Synthetic methods and intermediates for the preparation of therapeutic azaketolides

Abstract

The present invention relates to methods for preparing compounds of formula I and / or formula I'. The present invention also relates to methods for selectively cleaving the main ring of compounds of formula IV to provide starting materials for the synthesis of compounds of formula I or formula I'. The present invention further relates to intermediates of the methods described herein.

Description

[Technical Field]

[0001] Technical field of the invention The present invention relates to methods for preparing compounds of formula I and / or formula I'. The present invention also relates to methods for selectively cleaving the main ring of compounds of formula IV to provide starting materials for the synthesis of compounds of formula I or formula I'. The present invention further relates to intermediates of the methods described herein. [Background technology]

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

[0003] Effective treatments for genetic diseases caused by nonsense mutations remain elusive. As a result, there remains an unmet need for the discovery and development of novel compounds that are effective against nonsense and / or frameshift mutations that result in premature stop codons and are therefore useful for treating genetic diseases and disorders caused by nonsense mutations. As disclosed in PCT / US2019 / 062030, PCT / US2019 / 062045, PCT / US2022 / 031565, PCT / US2023 / 023971, and PCT / US2023 / 069034, azaketolides are one such recently discovered class of compounds that can be used to treat such conditions. There remains a need for methods of producing such compounds. Summary of the Invention

[0004] Summary of the Invention These and other needs are met by the present invention, which is directed to methods for producing azaketolides that can be used to treat genetic diseases caused by nonsense mutations.

[0005] In some embodiments, the present invention provides a compound of formula I or formula I': [ka] or a pharmaceutically acceptable salt thereof, comprising: (a1) Intramolecularly cyclizing 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: [ka] (b1) Intramolecularly cyclizing a compound of formula B (wherein PG is a protecting group) to form a compound of formula I': [ka] [During the ceremony, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other is halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or [ka] where R 3c is H or a protecting group; R 4a and R 4b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 6a is an optionally substituted C 1-10 is alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted aryl; R8a and R 8b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 9a is —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 12 is C 1-6 is alkyl; and L is an optionally substituted C 2-5 It is alkylene. This includes a method.

[0006] In one embodiment, the present invention provides 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: [ka] [During the ceremony: R 10a and R 10b one of which is OH and the other is H or R 10a and R 10b come together to form C=O. This includes a method.

[0007] Also provided are compounds useful as intermediates in the methods described in the schemes and experimental examples provided herein.

[0008] The compounds set forth in Table 1 are also provided.

[0009] The methods disclosed herein start from readily available macrolides found in nature. That is, the present invention relates to the chemical synthesis of azalides using natural products as a starting point, solving the problem of producing novel compounds with therapeutic activity in a minimal number of controlled steps. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. Furthermore, the materials, methods, and examples are merely illustrative and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety, including U.S. Patent Application Publication No. 2013 / 0090326. In case of conflict, the present specification, including these definitions, will control.

[0011] As used herein, the terms "a," "an," and "the" include aspects of one member as well as aspects of more than one member.

[0012] As used herein, the term "about" means "approximately" and is used to modify a numerical value to indicate a defined range around that value. If "X" is a value, "about X" generally refers to a value of 0.95X to 1.05X. Any reference to "about X" specifically refers to at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach, for example, "0.98X" and to support the limitation of claims thereto. If the numerical value "X" includes only integer values (e.g., "X carbons"), "about X" refers to (X-1) to (X+1). In this case, "about X" as used herein specifically refers to at least the values X, X-1, and X+1.

[0013] "About" and "approximately" can be used interchangeably. When "about" is added to the beginning of a range of values, it applies to both ends of that range. Thus, "about 5-20%" is equivalent to "about 5% to about 20%." When "about" is added to the first value in a series, it applies to all values in the series. Thus, "about 7%, 9%, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0014] The following abbreviations and terms have the indicated meanings throughout: [Table 1] [Table 2]

[0015] The symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. [ka] means a single or double bond. [ka] refers to a group on a double bond occupying either position on the terminus of the double bond to which the symbol is attached; i.e., the geometry of the double bond, E- or Z-, is ambiguous. When a group is depicted removed from its parent formula, the symbol "~" is used at the end of the theoretically cleaved bond to separate the group from the parent structural formula.

[0016] Chemical structures are drawn or described assuming that all carbons have hydrogen substitutions to satisfy a valence of four, unless explicitly stated otherwise. For example, in the structure on the left hand side of the diagram below, nine hydrogens are implied. Nine hydrogens are shown in the structure on the right hand side. Certain atoms in the structure may be described with a symbolic formula, e.g., -CHCH-, as having one or more hydrogens (well-defined hydrogens) as substitutions. Those skilled in the art will appreciate that such description methods are common in the chemical arts to shorten and simplify the description of otherwise complex structures. [ka]

[0017] The group "R" is a ring system, such as the following formula: [ka] If described as "floating," as in, unless otherwise defined, the substituent "R" may reside on any atom of the ring system, assuming stated, implied, or explicitly defined replacement of a hydrogen from one of the ring atoms, so long as a stable structure is formed.

[0018] The group "R" may be a fused or bridged ring system, such as the following formula: [ka] If described as "floating," as in, unless otherwise defined, the substituent "R" may reside at any atom of the fused or bridged ring system, assuming replacement of a stated (e.g., --NH-- in the formula above), implied (e.g., in the formula above, when a hydrogen is not shown but is understood to be present), or explicitly defined (e.g., in the formula above, when "Z" is =CH--) hydrogen from one of the ring atoms, so long as a stable structure is formed. In the examples described, the "R" group may reside on either a 5- or 6-membered ring of the fused or bridged ring system.

[0019] The group "R" may be, for example, [ka] (where in this example "y" can be greater than 1) When a ring system is described as containing a saturated carbon atom of the formula: [ka] The spirocyclic ring structure is formed with the rings described above.

[0020] As used herein, the term "acyl" includes alkanoyl, aroyl, heterocycloyl, or heteroaroyl groups, as defined herein. Examples of acyl groups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.

[0021] The term "alkanoyl," as used herein, includes alkyl-C(O)- groups, where alkyl is as defined herein. Examples of alkanoyl groups include, but are not limited to, acetyl and propanoyl.

[0022] As used herein, the term "agent" includes any compound or mixture of compounds that, when added to a composition, tends to produce a particular effect on the properties of the composition. For example, a composition containing a thickening agent may be more viscous than an otherwise identical comparative composition lacking the thickening agent.

[0023] 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 number of carbon atoms indicated. 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. If the number of carbon atoms indicated is 1, then C i The alkenyl is double-bonded to a carbon (i.e., the carbon equivalent of an oxo group). In some embodiments, the chain contains 1 to 12, about 2 to 15, about 2 to 12, about 2 to 8, or about 2 to 6 carbon atoms. The alkenyl group preferably has one stereoisomer (i.e., cis- or trans-). Examples of alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl, butadienyl, pentadienyl, 3-(1,4-pentadienyl), and hexadienyl.

[0024] An alkenyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkenyl group can be replaced with fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, so long as the hydrogen atom substituent at the carbon-carbon double bond is not replaced with a hydroxy, amino, or thio group. In some embodiments, an alkenyl group is unsubstituted or not optionally substituted.

[0025] As used herein, "alkenylene" includes di-substituted alkenyl groups, such as but-2-enylene (-CH2CH=CHCH2-).

[0026] As used herein, the term "alkyl" includes an aliphatic hydrocarbon chain that may be straight or branched. The chain may contain the indicated number of carbon atoms: for example, C-C 10 indicates that the group can have 1 to 10 (inclusive) carbon atoms in it. Unless otherwise specified, alkyl groups contain 1 to about 20 carbon atoms. In some embodiments, alkyl groups have 1 to about 10 carbon atoms. In some embodiments, alkyl groups ("lower alkyl") have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples can include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, docecyl, cyclopentyl, or cyclohexyl.

[0027] An alkyl group 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 alkyl group can be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, the alkyl group is unsubstituted or not optionally substituted.

[0028] As used herein, "alkylene" includes di-substituted alkyl groups. Examples include methylene (-CH2-), propylene (-CH2CH2CH2-), and the like.

[0029] As used herein, the term "alkoxy" includes straight or branched chain saturated or unsaturated hydrocarbons containing at least one oxygen atom in an ether group (e.g., EtO-). The chain may contain the number of carbon atoms indicated. 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.

