 10 min. Dimethyl sulfate (75 μL, 0.79 mmol) was added, the reaction mixture was slowly warmed and stirred at -15°C for 1.5 h. The reaction mixture was cooled to -40°C, quenched with Me3N (1.21 mL, 40% in water, 7.9 mmol) and NH4OAc (saturated aqueous solution, 10 mL), warmed to 10°C, and stirred for another 5 min. The mixture was diluted with EtOAc (20 mL), the organic layer was separated and washed with water (2×10 mL) and brine (10 mL). After drying over Na2SO4, the solvent was removed and the residue was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NH4OH), and the product S7-8-1a as a white solid came out at 100% B, 270 mg, 72%. (ESI+) m / z: 716.36 [M+H] + . 1 HNMR(400MHz, CDCl3)δ8.10-7.94(m,2H),7.62-7.48(m,1H),7.43(t,2H),5.03(dd,1H),4.61(d,1H),4.0 5(dd,1H),4.01-3.88(m,2H),3.63-3.54(m,1H),3.47(dq,1H),2.95-2.86(m,1H),2.84(s,3H),2.82-2.76 (m,1H),2.48(t,5H),2.41(t,2H),2.25(s,6H),2.22(s,2H),2.00-1.84(m,2H),1.76(dq,7H),1.56-1.44 (m,3H),1.38(s,3H),1.31(s,3H),1.26(d,3H),1.22(s,3H),1.04(d,3H),0.98-0.86(m,2H),0.82(d,3H).

[0492] A solution of compound S7-8-1a (200 mg, 0.28 mmol) in MeOH (5 mL) was heated at 50 °C for 16 h. HPLC purification gave S7-8-1 in a solution of 0.1% formic acid / water / CH3CN. The solution was concentrated and treated with saturated NaHCO3. It was extracted with DCM (3×10 mL), and the combined extracts were washed with brine (10 mL) and dried over Na2SO4. After filtration, the solvent was removed in vacuo, and the residue was dried in vacuo to give S7-8-1 as a white foam, 120 mg, 70%. (ESI+) m / z: 612.37 [M+H] + . 1HNMR (400 MHz, CHLOROFORM-d) δ4.45 (d, 1H), 4.26 (t, 2H), 3.85-3.63 (m, 2H), 3.41 (ddd, 3H), 3.31-3.21 (m, 5H), 3.15 (t, 2H), 3.05 (s, 5H), 2.78 (s, 9H), 2.19 (s, 1H), 2.13-1.97 (m, 6H), 1.86 (d, 3H), 1.60 (s, 3H), 1.54 (s, 4H), 1.45-1.23 (m, 12H), 1.05 (d, 3H).

[0493] Alternative azalactone synthesis starting from S5-6 (Scheme 5)

[0494] The synthesis of the alternative aza lactone is shown in Scheme 8. S5-6 and S7-1 are coupled under reductive amination conditions to give S8-1. N-substitution at the N-9a position with an aldehyde R5-CHO or a similar ketone under reductive amination conditions gives S8-2, where R 9a S8-2 is converted into acid S8-3, and then a mixed anhydride is formed and cyclized to obtain S8-4. The C-5 erythrosin of S8-4 is removed to obtain S8-5. Oxidation, C-2 alkylation (where R 2b The process consists of deprotection of the C-5 erythromycin deoxyglucosamine to afford the azalide S8-6.

[0495]

[0496]

[0497] To a solution of NaBH4 (19.7 g, 521 mmol) in THF (200 mL) was added 4-amino-1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (53.00 g, 216 mmol) at 20-25°C. The reaction mixture was cooled to 0°C under N2, and a solution of I2 (55 g, 216 mmol) in THF (500 mL) was slowly added. The mixture was then stirred at 80°C for 16 h. TLC (dichloromethane:methanol=10:1, R f=0.13) indicated that the starting material was exhausted and a new spot was formed. The reaction mixture was cooled to 25°C and MeOH (500 mL) was carefully added until the mixture became clear. After stirring at room temperature for 1 h, the solvent was removed to obtain a white residue, which was dissolved in 20% KOH aqueous solution (500 mL) and stirred at 20-30°C for 1 h. The reaction mixture was extracted with CH2Cl2 (300 mL, 3×), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=40-30 / 1, 0.5% NH3H2O). The product S7-1-2 tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (R f =0.30, dichloromethane / methanol=10 / 1, 0.5% NH3H2O) (33.5 g, 144 mmol, yield 66.7%, purity 99.5%). MS (ESI+) m / z: 461.4 [2M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.72-3.56 (m, 2H), 3.36 (s, 2H), 3.28 (ddd, 2H), 1.68 (s, 2H), 1.59-1.49 (m, 2H), 1.46 (s, 9H), 1.43-1.36 (m, 2H).