[0030] An alkoxy group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkoxy group can be replaced with fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, so long as the hydrogen atom alpha to the ether oxygen is not replaced with a hydroxy, amino, or thio group. In some embodiments, an alkoxy group is unsubstituted or not optionally substituted.

[0031] The term "alkynyl" as used herein includes straight, branched, or cyclic hydrocarbons containing at least one carbon-carbon triple bond. Examples can include, but are not limited to, ethynyl, propargyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, or decynyl.

[0032] As used herein, "alkynylene" includes di-substituted alkynyl groups, such as 2-butynylene (-CH2CCCH2-).

[0033] An alkynyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkynyl group can be replaced with fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, provided that the sp-hybridized hydrogen atom substituent is not substituted with a hydroxy, amino, or thio group. In some embodiments, an alkynyl group is unsubstituted or not optionally substituted.

[0034] The term "aryl" as used herein includes cyclic aromatic carbocyclic ring systems containing 6 to 18 carbons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl, and phenanthrenyl.

[0035] An aryl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 5, 1 to 2, or 1) hydrogen atoms of the aryl group can be replaced with a moiety independently selected from the group consisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, an alkoxy group is unsubstituted or not optionally substituted.

[0036] The term "arylalkyl" or "aralkyl," as used herein, includes alkyl groups in which at least one hydrogen substituent is 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.

[0037] An arylalkyl or aralkyl group may be unsubstituted or optionally substituted for each of its constituent groups. For example, the aryl group of an arylalkyl group may be substituted, as in, but not limited to, 4-methylbenzyl. In some embodiments, a group is not unsubstituted or optionally substituted, particularly if it contains a specified substituent, such as a hydroxyalkyl or alkylaminoalkoxy group.

[0038] As used herein, the term "cycloalkyl" includes non-aromatic saturated monocyclic or polycyclic ring systems, which may contain the indicated number of carbon atoms, e.g., C3-C 12 indicates that the group may have 3 to 12 (inclusive) carbon atoms in it. Unless otherwise specified, cycloalkyl groups contain from about 3 to about 20 carbon atoms. In some embodiments, cycloalkyl groups have 3 to about 12 carbon atoms in the group. In some embodiments, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.

[0039] A cycloalkyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the cycloalkyl group can be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, a substituted cycloalkyl group can contain an intracyclic or intracyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, a cycloalkyl group is unsubstituted or not optionally substituted.

[0040] As used herein, "fluoroalkyl" includes alkyl groups that contain one or more fluoro substituents. Examples include, but are not limited to, trifluoromethyl.

[0041] 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.

[0042] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0043] The term "heteroaryl" or "heterocycloaryl" includes monocyclic and bicyclic aromatic groups of about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms) containing at least one heteroatom. Heteroatoms as used in the term heteroaryl include oxygen, sulfur, and nitrogen. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Examples include, but are not limited to, pyrazinyl, furanyl, thienyl, pyridyl, 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, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl.

[0044] As used herein, the term "heteroarylene" or "heterocycloarylene" includes di-substituted heteroaryl groups.

[0045] Heteroaryl groups can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 5, 1 to 2, or 1) hydrogen atoms of the heteroaryl group can be replaced with a moiety independently selected from the group consisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, a heteroaryl group is unsubstituted or not optionally substituted.

[0046] As used herein, the term "heteroaroyl" includes heteroaryl-C(O)- groups, where heteroaryl is as defined herein. Heteroaroyl groups include, but are not limited to, thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, and pyridinoyl.

[0047] The term "heterocycloalkyl" may be used interchangeably herein and, as used herein, includes heterocyclyl-C(O)- groups, where heterocyclyl is as defined herein. Examples include, but are not limited to, N-methylprolinoyl and tetrahydrofuranoyl.

[0048] As used herein, "heterocyclyl" (heterocyclo; heterocyclic; heterocycloalkyl) includes a non-aromatic saturated ring of about 3 to about 8 ring atoms (e.g., 5 to about 10 ring atoms or 3 to about 6 ring atoms) in which one or more of the atoms in the ring system is one or more elements other than carbon, e.g., nitrogen, oxygen, or sulfur. A heterocyclyl group optionally contains at least one sp 2-contains a hybridizing atom (e.g., a ring containing a carbonyl, an endocyclic olefin, or an exocyclic olefin). In certain embodiments, the nitrogen or sulfur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Monocyclic heterocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include 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, piperazinyl, piperidinyl, pyranyl, pyrazolin ... These include, but are not limited to, thiazolinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.

[0049] As used herein, the term "heterocycloalkylene" includes di-substituted heterocyclyl (heterocyclo; heterocyclic) groups.

[0050] The term "heterocyclyl" also includes polycyclic rings such as bicyclic or tricyclic heterocycles that may be fused, bridged, or spiro-oriented. A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocyclic ring system in which 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.

[0051] Examples of tricyclic heterocycles are bicyclic heterocycles fused to a phenyl group, or bicyclic heterocycles fused to a monocyclic cycloalkyl, or bicyclic heterocycles fused to a monocyclic cycloalkenyl, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles in which 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.

[0052] Heterocyclyl groups can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the group can be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some embodiments, substituted heterocyclyl groups can contain an annular or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, heterocyclyl groups are unsubstituted or not optionally substituted.

[0053] The monocyclic, bicyclic, and tricyclic heterocycles can be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring, and can be unsubstituted or substituted.

[0054] As used herein, the term "hydrophilic moiety" or "hydrophilic group" includes moieties or functional groups that have a strong affinity for water. Examples can include, but are not limited to, charged moieties such as cationic or anionic moieties or polar uncharged moieties such as alkoxy or amine groups.

[0055] As used herein, the term "hydroxyalkyl" includes alkyl groups in which at least one hydrogen substituent is replaced with an alcohol (-OH) group. In some embodiments, the hydroxyalkyl group has one alcohol group. In some embodiments, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In some embodiments, the hydroxyalkyl group has one, two, three, four, five, or six alcohol groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0056] If any two substituents or any two instances of the same substituent are referred to as being "independently selected" from a list of alternatives, then these groups may be the same or different. For example, R a and R b is independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then two R a group and two R b A molecule having groups can have groups that are all alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a is alkyl and the second R a is fluoro and the first R b is hydroxyalkyl, and the second R b is amino (or any other substituent selected from the group). Alternatively, both R a and the first R b is fluoro and the second R bis alkyl (i.e., some pairs of substituents may be the same and other pairs may be different).

[0057] "Protecting group" refers to an "amino-protecting group" that is a protecting group suitable for preventing undesired reactions of an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, such as alkanoyl groups, e.g., acetyl; alkoxycarbonyl groups, e.g., tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, e.g., benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, e.g., trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and the like. Representative oxygen-protecting groups include, but are not limited to, silyl groups, e.g., TMS and TMDMS; esters, e.g., formate, acetate, and benzoate (Bz); ethers, e.g., methoxymethyl (MOM), tetrahydropyranyl (THP), and benzyl (Bn).

[0058] The "yield" for each reaction described herein is expressed as a percentage of the theoretical yield.

[0059] The terms "subject" and "patient" are used interchangeably. A "subject" or "patient" for purposes of the present invention includes humans and other animals, particularly mammals and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In a specific embodiment, the patient is a mammal, and in a more specific embodiment, the patient is human.

[0060] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, incorporated herein by reference. thed., Mack Publishing Company, Easton, PA, 1985, or SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference.

[0061] Examples of pharmaceutically acceptable acid addition salts include those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as those with acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic 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, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, These include those formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic 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, p-toluenesulfonic acid, and salicylic acid.

[0062] Examples of pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, or aluminum salts. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of 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, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, etc. Examples of organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. "Platin" and "platin-containing agents" include, for example, cisplatin, carboplatin, and oxaliplatin.

[0063] A "therapeutically effective amount" is an amount of a compound of the present invention that, when administered to a patient, relieves the symptoms of the disease. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient being treated, etc. A therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and this disclosure.

[0064] As used herein, the term "genetic disorder" refers to a genetic disorder, disease, condition, or syndrome.

[0065] "Preventing" or "preventing" a disease, disorder, or syndrome includes barring the disease from occurring in humans, i.e., preventing the clinical symptoms of the disease, disorder, or syndrome from developing in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome, but has not yet experienced or exhibited any symptoms of the disease, disorder, or syndrome.

[0066] As used herein, "treating" or "treatment" of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome, i.e., halting its progression; and (ii) alleviating the disease, disorder, or syndrome, i.e., causing the disease, disorder, or syndrome to regress. As known in the art, adjustments for systemic versus local delivery, age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the condition may be necessary and can be ascertained by routine experimentation by one of ordinary skill in the art.

[0067] As used herein, the term "oxidizing agent" refers to a substance or reagent that tends to oxidize by being reduced and gaining electrons. Examples of oxidizing agents include 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), peroxodisulfuric acid (H2S2O8), peroxosulfuric acid (H2SO5), chlorous acid, chloric acid, perchloric acid and other similar halogen compounds, hypochlorous acid and other hypohalous acid compounds, including household bleach (NaClO), hexavalent chlorine, and the like. The chromium compounds are selected from, but are not limited to, chromium compounds such as chromium and dichromate and chromium trioxide, pyridinium chlorochromate (PCC) and chromate / dichromate compounds, permanganate compounds such as potassium permanganate, sodium perborate, nitrous oxide (N2O), nitrogen dioxide / nitrogen tetroxide (NO2 / N2O4), potassium nitrate (KNO3), gun powder oxidizer, sodium bismuthate and sodium periodate (NaIO4).

[0068] As used herein, a CFTR modulator type is a drug or compound that targets a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The three types of modulators are potentiators, correctors, and amplifiers. [Accessed May 23, 2019, Cystic Fibrosis Foundation https: / / www.cff.org / Research / Developing-New-Treatments / CFTR-Modulator-Types / ]

[0069] Potentiators such as the drug ivacaftor (Kalydeco®) act on residual function and splice variants where there is insufficient amount of normal CFTR protein by keeping the gate open and allowing chloride to pass through.

[0070] The corrective agent helps CFTR proteins with two copies of the F508del mutation form the correct 3D shape so that they can be translocated -- or transported -- to the cell surface.

[0071] Amplifiers increase the amount of CFTR protein cells make. Many CFTR mutations produce insufficient CFTR protein. If cells produce more CFTR protein, enhancers and correctors can allow much more chloride to cross the cell membrane.

[0072] Implementation In some embodiments, the present invention provides a compound of formula I or formula I': [ka] or a pharmaceutically acceptable salt thereof, comprising: (a1) Intramolecularly cyclizing 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: [ka] (b1) Intramolecularly cyclizing a compound of formula B (wherein PG is a protecting group) to form a compound of formula I': [ka] [During the ceremony, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other is halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or [ka] where R 3c is H or a protecting group; R 4a and R 4b each independently represents —H and optionally substituted C 1-10selected from the group consisting of alkyl; R 6a is an optionally substituted C 1-10 is alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted aryl; R 8a and R 8b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 9a is —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 12 is C 1-6 is alkyl; and L is an optionally substituted C 2-5 It is alkylene. This includes a method.

[0073] In some embodiments, R3 is H or [ka] where R 3c is H or a protecting group. In some further embodiments, R3 is H. In some other further embodiments, R3 is [ka] where R 3c is H or a protecting group.

[0074] In certain embodiments, the intramolecular cyclization of the compound of formula B proceeds in the presence of a solvent under neutral conditions.

[0075] In other embodiments, the intramolecular cyclization of the compound of formula B proceeds at temperatures above 120°C.

[0076] In certain embodiments, the intramolecular cyclization of the compound of formula B proceeds at a temperature of from about 50°C to about 175°C.

[0077] In other embodiments, the intramolecular cyclization of the compound of formula B proceeds in the presence of m-xylene at a temperature of from about 60°C to about 150°C.

[0078] In other embodiments, the intramolecular cyclization of the compound of formula B proceeds in the presence of m-xylene at a temperature of about 100°C to about 150°C.

[0079] In a further embodiment, the intramolecular cyclization of the compound of formula B proceeds in the presence of m-xylene at a temperature of about 130°C to about 140°C.

[0080] In some embodiments, 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 diethyl ether. In a further embodiment, the intramolecular cyclization occurs in the presence of 4-dimethylaminopyridine (DMAP). In other further embodiments, the intramolecular cyclization occurs in the presence of a base. In yet a further embodiment, the base is an organic base such as trimethylamine, diisopropylethylamine, DBU, and others known to those skilled in the art.

[0081] In certain embodiments, the method of the present invention comprises converting a compound of formula A-1 to a compound of formula A: [ka]

[0082] In certain embodiments, LG is R'-(C=O)-.

[0083] In certain embodiments, R' is an optionally substituted phenyl.

[0084] In some embodiments, the method includes a base.

[0085] In further embodiments, 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), pempidine (PMP), tributylamine, triethylamine, diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine).

[0086] In other embodiments, the method further comprises the step of preparing a compound of formula A-2, wherein R x C is optional 1-4 Alkyl, hydroxyl, oxo, COOH, COO(C 1-6 C substituted with alkyl), amino, alkylamino, halo or cyano 1-6 alkyl) to a compound of formula A-1: [ka]

[0087] In some embodiments, R x is methyl, substituted methyl, ethyl, substituted ethyl, benzyl, substituted benzyl, or t-butyl. x is methyl, benzyl, pentyl substituted with one or more of oxo, hydroxyl, and methyl. In still further embodiments, R x is benzyl. In certain other embodiments, R x are pent-3-yl-2-one, 2-hydroxy-2-methyl-pentanal-3-yl and 1,2-dihydroxy-2-methyl-pentan-3-yl.

[0088] In other embodiments, the method further comprises converting the compound of formula A-3 to a compound of formula A-2: [ka]

[0089] In other embodiments, the method further comprises converting the compound of formula A-4 to a compound of formula A-3: [ka]

[0090] In other embodiments, 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: [ka]

[0091] In other embodiments, the method further comprises converting the compound of formula A-4A1 to a compound of formula A-4A: [ka]

[0092] In other embodiments, the method further comprises converting the compound of formula A-4A2 to a compound of formula A-4A1: [ka]

[0093] In other embodiments, the method further comprises converting the compound of formula A-4A3 to a compound of formula A-4A2: [ka]

[0094] In other embodiments, the method further comprises converting the compound of formula II to a compound of formula A-4A3: [ka]

[0095] In certain embodiments, the method comprises converting a compound of formula III to a compound of formula II: [ka]

[0096] In other embodiments, the method further comprises converting the compound of formula A-4B to a compound of formula A-4: [ka]

[0097] In other embodiments, the method further comprises converting the compound of formula A-4B1 to a compound of formula A-4B: [ka]

[0098] In other embodiments, the method further comprises converting the compound of formula A-4B2 to a compound of formula A-4B1: [ka]

[0099] In other embodiments, the method further comprises converting the compound of formula A-4B3 to a compound of formula A-4B2: [ka]

[0100] In other embodiments, the method further comprises converting the compound of formula II to a compound of formula A-4B3: [ka]

[0101] In some embodiments, R3 is [ka] and the method further comprises converting the compound of formula I to a compound of formula IA: [ka]

[0102] In other embodiments, the method further comprises converting the compound of formula IA to a compound of formula I': [ka]

[0103] In other embodiments, the method further comprises converting the compound of formula I' to a compound of formula IC: [ka]

[0104] In one embodiment, the method comprises: (b1) forming a compound of formula I by intramolecular cyclization of a compound of formula B (wherein PG is a protecting group) followed by removal of the protecting group: [ka]

[0105] In other embodiments, the method further comprises converting the compound of formula B-1 to a compound of formula B: [ka]

[0106] In other embodiments, the method further comprises converting the compound of formula B-2 to a compound of formula B-1: [ka]

[0107] In other embodiments, the method further comprises converting the compound of formula B-3 to a compound of formula B-2: [ka]

[0108] In other embodiments, the method further comprises: [ka] ) to a compound of formula B-3: [ka]

[0109] In other embodiments, the method further comprises converting the compound of formula B-5 to a compound of formula B-4: [ka]

[0110] In other embodiments, the method further comprises converting the compound of formula B-6 to a compound of formula B-5: [ka]

[0111] In other embodiments, the method further comprises converting the compound of formula B-7 to a compound of formula B-6: [ka]

[0112] In other embodiments, the method further comprises converting the compound of formula B-8 to a compound of formula B-7: [ka]

[0113] In other embodiments, the method further comprises the step of: 10a is OH and R 10b is H or R 10a and R 10b forms C=O) to a compound of formula B-6: [ka]

[0114] In other embodiments, the method further comprises the step of: 10a is OH and R 10b is H or R 10a and R 10b forms C=O) to a compound of formula B-9: [ka]

[0115] In some embodiments, R 12 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. 12 is methyl or t-butyl. In still further embodiments, R 12 is t-butyl.