[0498]

[0499] General procedure: A solution of S7-1 (1.2 eq.) in DCM (0.2 M) was stirred with acetic acid (2 eq.) and Na(OAc)3BH (2 eq.) at 0°C for 10 min. S5-6 (1 eq.) was added. The reaction mixture was stirred at room temperature until completion (30 min to overnight). The solution was used directly in the next step.

[0500]

[0501] General Procedure: To the above solution was added R5CHO (3 eq.) and Na(OAc)3BH (2 eq.). The resulting mixture was stirred for 30 min to overnight. The mixture was diluted with EtOAc (3×DCM volume) and washed with saturated aqueous NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by ISCO (A: DCM, B: gradient of 20% MeOH in DCM containing 0.5% NH4OH) to give the title compound, S8-2.

[0502]

[0503] AcOH (20 g, 333 mmol, 19 mL) and NaBH(OAc)3 (35.3 g, 166 mmol) were added to a solution of compound S7-1-2 (23 g, 100 mmol) in CH2Cl2 (600 mL) at 25°C. After the solution was cooled to -10°C, a solution of S5-6 (75.4 g, 83.4 mmol) in CH2Cl2 (150 mL) was slowly added under N2. The reaction solution was slowly heated and stirred at 20-25°C for 2 h. S8-1-1 was observed in the solution as the main peak in LCMS, MS (ESI) m / z: 1118.6 [M+H] + . Cool to 5-10°C, then add NaBH(OAc)3 (35.3 g, 166 mmol) and HCHO (135 g, 1670 mmol, 124 mL, 37% in water) to the mixture. Slowly warm the reaction mixture and stir at 20-25°C for 12 h. Cool the reaction mixture to 0°C, then slowly add saturated aqueous NaHCO3 solution (900 mL). Extract the mixture with CH2Cl2 (2×1.5 L). Dry the combined extracts over Na2SO4, filter, and concentrate to give the crude product. Purify by column chromatography (SiO2, dichloromethane:methanol=100:1 to 40:1; plate 1; R f =0.24) to purify the crude product to obtain compound S8-2-1 (80 g, 63.8 mmol, yield 76.6%, purity 96%) as a white solid. MS (ESI) m / z: 1132.7 [M+H] + ,567.0[M / 2+H] + . 1 H NMR (400MHz, chloroform-d) δ7.97-8.05(m,4H),7.46-7.65(m,4H),7.39-7.46(m,2H),7.29-7.39(m,5H),5.07-5.1 9(m,2H),4.97-5.04(m,1H),4.92(d,1H),4.79-4.89(m,2H),4.34-4.46(m,1H),3.75-4.07(m,6H),3.71(br s,1H),3.45-3.50(m,3H),3.39(s,3H),3.17(br s,3H),2.79-2.99(m,3H),2.65-2.79(m,4H),2.62(s,2H),2.25-2.58(m,8H),1.86(s,2H),1 .55-1.70(m,3H),1.44(s,9H),1.20-1.40(m,6H),1.05-1.19(m,12H),0.95(d,3H),0.64(br d,3H).

[0504]

[0505] General procedure: To a solution of S8-2 in DCM (10 mM) was added 10% Pd / C (10 to 50 mol%). The reaction vessel was evacuated and backfilled with hydrogen. Hydrogen was passed through the solution for 2-3 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was dried under vacuum.

[0506]

[0507] To a solution of compound S8-2-1 (50.00 g, 39.3 mmol) in MeOH (500 mL) was added 10% Pd / C (25.00 g, 50% of the weight of S8-2-1) under N2 atmosphere. The mixture was stirred at 25 °C under H2 (15 psi) for 2 h. The reaction mixture was vacuum filtered and the filter cake was washed with MeOH (2×1000 mL). The filtrate was concentrated to give S8-3-1 as a white solid. MS (ESI) m / z: 522.0 [M / 2+H] + . 1 H NMR (400MHz, chloroform-d) δ8.10-7.96(m,4H),7.64-7.51(m,2H),7.50-7.38(m,4H),5.17-4.87(m,4H),4.59-4.43(m, 1H),4.10-3.64(m,7H),3.52(s,3H),3.31(brs,3H),3.07-2.76(m,3H),2.71-2.42(m,6H),2.33(s,7H),2.15(br d,1H),2.00-1.85(m,1H),1.82-1.56(m,6H),1.51-1.40(m,10H),1.35-1.26(m,3H),1.24-1.08(m,9H),1.04-0.93(m,6H),0.73(br d,3H).