[0116] In some embodiments, R 8a and R 8b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0117] In a further embodiment, R 8a and R 8b One of them is H and the other is methyl.

[0118] In some embodiments, R 6ais selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0119] In some embodiments, R 6b is selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0120] In a further embodiment, R 6a and R 6b are each methyl.

[0121] In some embodiments, R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether, or silyl ether protecting groups; [ka] and R 3c is H or a benzoyl group.

[0122] In some embodiments, R 4a and R 4b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0123] In a further embodiment, R 4a and R 4b One of them is H and the other is methyl.

[0124] In some embodiments, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0125] In other embodiments, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b The other is methyl.

[0126] In some embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2b the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0127] In other embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R2b The other is methyl, ethyl, propyl or isopropyl.

[0128] In other embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2b The other is methyl.

[0129] In one embodiment, the present invention provides 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: [ka] [During the ceremony: R 10a and R 10b one of which is OH and the other is H or R 10a and R 10b come together to form C=O; R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other is halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or [ka] where R 3c is H or a protecting group; R 4a and R 4b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 6a is an optionally substituted C 1-10 is alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted aryl; R 8a and R 8b each independently represents —H and optionally substituted C 1-10 alkyl; and PG is a suitable protecting group. This includes a method.

[0130] In certain embodiments, the compound of formula IV is contacted with ozone in the presence of an acid to form a compound of formula B-9: In further embodiments, the acid is soluble in dichloromethane.

[0131] In still further embodiments, the acid is trifluoroacetic acid.

[0132] In certain embodiments, the contacting occurs in dichloromethane.

[0133] In other embodiments, R 8a and R 8b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0134] In a further embodiment, R 8a and R 8b One of them is H and the other is methyl.

[0135] In some embodiments, R 6a is selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0136] In some embodiments, R 6b is selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0137] In a further embodiment, R 6a and R 6b are each methyl.

[0138] In some embodiments, R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether, or silyl ether protecting groups; [ka] and R 3c is H or a benzoyl group.

[0139] In some embodiments, R 4a and R 4b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0140] In a further embodiment, R 4a and R 4b One of them is H and the other is methyl.

[0141] In some embodiments, R 2a and R2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0142] In some embodiments, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b The other is methyl.

[0143] In some embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2bthe other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0144] In other embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2b The other is methyl, ethyl, propyl or isopropyl.

[0145] In a further embodiment, R 2a and R 2b One of the two is H and the other is R 2a and R 2b The other is methyl.

[0146] In one embodiment, the present invention provides a method for preparing a compound of formula A-3 from a compound of formula A-4, comprising contacting a compound of formula A-4 with an amine having the formula NH-L-OH under reductive amination conditions to form a compound of formula A-3: [ka] [During the ceremony: R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b the other is halo, optionally substituted C 1-10Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R3 is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or [ka] where R 3c is H or a protecting group; R 4a and R 4b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; R 6a is an optionally substituted C 1-10 is alkyl; R 6b is -H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 hydroxyalkyl and optionally substituted aryl; R 8a and R 8b each independently represents —H and optionally substituted C 1-10 selected from the group consisting of alkyl; PG is a suitable protecting group; and L is an optionally substituted C 2-5 It is alkylene. The present invention includes a method comprising the steps of:

[0147] In certain embodiments, the coupling of a compound of formula A-4 with an amine having the formula NH2-L-OH is carried out in the presence of a solvent.

[0148] In a further embodiment, the solvent is dichloromethane.

[0149] In certain embodiments, the coupling of a compound of formula A-4 with an amine having the formula NH2-L-OH is carried out in the presence of NaB(OAc)3H and acetic acid.

[0150] In certain embodiments, NaB(OAc) 3 H and acetic acid are each present in about 2 molar equivalents relative to the compound of formula A-4.

[0151] In certain embodiments, L is an optionally substituted C2-8 alkylene. In certain embodiments, L is an optionally substituted C2-6 alkylene. In certain embodiments, L is an optionally substituted C2-5 alkylene. In certain embodiments, L is an optionally substituted C2-4 alkylene. In certain embodiments, L is ethylene optionally substituted with up to three halo, CN, NO2, amino, amido, carboxy, alkylcarbonyl, alkoxycarbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with halo or alkyl.

[0152] In certain embodiments, L is ethylene optionally substituted with up to three halo, alkyl, or alkoxy.

[0153] In some embodiments, NH-L-OH is NH-CH-L-OH, NH-CH(C 1-6 alkyl)-L1-OH, NH2-L1-CH2-OH or NH2-L1-CH(C 1-6 alkyl)-OH; L1 is CR 14a R 14b and; R 14b is H or C 1-6is alkyl; R 14a is an 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, optionally substituted saturated or partially unsaturated heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl containing at least one double bond; or R 14a and R 14b together with the carbon atoms to which they are attached. [ka] where Q is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocyclic ring, [ka] indicates the attachment point, and R 11a and R 11b each independently represents H, halo, and optionally substituted C 1-10 In some embodiments, NH2-L-OH is NH2-L1-CH2-OH.

[0154] In some embodiments, NH-L-OH is NH-L-CH-OH or NH-L-CH(C 1-6 alkyl)-OH.

[0155] In certain embodiments, NH2-L-OH is NH2-L1-CH2-OH.

[0156] In some embodiments, L1 is CR14a R 14b where R 14b is H or C 1-6 alkyl, and R 14a is an optionally substituted R 101 -CH2-, R 101 -CH2CH2-, R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 In this embodiment, R 101 teeth [ka] is selected from the group consisting of: [ka] indicates the point of attachment.

[0157] In some embodiments, L1 is CR 14a R 14b where R 14b is H or C 1-6 alkyl, and R 14a is optionally substituted saturated or partially unsaturated cycloalkyl containing at least one double bond, optionally substituted saturated or partially unsaturated heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In certain embodiments, R 14a teeth [ka] [ka] [ka] where: [ka] indicates the point of attachment.

[0158] In some embodiments, L1 is CR 14a R 14b where R 14a and R 14b together with the carbon atoms to which they are attached. [ka] where Q is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocyclic ring, [ka] indicates a point of attachment. In certain embodiments, each R q are independently H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, [ka] [ka] or two R q together with the atom to which they are attached, [ka] (as a salt) (e.g., a formate salt), wherein: [ka] indicates the point of attachment.

[0159] In one embodiment, [ka] teeth [ka] In one embodiment, [ka] teeth [ka] and each R q are independently H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, [ka] [ka] or two R q together with the atom to which they are attached, [ka] (as a salt) (e.g., a formate salt), wherein: [ka] indicates the point of attachment.

[0160] In one embodiment, [ka] teeth [ka] and R q -H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me, [ka] [ka] wherein: [ka] indicates the point of attachment.

[0161] In certain embodiments, L in compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B, and B-1 is CH-CR 14a R 14b where R 14a and R 14b is as defined herein.

[0162] In embodiments of compounds of formula I, IA, I', IC, A, A-1, A-2, A-3, B, and B-1, L is CHCH-R 14a where R 14a is an optionally substituted R 101 -CH2-, R 101 -CH2CH2-, R 101 -CH2CH2CH2-, optionally substituted R 101 -CH2CH2CH-OH- and optionally substituted R 101 In this embodiment, R 101 teeth [ka] is selected from the group consisting of: [ka] indicates the point of attachment.

[0163] In some embodiments of formula I, IA, I', IC, A, A-1, A-2, and A-3, B and L are CHCH-R 14a where R 14a is an optionally substituted saturated or partially unsaturated cycloalkyl containing at least one double bond, an optionally substituted saturated or partially unsaturated heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl.

[0164] In some embodiments, R 14a teeth [ka] [ka] [ka] where: [ka] indicates the point of attachment.

[0165] In embodiments of compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B, and B-1, L is CHCR 14a R 14b where R 14a and R 14b together with the carbon atoms to which they are attached. [ka] where Q is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocyclic ring, [ka] indicates the attachment point, and R 11a and R 11b each independently represents H, halo, and optionally substituted C 1-10 In certain embodiments, each R q are independently H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, [ka] [ka] or two R q together with the atom to which they are attached, [ka] (as a salt) (e.g., a formate salt), wherein: [ka] indicates the point of attachment.

[0166] In embodiments of compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B, and B-1, [ka] teeth [ka] In one embodiment, [ka] teeth [ka] and each R q are independently H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, [ka] [ka] or two R q together with the atom to which they are attached, [ka] (as a salt) (e.g., a formate salt), wherein: [ka] indicates the point of attachment.

[0167] In embodiments of compounds of Formula I, IA, I', IC, A, A-1, A-2, A-3, B, and B-1, [ka] teeth [ka] and R q -H, -CH2Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, -C(=O)-Me, [ka] [ka] wherein: [ka] indicates the point of attachment.

[0168] In some embodiments, R 8a and R 8b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0169] In a further embodiment, R 8a and R 8b One of them is H and the other is methyl.

[0170] In some embodiments, R 6a is selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

[0171] In some embodiments, R 6bis selected from H, methyl, ethyl, propyl, isopropyl and tert-butyl.

[0172] In a further embodiment, R 6a and R 6b are each methyl.

[0173] In some embodiments, R 3c is a protecting group selected from benzoyl, p-nitrobenzoyl, TMS, TES IPDMS, TBS, or methoxymethyl. 3c is a benzoyl group.

[0174] In some embodiments, R 4a and R 4b one of which is H and the other is optionally substituted C 1-10 It is alkyl.

[0175] In a further embodiment, R 4a and R 4b One of them is H and the other is methyl.

[0176] In some embodiments, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2bthe other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0177] In some embodiments, R 2a and R 2b one of which is H, halo, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 2-10 alkenyl, wherein C 1-10 Alkyl, C 1-10 Alkoxy and C 2-10 The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and R 2a and R 2b The other is methyl.

[0178] In some embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2b the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. 1-10 It is alkyl.

[0179] In other embodiments, R 2a and R 2b One of the two is H and the other is R 2a and R 2b The other is methyl, ethyl, propyl or isopropyl.

[0180] In some embodiments, R 2a and R 2b One of the two is H and the other is R2a and R 2b The other is methyl.

[0181] In another embodiment, the invention relates to compounds of formula A, B, A-1, A-2, A-3 and B-1.

[0182] In another embodiment, the invention relates to compounds 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.

[0183] In other aspects, the present invention relates to compounds set forth in Table 1. [ka] [ka] [ka] [Example]

[0184] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting the scope in any way.

[0185] Ozonolysis and intermediate production Ozonolysis pathway 1 Scheme 1 describes the ozonolysis products S1-5, S1-6, and S1-8 starting from S1-1, optionally via an intermediate protected at the C-5 desosamine hydroxyl group. In this process, S1-1 was converted to S1-2 by known methods (see, for example, WO2009 / 053259). In one alternative method, the C-5 desosamine hydroxyl group of S1-2 was then protected, for example, by converting the C-5 desosamine hydroxyl group to a benzoyl group by known methods to obtain S1-3. S1-3 was then ozonolyzed in dichloromethane in the presence of an acid such as trifluoroacetic acid. Quenching with dimethyl sulfide provided the ozonation product S1-5. Alternatively, the C-9 ketone in S1-3 was reduced to the corresponding alcohol S1-4, which, after ozonolysis, provided S1-6. In another alternative, S1-2 was reduced to give the alcohol S1-7 and then, after subsequent ozonolysis, S1-8. [ka]

[0186] [ka] (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 known methods (PCT International Application No. 2009053259, April 30, 2009).

[0187] 163.2 kg of clarithromycin and 180.4 kg of TEA were added to a 1000 L glass-lined reactor. The temperature was adjusted to 75-95°C (white suspension). The reaction mixture was stirred at 45-50°C for approximately 10-20 minutes to obtain a white suspension. Next, 111.6 kg of ethylene carbonate (5.78 equivalents) and 60.3 kg of TEA were added to the 1000 L glass-lined reactor. The temperature was adjusted to 85-95°C, and the mixture was stirred for approximately 20-22 hours. IPC: 9.2% residual clarithromycin. 53.8 kg of ethylene carbonate was added to the 1000 L glass-lined reactor. 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 an additional 4 hours. IPC, 0.91% residual clarithromycin. The temperature was then adjusted to 45-55°C. 122.9 kg HO was then added dropwise to the reaction mixture at 45-55°C. The mixture was stirred at approximately 45-55°C for 1 hour. The temperature was adjusted to 15-25°C and stirred for 15-17 hours. The liquid was then removed from the reaction mixture. The filter cake was washed with 163.3 kg HO. The filter cake (bright white solid) was sampled for IPC, S1-2: 96.0%. The cake was then dried at 45-55°C for 23-25 hours. 128.61 kg of S1-2 was obtained as a gray-white solid, 80.85% yield.

[0188] [ka] (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 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 NaHCO (saturated, aqueous, twice), dried over NaSO, filtered, and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 40% B) to give the title compound (3.9 g, 90%). MS (ESI+) m / z: 834.21 [M + H] + ; 1H NMR (400 MHz, chloroform-d) δ 8.02 - 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).

[0189] Preparation 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 RT and stirred for 1 h. The mixture was then heated to reflux overnight. The solution was washed with NaHCO (saturated, aqueous, twice), dried over NaSO, filtered, and concentrated. The residue was purified by ISCO (120 g silica gel column, A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 40% B) to give the title compound (22.7 g, 100%).

[0190] [ka] (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 benzoate (S1-4). NaBH (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 with 0.5% NH4OH, gradient elution from 0 to 50% B) afforded the title compound (1.86 g, 82%). MS (ESI+) m / z: 836.23 [M + H] + ; 1H NMR (400 MHz, クロロホルム-d) δ 8.05 - 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, 1H), 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).

[0191]

change

[0192] [ka] (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-dioxoundecan-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (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. O was bubbled through the solution until a blue color was observed. Nitrogen was bubbled through the solution until no blue color was observed. MeS (0.67 mL) was added, and the solution was stirred in the dry ice-acetone bath for 40 minutes. The solution was washed with saturated aqueous NaHCO. The organic layer was dried over NaSO, filtered, and concentrated to give crude S1-6. MS (ESI+) m / z: 868.25 [M + H] + .

[0193] [ka] (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 NaBH (824 mg, 21.8 mmol) were added. The mixture was stirred overnight and concentrated. The residue was triturated with DCM, the solids removed by filtration, and the filtrate concentrated and purified by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 100% B) to give the title compound (6.8 g, 85%). MS (ESI+) m / z: 732.4 [M + H] + .

[0194] [ka] (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-oxoundecanoate (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 bubbled through the solution until a blue color was observed. Nitrogen was bubbled through the solution until no blue color was observed anymore. Me2S (0.3 mL) was added and the solution was stirred in dry ice-acetone for 1 hour. 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] + .

[0195] Ozonolysis pathway 2 Scheme 2 provides an ozonolysis route to S2-3 by first protecting compound S1-2 with a Cbz protecting group instead of the benzyl protecting group described previously. According to Scheme 2, S1-2 (see Scheme 1) is Cbz protected at the hydroxyl group of the C-5 desosamine to give S2-1. Reduction to S2-2, followed by ozonolysis as described previously, gives S2-3. [ka]

[0196] [ka] 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-dioxooxacyclotetradec-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 / HO (1:1, 6.8 mL) was added NaOH (20% aqueous solution, 409 mg, 2.05 mmol), followed by 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 NaSO, filtered, and concentrated. Purification by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 40% B) afforded the title compound (516 mg, 87%). MS (ESI+) m / z: 864.29 [M + H] + .

[0197] [ka] 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 NaBH (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 with 0.5% NH4OH, gradient elution from 0 to 50% B) afforded the title compound (460 mg, 92%). MS (ESI+) m / z: 866.26 [M + H] + .

[0198] [ka] (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-oxoundecanoate (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 bubbled through the solution until a blue color was observed. Nitrogen was bubbled 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 minutes. 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] + .