[0508]

[0509] General Procedure: To a solution of S9-3 (1 eq.) in dry DCM (38 V) was added Et3N (2 eq.) and 1,3,5-trichlorobenzoyl chloride (1.2 eq.). After 30 min, DMAP (0.02 eq.) was added. The mixture was stirred at room temperature for 30 min. The solution was washed with saturated aqueous NaHCO3 (3 times) and brine (1 time). The DCM solution was dried over Na2SO4, filtered, and concentrated. The residue was dried in vacuo to give the title compound, S8-4.

[0510]

[0511] To a solution of 2,4,6-trichlorobenzoyl chloride (16.2 g, 66.6 mmol, 10.4 mL) in CH2Cl2 (3900 mL) in a 5 L three-necked flask was added Et3N (17.9 g, 177 mmol, 24.7 mL) and DMAP (5.43 g, 44.4 mmol) at 20-25°C. A solution of compound S8-3-1 (26 g, 22.2 mmol) in CH2Cl2 (260 mL) was then slowly added to the mixture over 48 h using a syringe pump. After addition, the reaction was stirred at 20-25°C for 2 h. The reaction solution was washed with saturated NaHCO3 (3×600 mL). The solvent was dried over Na2SO4 and removed in vacuo, and the product was purified by column chromatography (SiO2, dichloromethane:methanol=100:1 to 30:1; plate 1; R f =0.24) to purify the residue to obtain compound S8-4-1 as a white solid (2 batches, 31.9 g, 27 mmol, yield 50.6%, purity 86.7%). MS (ESI) m / z: 512.9 [M / 2+H] + . 1 H NMR (400 MHz, chloroform-d) δ8.02-8.13 (m, 4H), 7.51-7.63 (m, 2H), 7.41-7.51 (m, 4H), 5.03-5.15 (m, 1H), 4.89-4.99 (m, 2H), 4.49-4.59 (m, 2H), 4.12-4.21 (m, 1H), 3.68-3.85 (m, 4H), 3.45 (s, 3H), 3 .25(s,3H),2.82-2.99(m,3H),2.57-2.69(m,1H),2.46(d,1H),2.26-2.38(m,8H),2.11-2.26 (m,5H),1.61-1.83(m,7H),1.46(s,10H),1.15-1.31(m,14H),1.05(d,3H),0.78-0.92(m,7H).

[0512]

[0513] General Procedure: A solution of S8-4 (1 eq.) in DCM (0.12 M) and a solution of HCl in dioxane (4 M, 6 eq.) were stirred for 20 min. Water was added, the DCM layer was separated, and the aqueous layer was extracted with DCM (1 time). The aqueous layer was treated with saturated aqueous NaHCO3 and extracted with DCM (3 times). The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dried in vacuo to give the desired product, S8-5.

[0514]

[0515] Trifluoroacetic acid (92.3 g, 810 mmol, 59.9 mL) was added to a solution of compound S8-4-1 (31.9 g, 27 mmol) in CH2Cl2 (320 mL) at 0-5°C. The mixture was stirred at 20-25°C for 3 h. Water (300 mL) was added to the reaction mixture and the aqueous layer was separated. After extraction with CH2Cl2 (2×80 mL), the aqueous layer was adjusted to pH 8-9 with Na2CO3 solid. The aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (SiO2, dichloromethane: methanol = 60: 1 to 10: 1; plate 1; R f =0.24) to purify the residue to obtain compound S8-5-1 (21 g, 26.4 mmol, yield 98.1%) as a white solid. MS (ESI) m / z: 662.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.14-7.97 (m, 3H), 7.59-7.48 (m, 1H), 7.48-7.42 (m, 1H), 7.48-7.42 (m, 1H), 7.50-7.38 (m, 2H), 7.37 -7.34 (m, 1H), 5.11-4.90 (m, 3H), 4.11 (s, 2H), 3.82 (d, 1H), 3.61 (br dd,2H),3.44(brd,1H),3.21-3.07(m,5H),3.06-2.93(m,3H),3.07-2.88(m,4H),2.86-2.55(m,5H),2.46-2.33(m,3H),2.24 -2.23(m,1H),2.30-2.14(m,15H),1.88-1.75(m,4H),1.70-1.54(m,4H),1.38-1.13(m,13H),0.98-0.78(m,8H),0.49(d,3H).

[0516]

[0517] To a solution of 3-methoxybenzaldehyde (5.41 g, 39.7 mmol) in CH2Cl2 (100 mL) was added AcOH (6.36 g, 105 mmol, 6.06 mL) and NaBH(OAc)3 (11.2 g, 52.9 mmol) at 0°C. Then a solution of compound S8-5-1 (21.0 g, 26.4 mmol) in CH2Cl2 (100 mL) was slowly added at 0-10°C. The mixture was warmed to 20-25°C and stirred for another 6 h. Saturated aqueous NaHCO3 solution (400 mL) and CH2Cl2 (100 mL) were added to the reaction mixture at 0°C, and the mixture was extracted with CH2Cl2 (2×100 mL). The combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified using a MEGA series liquid chromatography pump in a 0.50 kg column (column core (SiO2: 0.50 kg), A: DCM containing 0.1% NH4OH, B: MeOH). Most of the product came out at ~2% B, and some of the product did not come out until 4% B. The brown foam compound S8-6-1a (11.8 g, 14.9 mmol, yield 56.3%, purity 98.9%) was obtained. MS (ESI) m / z: 782.6 [M+H] + . 1 HNMR (400MHz, methanol-d4) δ8.01-8.17(m,2H),7.50-7.60(m,1H),7.36-7.49(m,2H),7.23(t,1H),6.89(br d,2H),6.80(dd,1H),4.98(br d,2H),4.06(s,2H),3.78-3.86(m,4H),3.55-3.65(m,1H),3.40-3.52(m,3H),3.16(s,3H),2.71-2.86(m,3H),2.64(br s,1H),2.36(br dd,2H),2.24(s,10H),1.97-2.15(m,2H),1.62-1.90(m,7H),1.40-1.59(m,4H),1.32(t,6H),1.27(br d,2H),0.90(dd,6H),0.50(d,3H).

[0518]

[0519] A mixture of NCS (13 g, 97 mmol) in CH2Cl2 (118 mL) was stirred at -15 to -20 ° C for 10 min under N2. Me2S (6.03 g, 97 mmol, 7.12 mL) was added dropwise to the solution. The mixture was stirred at the same temperature for 30 minutes. A mixture of compound S8-6-1a (11.8 g, 14.9 mmol) in CH2Cl2 (118 mL) was added dropwise to the suspension at -15 to -20 ° C, and the resulting mixture was stirred for another 1 h at -15 to -10 ° C. TEA (10.5 g, 104 mmol, 14.5 mL) was added to the mixture at -15 to -10 ° C and stirred for 1 h. The reaction was quenched by adding saturated NaHCO3 aqueous solution (224 mL) at 0-10 ° C. The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×160 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using a MEGA series liquid chromatography pump in a 0.25 kg column (column core (SiO2: 0.25 kg), A: DCM containing 0.2% NH4OH, B: MeOH). Most of the product came out at ~2% B, and some of the product did not come out until 4% B. The brown foam compound 8-6-1b (8.55 g, 10.4 mmol, yield 69.7%, purity 94.9%) was obtained. MS (ESI) m / z: 780.4 [M+H] + ,390.9[M / 2+H] + . 1 H NMR (400MHz, methanol-d4) δ8.04(br d,2H),7.50-7.59(m,1H),7.38-7.49(m,2H),7.22(t,1H),6.89(br d,2H),6.80(br d,1H),4.99-5.14(m,1H),4.46-4.64(m,1H),4.10-4.29(m,2H),3.96-4.09(m,1H),3.81 (s,3H),3.40-3.66(m,4H),3.10-3.26(m,1H),3.03(s,1H),2.80-2.92(m,3H),2.67-2.7 8(m,1H),2.44-2.63(m,2H),2.37(s,2H),2.18-2.31(m,8H),1.89-2.17(m,4H),1.54-1. 85(m,6H),1.38-1.53(m,3H),1.11-1.36(m,10H),0.92-1.06(m,4H),0.81-0.89(m,3H).