[0199] Conversion of S1-5 or S1-6 (ozonolysis pathway 1, Scheme 1) to the t-butyl ester S3-6 The ozonolysis products S1-5 and S1-6 were readily converted to the azalide building block S3-6 according to Scheme 3. According to Scheme 3, reduction of S1-5 or S1-6 and subsequent periodate oxidation of the resulting alcohol S3-1 gave the diketone 3-2. Reduction of S3-2 gave S3-3. Ester hydrolysis of S3-3 using LiOH gave the acid S3-4, which was converted to the t-butyl ester S3-5. Removal of the cladinose residue at C-4 of S3-5 gave S3-6. [ka]

[0200] [ka] (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-oxoundecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-1a). A solution of S1-5 (12.9 g, 14.8 mmol) in EtOH (125 mL) was cooled to −25° C. for 10 minutes. Powdered NaBH4 (1.14 g, 30.3 mmol) was added portionwise. Once the addition was complete, the reaction mixture was stirred at -10 to -20 °C for 1 h. NaHCO3 (saturated, aqueous, 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] + .

[0201] (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-oxoundecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-1b) was synthesized using the same conditions as those detailed above for compound S3-1a.

[0202] [ka] (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-yl benzoate (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. NaIO (4.4 g, 20.6 mmol) was added, and the mixture was stirred at rt for 2 h. The solution was decanted, diluted with EtOAc, and washed with 10% NaSO, water, and brine. The organics were dried over NaSO, filtered, and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 30% B) to afford the title compound (2.8 g, 62%) as a white foam. MS (ESI+) m / z: 794.15 [M + H] + ; 1 H NMR (400 MHz, chloroform-d) δ 9.27 (d, 1H), 8.11 - 7.93 (m, 2H), 7.58 - 7.49 (m, 1H), 7.42 (q, 2H), 5.07 (dd, 1H), 4.91 - 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).

[0203] [ka] (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-oxononan-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-3). To a solution of S3-2 (9.2 g, 11.5 mmol) in EtOH (100 mL) was added NaBH (870 mg, 23 mmol), and the mixture was stirred at rt for 1 h. The solution was concentrated, and the residue was redissolved in EtOAc (200 mL), washed with water (2 x 100 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated. The material was purified by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH, gradient elution from 0 to 80% B) to afford the title compound (7.2 g, 78%) as a white foam. MS (ESI+) m / z: 798.25 [M + H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.11 - 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).

[0204] [ka] (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 HO / THF (1:3, 19.3 mL) was stirred with LiOH (134 mg, 5.6 mmol) for 60 h at rt. 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 x 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 (400 MHz, chloroform-d) δ 7.99 (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).

[0205] [ka] (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-yl benzoate (S3-5). A solution of S3-4 (160 mg, 0.224 mmol) in toluene (2.2 mL) was heated with N,N-dimethylformamide di-tert-butyl acetal (225 mg, 1.11 mmol) at 80° C. for 2 hours. 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] + .

[0206] [ka] (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-yl benzoate (S3-6). The above reaction solution was stirred with HCl (4 M in dioxane, 0.36 mL, 1.45 mmol) for 15 min at rt. 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: CHCN / 0.1% formic acid, gradient elution of 2-40-90% B over 15 min) to afford the title compound (83 mg, 61%) as a white foam. Formate salt. MS (ESI+) m / z: 610.2 [M + H] + ; 1H NMR (400 MHz, chloroform-d) δ 8.06 - 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).

[0207] Alternative preparation of S3-6 (Scheme 3) via ozonolysis route 3 An alternative preparation of azalide building block S3-6 is described in Scheme 4. According to Scheme 4, the C-4 cladinose residue was first removed under acidic conditions to give S4-1. Protection of the C-5 desosamine hydroxyl group, followed by reduction of the resulting compound S4-2, gave the ozonolysis substrate S4-3. S4-5 was prepared via ozonolysis and reduction of S4-3, with or without isolation of intermediate S4-4. The conversion of S4-5 to S3-6 was achieved via several four-step pathways, including (i) hydrolysis, esterification, periodate oxidation, and reduction (S4-5 → S4-10 → S4-11 → S4-12 → S3-6); (ii) periodate oxidation, hydrolysis, esterification, and reduction (S4-5 → S4-6 → S4-9 → S4-10 → S3-6); and (iii) periodate oxidation, reduction, hydrolysis, and esterification (S4-5 → S4-6 → S4-7 → S4-8 → S3-6). [ka]

[0208] [ka] (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 2 L three-neck round-bottom flask equipped with an overhead stirrer, temperature probe, and nitrogen inlet and outlet, S1-2 (97 g, 133 mmol) was added, followed by methanol (500 mL). The reaction mixture was stirred until a clear solution was formed. The solution was cooled in a water bath, and 6 N HCl (161 mL, 798 mmol, 6 equiv.) was added over approximately 20 min, maintaining the internal temperature at 20–25 °C. After 2 h, UPLC-MS analysis indicated >99% conversion. 28–30% aqueous NH OH (200 mL) was added to adjust the pH to 9–10, followed by water (100 mL). The reaction mixture was stirred for an additional 16 h. The resulting white solid was collected by filtration, washed with MeOH / HO (2:3, 300 mL), and dried in a vacuum oven at 35–40 °C for 72 h. This afforded the title compound (45 g, 59%) as a white solid. MS (ESI+) m / z: 572.27 [M + H] + .

[0209] [ka] (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-yl benzoate (S4-2). A 500 mL three-neck round-bottom flask equipped with a temperature probe, a stir bar, and a nitrogen inlet and outlet was charged with S4-1 (26 g, 45.4 mmol), followed by 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 equiv.) and benzoic anhydride (20.5 g, 90.8 mmol, 2 equiv.) were charged. The reaction mixture was heated at 40 °C for 24 h, at which point UPLC-MS indicated >99% conversion. After cooling to room temperature, the reaction mixture was washed with 2 N NaOH (50 mL × 2) and brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–100% 80% DCM / 20% MeOH / 0.5% aqueous NHOH in DCM) to give the desired product (26 g, 85%) as a white foam. MS (ESI+) m / z: 676.27 [M + H].

[0210] [ka] (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-yl benzoate (S4-3). A 1 L round-bottom flask equipped with a temperature probe, a stir bar, and a nitrogen inlet and outlet was charged with S4-2 (22 g, 32.5 mmol), followed by anhydrous EtOH (200 mL). The mixture was stirred at room temperature until a clear solution was obtained. NaBH (2.45 g, 65 mmol, 2 equiv.) was added in one portion. The mixture was stirred at rt for 16 h, at which time UPLC-MS indicated >99% conversion. Water (50 mL) and saturated aqueous NH4Cl (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 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 rt 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 give the title compound (12.7 g, 58%). MS (ESI+) m / z: 678.22 [M + H].

[0211] [ka] (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-dioxoundecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (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 using a dry ice / acetone cooling bath, and O3 was bubbled through the solution until the color turned blue (approximately 5 min). Nitrogen was then bubbled through the solution until the blue color disappeared. Dimethyl sulfide (0.3 mL, 6.7 equiv.) was added and the reaction mixture was stirred for 1 h. Saturated aqueous NaHCO3 (5 mL) was added and the two phases were separated. 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].

[0212] [ka] (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-oxoundecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S4-5).

[0213] Method 1: Crude S4-4 (490 mg, 0.6 mmol) was added to a 100 mL round-bottom flask, followed by EtOH (5 mL). NaBH (51 mg, 2 equiv.) was added at room temperature, and the reaction mixture was stirred overnight. Saturated aqueous NH Cl (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].

[0214] 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 equiv). The solution was cooled to -78 °C to -45 °C. O was bubbled through the solution for 20 min, at which point UPLC-MS indicated consumption of the starting material. NaBH (446 mg, 5 equiv) was added, and the reaction mixture was stirred at room temperature for 5 h. Saturated aqueous NH Cl (2 mL), water (10 mL), and EtOAc (20 mL) were added, and the mixture was stirred for 16 h. The organic phase was separated and concentrated, and the residue was purified by silica gel column chromatography (0-100% gradient of 80% DCM / 20% MeOH / 0.5% aqueous NH OH in DCM) to give the desired product (400 mg, 24%) as a white foam. MS (ESI+) m / z: 714.25 [M + H].

[0215] [ka] (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-yl benzoate (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). NaIO (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 thick oil (410 mg). The material was used in the next step without purification. MS (ESI+) m / z: 636.19 [M + H].

[0216] [ka] (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-yl benzoate (S4-7). Crude S4-6 (410 mg, 0.6 mmol) was added to a 100 mL round-bottom flask, followed by EtOH (5 mL). NaBH (48 mg, 2 equiv.) was added and the reaction mixture was stirred for 30 min. Water (2 mL) was added and 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 (0-100% gradient of 80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM) to give the desired product (180 mg, 44% from S3-3) as a white foam. MS (ESI+) m / z: 640.24 [M + H].

[0217] [ka] (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 ∼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].

[0218] [ka] (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 equiv.) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was neutralized to pH ∼5 and saturated with solid NaCl. The mixture was extracted with EtOAc (3 × 5 mL), and the combined extracts were concentrated. The residue was purified by silica gel column chromatography (0-100% gradient of 0.5% aqueous NH4OH in 80% DCM / 20% MeOH / DCM) to give the title compound (160 mg, 100%) as a white foam. MS (ESI+) m / z: 552.13 [M + H].

[0219] [ka] (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, followed by THF / hexane (0.3 mL / 0.3 mL). Under nitrogen, tert-butyl 2,2,2-trichloroethaneimidate (24 mg, 2 equiv.) and BF EtO complex (1 drop) were added. After 24 h, additional tert-butyl 2,2,2-trichloroethaneimidate (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 (0-100% gradient of 0.5% aqueous NH4OH in 80% DCM / 20% MeOH / DCM) to give the title compound (14 mg, 42%) as a white foam. MS (ESI+) m / z: 608.10 [M + H].

[0220] [ka] (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 CHCN (25 mL) and water (10 mL). LiOH (96 mg, 1.5 equiv) was added, and the reaction mixture was stirred for 3 h at rt. The reaction mixture was concentrated to remove most of the ACN, and 6 N HCl was added dropwise until the pH of the solution reached approximately 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 give the title compound (1.35 g, 85%) as a white foam, which was used in the next step without purification. MS (ESI+) m / z: 598.16 [M + H].

[0221] [ka] (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-oxoundecan-5-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S4-11). S4-10 (1.35 g, 2.25 mmol) was added to a 100 mL round-bottom flask, followed by anhydrous DCM (15 mL). Under nitrogen, tert-butyl 2,2,2-trichloroethanimidate (2 g, 4 equiv.) and BF EtO 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 (0-100% gradient of 80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM) to give the title compound (1 g, 68%) as a white foam. MS (ESI+) m / z: 654.28 [M + H].

[0222] [ka] (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, followed by DCM (1 mL). NaIO4 / SiO2 (226 mg, 3 equivalents, 14.6% w / w, prepared according to the literature published by 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 (0-100% gradient of 80% DCM / 20% MeOH / 0.5% aqueous NH4OH in DCM) 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) δ 9.15 (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).

[0223] [ka] (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-yl benzoate (S3-6). S4-12 (100 mg, 0.16 mmol) was added to a 20 mL vial, followed by EtOH (1 mL). NaBH (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 (0-100% gradient of 80% DCM / 20% MeOH / 0.5% aqueous NHOH in DCM) to give the title compound (88 mg, 88%) as a white foam. MS (ESI+) m / z: 610.30 [M + H].

[0224] Conversion of S1-2 to S5-7 using ozonolysis pathway 4 Further methods for preparing azalide building blocks S5-7 via ozonolysis pathway 4 are described in Scheme 5. Protection of S1-2 gave S5-1. Conversion of S5-1 to S5-7 was achieved via two routes. First, ozonolysis of S5-1, followed by reduction, hydrolysis, and esterification with benzyl bromide (protected) gave the ester S5-5. Periodate oxidation of S5-5, followed by reduction of S5-6, gave S5-7. Alternatively, reduction of S5-1, followed by ozonolysis, hydrolysis, and esterification with benzyl bromide (protected) gave S5-11. Periodate oxidation of S5-11 gave S5-6, followed by reduction to give S5-7. [ka]

[0225] [ka] (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). A 500 mL three-neck round-bottom flask equipped with a stir bar, temperature probe, and nitrogen inlet and outlet was charged with S1-2 (30 g, 41 mmol), followed by anhydrous DCM (150 mL). The solution was cooled in 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, maintaining the internal temperature below 25 °C. The addition was complete in approximately 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 HO (50 mL), 50% saturated KCO (50 mL), and 50% saturated NaHPO (2 × 50 mL), dried over NaSO, and concentrated to a thick oil. The product was crystallized from EtOH / HO (2:1) to give the title compound (29.5 g, 79%) as a white solid. MS (ESI+) m / z: 938.30 [M + H].

[0226] S5-1 Large-Scale Procedure Method 1. S1-2 (745 g, 1.02 mol) was placed in a 4 L, three-necked jacketed reactor equipped with an overhead stirrer. Dichloromethane (2.5 L) was then added and cooled to 0 °C, and the reactor was then equipped with a thermometer and nitrogen flow. To the orange solution was added DMAP (124 g, 1.02 mol, 1 equiv.), followed by TEA (212 mL, 1.53 mol, 1.5 equiv.). BzCl (241 mL, 2.09 mol, 2.05 equiv.) was added slowly, maintaining 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 title compound (666.9 g, 70%).

[0227] Method 2. A 400 L jacketed reactor was equipped with an overhead stirrer, thermometer, and 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 to the reactor over 1-1.5 hours, maintaining the internal temperature below 15°C. The reaction mixture was stirred at 23-27°C for 16-18 hours, then at 35-40°C for 5 hours. After cooling to 0-15°C, water (5.0 kg) was slowly charged to the mixture over 1-1.5 hours, maintaining the internal temperature below 15°C. Stirring was continued for 30 minutes at 0-15°C. 40% NaH2PO4 (12.5 kg) was slowly added, maintaining the internal temperature below 25°C. After stirring for 20-30 minutes at 0-15°C, the mixture was allowed to settle until two clear layers 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. This EtOH (18 kg) exchange 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 added slowly to the mixture with stirring at this temperature for 1 hour, then 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%).

[0228] Method 3. 49.1 kg S1-2, 230.4 kg DCM, 21.8 kg TEA, and 4.3 kg DMAP were placed in a glass-lined reactor. The temperature was adjusted to -5 to 5°C. 25.0 kg BzCl was slowly added dropwise to the reaction mixture at -5 to 5°C. The temperature was adjusted to 15 to 25°C, and the mixture was stirred for 20 to 22 hours. 100.9 kg H2O was slowly added dropwise to the reaction mixture at approximately 0 to 10°C. NaH2PO4 (wt% = 20%, aqueous solution) was added to the reaction mixture, which was then stirred for 10 to 20 minutes. The aqueous phase was removed. NaH2PO4 (wt% = 20%, aqueous solution) was added to the reaction mixture, which was then stirred for 10 to 20 minutes. The aqueous phase was removed. 35.9 kg K2CO3 (wt% = 25%, aqueous solution) was added to the reaction mixture, which was then stirred for 10 to 20 minutes. The aqueous phase was removed. 35.9 kg K2CO3 (wt% = 25%, aqueous solution) was added to the reaction mixture, which was then stirred for 10 to 20 minutes. The aqueous phase was removed. 110 kg MTBE was added to the organic phase. The organic phase was then concentrated to 5 to 6 volumes at 30 to 40°C under reduced pressure (approximately -60 kPa to -100 kPa). 109.7 kg MTBE was added to the organic phase. The organic phase was then concentrated to 5 to 6 volumes at 30 to 40°C under reduced pressure (approximately -60 kPa to -100 kPa). 73.0 kg MTBE was added to the residue. The mixture was stirred at approximately 30 to 40°C for approximately 1 to 2 hours. 339.6 kg n-heptane was then slowly added dropwise to the reaction mixture, which was then stirred at 30 to 40°C for 1 to 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 S5-1 was obtained as a white solid, 94.2% yield.

[0229] [ka] (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-trioxoundecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-2). Prepared from S5-1 (14.4 g, 15.3 mmol) using the method of S4-4, the title compound (14.3 g) was obtained as a white foam, which was used in the next step without purification. MS (ESI+) m / z: 970.39 [M + H] + .

[0230] [ka] (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-oxoundecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-3). Prepared starting from S5-2 (15 g, 15.4 mmol) by NaBH reduction according to the method of S4-5 to give the title compound (14 g) as a white foam, which was used in the next step without purification. MS (ESI+) m / z: 976.19 [M + H] + .

[0231] [ka] (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 according to the method of S4-10 starting from S5-3 (2.25 g, 2.3 mmol) to afford the title compound (1.4 g, 71%) as a white foam. MS (ESI+) m / z: 860.15 [M + H] + .