[0520]

[0521] The solution of compound S8-6-1b (7.0 g, 8.52 mmol) in 2-MeTHF (70 mL) was degassed and purged with N2 for 3 times, and then the mixture was cooled to -42 ° C. KHMDS (1.0 M, 11 mL, 11 mmol) was added dropwise and kept at -40 to -42 ° C. The mixture was stirred at the same temperature for 30 min. Me2SO4 (1.84 g, 14.5 mmol, 1.38 mL) was added, and the reaction mixture was slowly warmed to -20 to -10 ° C and kept for 1 h. The reaction was quenched by adding saturated NH4Cl (60 mL) and trimethylamine (120 mL, 40% in water). The reaction mixture was poured into saturated NH4Cl (200 mL) and extracted with 2-MeTHF (2×200 mL). The combined extracts were washed with brine (200 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified using a MEGA series liquid chromatography pump on a 0.1 kg column (column core (SiO2: 0.1 kg), A: DCM containing 0.1% NH4OH, B: MeOH). Most of the product came out at ~1% B, and some of the product did not come out until 4% B. By TLC (dichloromethane / methanol = 10 / 1, 0.1% NH4OH, R f =0.30) to detect the product. The brown foamy product S8-6-1c (6.55 g, 8.18 mmol, yield 78.7%, purity 99.2%) was obtained. MS (ESI) m / z: 397.9 [M / 2+H]. 1 H NMR (400MHz, methanol-d4) δ7.95-8.09(m,2H),7.51-7.59(m,1H),7.38-7.47(m,2H),7.22(t,1H),6.89(br d,2H),6.79(dd,1H),5.04(dd,1H),4.62(d,1H),4.07-4.21(m,1H),3.92-4.05(m,2H),3.81(s,3H) ,3.54-3.68(m,1H),3.36-3.53(m,2H),3.13-3.28(m,1H),2.93(s,3H),2.77-2.88(m,1H),2.65(br d,2H),2.23-2.39(m,9H),2.07-2.23(m,4H),1.57-1.95(m,8H),1.14-1.52(m,14H),1.02(d,3H),0.94(brdd,1H),0.83(d,3H).

[0522]

[0523] A solution of compound S8-6-1c (6.55 g, 8.18 mmol) in EtOH (66 mL) was stirred at 80 ° C for 36 h. After cooling to room temperature, the reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water (TFA)-ACN]; B%: 2%-27%, 20min). Compound S8-6-1 (3.23 g, 4.66 mmol, yield 56.9%, purity 99.5%) was obtained as a light yellow solid. (MS (ESI) m / z: 690.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ7.22 (t, 1H), 6.79-6.95 (m, 3H), 5.49 (s, 1H), 4.40 (d, 1H), 4.19 (d, 1H), 3.98-4.10 (m, 2H), 3.79 (s, 3H), 3.53-3.60 (m, 1H), 3.50 (s, 2H), 3.40 (br t,1H),3.26(dd,1H),2.95(s,3H),2.54-2.76(m,3H),2.09-2.48(m,14H),1.59 -2.06(m,7H),1.46-1.58(m,4H),1.37(s,3H),1.15-1.33(m,11H),0.85(d,3H).

[0524] Equivalents and scope

[0525] In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless indicated to the contrary or obvious from the context. Claims or descriptions that include "or" between one or more members of the group are considered satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or method, unless indicated to the contrary or obvious from the context. The invention includes embodiments in which only one member of the group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

[0526] In addition, the present invention encompasses all variations, combinations and arrangements, wherein one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim subordinate to another claim can be modified to include one or more limitations present in any other claim subordinate to the same basic claim. In the case where the element is presented as a list (e.g., in Markush group format), each subgroup of the element is also disclosed, and any one or more elements can be deleted from the group. It should be understood that, in general, in the case where the present invention or aspects of the present invention are referred to as comprising specific elements and / or features, certain embodiments of the present invention or aspects of the present invention are composed of these elements and / or features, or are substantially composed of these elements and / or features. For simplicity, those embodiments are not specifically stated verbatim in this article. It should also be noted that the terms "include" and "contain" are intended to be open, allowing the inclusion of additional elements or steps.

[0527] In the case of giving a range, the endpoints are included. In addition, unless otherwise stated or it is obvious from the context and the understanding of a person of ordinary skill in the art to be different, the values ​​expressed as ranges may take any specific value or sub-range within the range in different embodiments of the present invention, unless the context clearly requires otherwise, otherwise accurate to one tenth of the unit of the lower limit of the range.

[0528] This application is related to various granted patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and this specification, the present specification shall prevail. In addition, any specific embodiment of the present invention within the prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if they are not explicitly stated to be excluded herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of the prior art.

[0529] Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments described herein using only routine experimentation. The scope of the embodiments of the present invention described herein is not intended to be limited to the above description, but is as described in the appended claims. It will be understood by those of ordinary skill in the art that various changes and modifications may be made to this description without departing from the spirit or scope of the present invention as defined in the following claims.

Claims

1. A method for preparing a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof: It includes: (a1) Intramolecular cyclization of a compound of formula A to form a compound of formula I, wherein O-LG is a leaving group and PG is a protecting group: (b1) Intramolecular cyclization of a compound of formula B to form a compound of formula I', wherein PG is a protecting group: in: R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R 2a and R 2b The other of which is selected from halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group; R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl; R 6a is an optionally substituted C 1-10 alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl; R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl; R 9a is selected from -H and optionally substituted C 1-10 alkyl; R 12 C 1-6 alkyl; and L is C 2-5 Optionally substituted alkylene.

2. The method of claim 1, wherein the intramolecular cyclization of the compound of formula B is carried out under neutral conditions in the presence of a solvent.

3. The process of claim 1 or claim 2, wherein the intramolecular cyclization of the compound of formula B is carried out at a temperature of about 50°C to about 175°C.

4. The process of any one of claims 1 to 3, wherein the intramolecular cyclization of the compound of formula B is carried out in the presence of meta-xylene at a temperature of about 60°C to about 150°C.

5. The method of claim 1, comprising the step of converting the compound of formula A-1 into the compound of formula A:

6. The method of claim 5, wherein LG is R'-(C=O)-.

7. The method of claim 6, wherein R' is an optionally substituted phenyl group.

8. The method of any one of claims 5-7, further comprising a base.

9. The method of claim 8, wherein the base is an amine base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pentamethylpiperidine (PMP), tributylamine, triethylamine, diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine).

10. The method of any one of claims 5-9, wherein the intramolecular cyclization occurs in an aprotic solvent.

11. The method of any one of claims 5 to 10, further comprising the step of converting the compound of formula A-2 into a compound of formula A-1, wherein R x For optionally C 1-4 Alkyl, hydroxyl, oxo, COOH, COO(C 1-6 alkyl), amino, alkylamino, halo or cyano substituted C 1-6 alkyl:

12. The method of claim 11, further comprising the step of converting the compound of formula A-3 into the compound of formula A-2:

13. The method of claim 12, further comprising the step of converting the compound of formula A-4 into the compound of formula A-3:

14. The method of claim 13, further comprising the step of converting the compound of formula A-4A to a compound of formula A-4 by contacting the compound of formula A-4A with an oxidizing agent:

15. The method of claim 14, further comprising the step of converting the compound of formula A-4A1 into the compound of formula A-4A:

16. The method of claim 15, further comprising the step of converting the compound of formula A-4A2 into the compound of formula A-4A1:

17. The method of claim 16, further comprising the step of converting the compound of formula A-4A3 into the compound of formula A-4A2:

18. The method of claim 17, further comprising the step of converting the compound of formula II into a compound of formula A-4A3:

19. The method of claim 18, comprising the step of converting the compound of formula III into the compound of formula II:

20. The method of claim 13, further comprising the step of converting the compound of formula A-4B into the compound of formula A-4:

21. The method of claim 20, further comprising the step of converting the compound of formula A-4B1 into the compound of formula A-4B:

22. The method of claim 21, comprising the step of converting a compound of formula A-4B2 into a compound of formula A-4B1:

23. The method of claim 22, comprising the step of converting a compound of formula A-4B3 into a compound of formula A-4B2:

24. The method of claim 23, comprising the step of converting the compound of formula II into a compound of formula A-4B3:

25. The method of any one of claims 1 to 24, wherein R3 is It also includes the step of converting the compound of formula I to the compound of formula IA:

26. The method of claim 25, further comprising the step of converting the compound of formula IA to the compound of formula I':

27. The method of claim 26, further comprising the step of converting the compound of formula I' into a compound of formula IC:

28. The method of claim 1, comprising the steps of: (b1) Intramolecular cyclization of a compound of formula B, wherein PG is a protecting group, followed by removal of the protecting group to form a compound of formula I:

29. The method of claim 28, further comprising the step of converting the compound of formula B-1 into a compound of formula B:

30. The method of claim 29, further comprising the step of converting the compound of formula B-2 into the compound of formula B-1:

31. The method of claim 30, further comprising the step of converting the compound of formula B-3 into the compound of formula B-2:

32. The method of claim 31, further comprising treating a compound of formula B-4, wherein R3 is Steps for conversion to compounds of formula B-3:

33. The method of claim 32, further comprising the step of converting the compound of formula B-5 into the compound of formula B-4:

34. The method of claim 33, further comprising the step of converting the compound of formula B-6 into the compound of formula B-5:

35. The method of claim 34, further comprising the step of converting the compound of formula B-7 into the compound of formula B-6:

36. The method of claim 35, further comprising the step of converting the compound of formula B-8 into the compound of formula B-7:

37. The method of claim 36, further comprising treating a compound of formula B-7, wherein R 10a is OH and R 10b H or R 10a and R 10b Steps for forming C=O and converting into a compound of formula B-6:

38. The method of claim 37, further comprising treating a compound of formula IV, wherein R 10a is OH and R 10b H or R 10a and R 10b Steps for forming C=O and converting to a compound of formula B-9:

39. The method of any one of claims 1-38, wherein R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

40. The method of any one of claims 1-39, wherein R 8a and R 8b One is H and the other is methyl.

41. The method of any one of claims 1-40, wherein R 6a is selected from methyl, ethyl, propyl, isopropyl and tert-butyl, and R 6b Selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

42. The method of any one of claims 1-41, wherein R 6a and R 6b Each is a methyl group.

43. The method of any one of claims 1-42, wherein R3 is H or And R 3c is H or benzoyl.

44. The method of any one of claims 1-43, wherein R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

45. The method of any one of claims 1-44, wherein R 4a and R 4b One is H and the other is methyl.

46. ​​The method of any one of claims 1-45, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

47. The method of any one of claims 1-46, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one is methyl.

48. A method for preparing a compound of formula B-9 from a compound of formula IV, comprising contacting the compound of formula IV with ozone, optionally in the presence of an acid, to form a compound of formula B-9: in: R 10a and R 10b One is OH and the other is H or R 10a and R 10b Together they form C=O; R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R 2a and R 2b The other of which is selected from halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group; R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl; R 6a is an optionally substituted C 1-10 alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl; R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl; and PG is a suitable protecting group.

49. The method of claim 48, wherein the compound of formula IV is contacted with ozone in the presence of an acid to form the compound of B-9.

50. The method of claim 49, wherein the acid is trifluoroacetic acid.

51. The method of any one of claims 48-50, wherein the contacting occurs in dichloromethane.

52. The method of any one of claims 48-51, wherein R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

53. The method of any one of claims 48-52, wherein R 8a and R 8b One is H and the other is methyl.

54. The method of any one of claims 48-53, wherein R 6a is selected from methyl, ethyl, propyl, isopropyl and tert-butyl, and R 6b Selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

55. The method of any one of claims 48-54, wherein R 6a and R 6b Each is a methyl group.

56. The method of any one of claims 48-55, wherein R3 is H or And R 3c is H or benzoyl.

57. The method of any one of claims 48-56, wherein R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

58. The method of any one of claims 48-57, wherein R 4a and R 4b One is H and the other is methyl.

59. The method of any one of claims 48-58, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

60. The method of any one of claims 48-59, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one of them is methyl, ethyl, propyl or isopropyl.

61. The method of any one of claims 48-60, wherein R 2a and R 2b One of them is H and R 2a and R 2b The other one is methyl.

62. A method for preparing a compound of formula A-3 from a compound of formula A-4, comprising coupling a compound of formula A-4 with an amine having the formula NH2-L-OH under reductive amination conditions to form a compound of formula A-3: in: R 2a and R 2b one is selected from H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R 2a and R 2b The other of which is selected from halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 Alkenyl, where C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl group is optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is H, a suitable protecting group selected from acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or Where R 3c is H or a protecting group; R 4a and R 4b are each independently selected from -H and optionally substituted C 1-10 alkyl; R 6a is an optionally substituted C 1-10 alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted allyl; R 8a and R 8b are each independently selected from -H and optionally substituted C 1-10 alkyl; PG is a suitable protecting group; and L is an optionally substituted C 2-5 Alkylene.

63. The method of claim 62, wherein the coupling of the compound of formula A-4 with the amine having the formula NH2-L-OH is carried out in the presence of a solvent.

64. The method of claim 62 or claim 63, wherein the solvent is dichloromethane.

65. The method of any one of claims 62-64, wherein the coupling of the compound of formula A-4 with the amine having the formula NH2-L-OH is carried out in the presence of NaB(OAc)3H and acetic acid.

66. The method of claim 65, wherein NaB(OAc)3H and acetic acid are each present in about 2 molar equivalents relative to the compound of formula A-4.

67. The method of claims 62-66, wherein L in NH2-L-OH is ethylene, which is optionally substituted up to three times with halo, CN, NO2, amino, amido, carboxyl, alkylcarbonyl, alkoxycarbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently and optionally substituted with halo or alkyl.

68. The method of claim 67, wherein L is ethylene, optionally substituted up to three times with halo, alkyl, or alkoxy.

69. The method of claim 67, wherein NH2-L-OH is NH2-CH2-L1-OH, NH2-CH(C 1-6 alkyl)-L1-OH, NH2-L1-CH2-OH or NH2-L1-CH(C 1-6 alkyl)-OH, wherein L1 is CR 14a R 14b ; R 14b H or C 1-6 alkyl; R 14a Selected from optionally substituted R 101 -CH2-、R 101 -CH2CH2-, R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 -CH2CH2CH-OMe-; or R 14a is an optionally substituted saturated or partially unsaturated cycloalkyl group, an optionally substituted saturated or partially unsaturated heterocycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group containing at least one double bond, or R 14a and R 14b Together with the carbon atoms to which they are attached, they form Wherein Q is a 3, 4, 5 or 6-membered cycloalkyl or heterocyclic ring, wherein Represents a connection point and R 11a and R 11b are each independently selected from H, halo and optionally substituted C 1-10 alkyl.

70. The method of claim 69, wherein NH2-L-OH is NH2-L1-CH2-OH.

71. The method of claim 70, wherein L1 is CR 14a R 14b , where R 14b H or C 1-6 Alkyl and R 14a Selected from optionally substituted R 101 -CH2-、R 101 -CH2CH2-、R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 -CH2CH2CH-OMe-.

72. The method of claim 71, wherein R 101 Selected from in Represents a connection point.

73. The method of claim 70, wherein L1 is CR 14a R 14b , where R 14b H or C 1-6 Alkyl and R 14a are optionally substituted saturated or partially unsaturated cycloalkyl, optionally substituted saturated or partially unsaturated heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl containing at least one double bond.

74. The method of claim 73, wherein R 14a for Pyridyl, in Represents a connection point.

75. The method of claim 70, wherein L1 is CR 14a R 14b , where R 14a and R 14b Together with the carbon atoms to which they are attached, they form Wherein Q is a 3, 4, 5 or 6-membered cycloalkyl or heterocyclic ring, wherein Represents a connection point.

76. The method of claim 75, wherein each R q are independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me, or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

77. The method of claim 75, wherein for In one embodiment, for And each R q are independently selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me, or two R q Together with the atoms to which they are attached, they form the oxygen group, (as a salt) (e.g. formate), wherein Represents a connection point.

78. The method of claim 75, wherein for And R q is selected from H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me, in Represents a connection point.

79. The method of any one of claims 62-78, wherein R 8a and R 8b One of them is H and the other is an optionally substituted C 1-10 alkyl.

80. The method of any one of claims 62-79, wherein R 8a and R 8b One is H and the other is methyl.

81. The method of any one of claims 62-80, wherein R 6a is selected from methyl, ethyl, propyl, isopropyl and tert-butyl, and R 6b Selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

82. The method of any one of claims 62-81, wherein R 6a and R 6b Each is a methyl group.

83. The method of any one of claims 62-82, wherein R3 is a protecting group selected from benzoyl, p-nitrobenzoyl, TMS, TES, IPDMS, TBS or methoxymethyl.

84. The method of any one of claims 62-82, wherein R3 is benzoyl.

85. The method of any one of claims 62-84, wherein R 4a and R 4b One of them is H and the other is an optionally substituted C 1-10 alkyl.

86. The method of any one of claims 62-85, wherein R 4a and R 4b One is H and the other is methyl.

87. The method of any one of claims 62-86, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one is C 1-10 Alkyl groups are optionally substituted with one or more groups selected from halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl.

88. The method of any one of claims 62-87, wherein R 2a and R 2b One of them is H, And R 2a and R 2b The other one of them is methyl, ethyl, propyl or isopropyl.

89. The method of any one of claims 62-88, wherein R 2a and R 2b One of them is H and R 2a and R 2b The other one is methyl.

90. Compounds of formula A, B, A-1, A-2, A-3 and B1, wherein L is CH2CR 14a R 14b , where R 14a and R 14b As defined in claims 69-78.

91. Compounds of formula A-4, A-4A, A-4A1, A-4A2, A-4A3, A-4B, A-4B1, A-4B2, A-4B3, B-2, B-3, B-4, B-5, B-6, B-7, B-8 and B-9.

92. A compound as shown in Table 1.

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