[0232] [ka] (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-oxoundecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-5). S5-4 (8.7 g, 10.1 mmol) was dissolved in CHCN (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 rt for 16 h. The mixture was concentrated under reduced pressure, and the residue was redissolved in IPAC (120 mL). This was washed with 13% NaCl (50 mL), dried over NaSO, and concentrated to give the title compound (8.8 g) as a white foam. MS (ESI+) m / z: 950.18 [M + H] + .

[0233] [ka] (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). Starting from a solution of S5-1 (10.5 g, 12.2 mmol) in EtOH / THF (1 / 1), the title compound (11.5 g) was obtained as a white foam and used in the next step without further purification. MS (ESI+) m / z: 940.30 [M + H] + .

[0234] S5-8 large-scale procedures Method 1. S5-1 (315.56 g) was added to a 5 L jacketed reactor equipped with a mechanical stirrer, followed by the addition of THF (1.39 L) and MeOH (1.39 L) under nitrogen balloon protection. The mixture was stirred at approximately 0-3 °C to form a yellow solution. CeCl3·7H2O (275.71 g, 2.2 equiv.) was added to the solution and stirred until all solids dissolved. NaBH4 (27.99 g, 2.2 equiv.) was added in portions, and the mixture was then stirred at approximately 2-5 °C for 50 min, at which point HPLC indicated >99% conversion. HO (316 mL) was slowly added to the reaction mixture, and the pH of the mixture was adjusted to approximately 5-6 with 3 N HCl, resulting in the appearance of a small amount of white solid. 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 crude S5-8 as a yellowish oil. MTBE (945 mL, 3 volumes) was added to the reaction mixture with stirring to form a white opaque mixture. Hexane (1.89 L, 6 volumes) was then added slowly, and the mixture was stirred for 1 hour. 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 hours to give S5-8 (287 g, 90.6% yield).

[0235] Method 2. 65.0 kg S5-1, 578.6 kg THF, and 1026.8 kg MeOH were placed in a glass-lined reactor (3000 L). The mixture was stirred at 100 rpm at 15-25°C for 10-20 minutes. Then, 57.0 kg CeCl3·7H2O was added to the reaction mixture. The mixture was stirred at 15-25°C for 10-20 minutes. The temperature was then adjusted to 0-10°C. 6.3 kg NaBH4 was added portionwise to the reaction mixture while maintaining the internal temperature at 0-10°C. The temperature was then 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 maintaining the internal temperature at 0-10°C. The temperature was then adjusted to 15-25°C, and the mixture was stirred for 10-20 minutes. Next, 23.9 kg HCl (wt%=10.5%, aqueous solution) was added to the reaction mixture and stirred for 10-20 minutes, adjusting the pH to 5-6. Then, 325.0 kg HO was charged to the reaction mixture. The mixture was then concentrated to 3-4 volumes under reduced pressure at 35-45°C to remove most of the THF and MeOH. Then, 585.0 kg DCM was charged to 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 and aqueous layers were separated. 429.1.0 kg DCM was charged to 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 and aqueous layers were separated. The organic layers were combined. 130.0 kg HO was charged to the combined organic layers. The mixture was stirred at 15-25°C for 20-40 minutes. The organic and aqueous layers were separated, and the aqueous layer was discarded. 429.0 kg of n-hexane was added to the organic layer. The mixture was then concentrated to 8-10 volumes at 20-30°C. 214.5 kg of n-hexane was added to the mixture. The mixture was then concentrated to 8-10 volumes at 20-30°C to obtain a white suspension. 215.5 kg of n-hexane was added to the mixture. The mixture (suspension) was then concentrated under reduced pressure at 20-30°C to 8-10 volumes to obtain a white suspension. 48.1 kg of MTBE was added to the white suspension. The temperature was adjusted to 20-30°C for 2-3 hours. The white suspension was then filtered to remove the organic layer. The resulting filter cake was then washed with 133.3 kg of n-hexane. The filtrate was discarded.The filter cake was slurried with 51.8 kg (0.796 w / w) MeOH, 167.2 kg (2.57 w / w) MTBE, and 86.7 kg (1.33 w / w) n-hexane at 35-45°C. The slurry was stirred for 1-2 hours at 35-45°C and 1-2 hours at 0-10°C. 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 dried under reduced pressure at 45-55°C for 15-17 hours. S5-8 was obtained as a white solid, 55.64 kg, 85.42% yield, 92.3% purity.

[0236] [ka] (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-dioxoundecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-9). Prepared according to the method of S4-4 starting from S5-8 (11.4 g, 12.2 mmol), the title compound (12.2 g) was obtained as a white foam, which was used in the next step without purification. MS (ESI+) m / z: 972.39 [M + H] + .

[0237] Prepared starting from S5-8 (30.0 g, 32.0 mmol) using the method of S4-4, using 3.6 equivalents of TFA and substituting triphenylphosphine (1.2 equivalents) for MeS, the crude title compound (45 g) was obtained as a white foam, which was used in the next step without purification.

[0238] Starting from S5-8 (0.5-30 g), the method of S4-4 was used, using 2.4-4.8 equivalents of TFA and quenching the reaction with a reducing agent including triphenylphosphine, HOAc / Zn, trimethoxyphosphine, and triethoxyphosphine. The crude title compound was used in the next step without purification.

[0239] [ka] (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 using the method of S4-10 starting from S5-9 (11.8 g, 12.2 mmol) to give the title compound (11.5 g) as a white foam. MS (ESI+) m / z: 858.15 [M + H] + ; 1H 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, 1H), 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, 1H), 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).

[0240] Method 2. S5-9 (100 g) was poured into CH3CN (500 mL) and stirred at 25-26 °C until all solids were dissolved. HO (500 mL) was added to the reaction mixture. LiOH·HO (4.82 g, 1.1 equiv.) 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, stirred for 10 min, and the two phases were separated. This MTBE extraction was repeated. The aqueous phase was separated and concentrated to remove most of the MTBE dissolved in water. 3 N aqueous HCl was added to the aqueous phase by adjusting the pH to 6-7 until the phase became cloudy. The white solid was filtered and dried under high vacuum at 45-46 °C for 16 h to give the title compound (57.18 g, 64.4% yield).

[0241] Method 3. S5-9 (41.2 g) was dissolved in CHCN (200 mL) followed by water (136 mL). The mixture was cooled to 0-5 °C. Aqueous NaOH (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 CHCN (approximately 200 mL) to a viscous residue (approximately 240 g). Water (100 mL) was added, and the diluted mixture was extracted with MTBE (200 mL). The aqueous phase was neutralized to pH approximately 5-7 with 3N HCl (approximately 22 mL) followed by extraction with DCM (250 mL). The aqueous phase was re-extracted with DCM (100 mL), and the combined organic phases were concentrated. The residue was dissolved in EtOH (160 mL) at 65-75 °C, followed by the addition of heptane (200 mL). 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 hours to give the title compound (28.6 g, 78.8%).

[0242] S5-10 large-scale procedures Method 4. A 5279.2 kg solution of S5-9 in DCM (source: 98.0 kg S5-8) was stirred in a glass-lined reactor (3000 L). The solution was concentrated to 3-6 volumes under reduced pressure at 15-25°C. 363.0 kg ACN was added to the reactor. The mixture was concentrated to 3-6 volumes under reduced pressure at 15-25°C. 160.2 kg ACN was added to the reactor. The mixture was concentrated to 4-6 volumes under reduced pressure at 15-25°C. 121.3 kg ACN was added to the reactor. The mixture was concentrated to 3-6 volumes under reduced pressure at 15-25°C, thereby obtaining 425.7 kg of S5-9 as an ACN solution. 509.6 kg HO was added to the solution. The internal temperature was adjusted to 5-15°C, and 125.3 kg 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 to 5-7 volumes under reduced pressure at 20-30°C to remove most of the ACN. 305.6 kg HO and 454.5 kg MTBE were then charged to the reactor. The mixture was stirred for 15-25 minutes and then allowed to settle at 10-20°C for 25-35 minutes. The organic and aqueous layers were separated. The organic layer was discarded. 34.3 kg HCl (wt% = 9.75%, aqueous solution) was then slowly added to the aqueous layer to adjust the pH to 5-7 at 10-20°C. 944.2 kg DCM was added to the quenched solution, which was then stirred at 10-20°C for 25-35 minutes. The mixture was then allowed to stand for 25-35 minutes. The organic and aqueous layers were separated. 405.7 kg DCM was added to the aqueous layer, and the resulting solution was stirred at 10-20°C for 25-35 minutes, then allowed to stand at 10-20°C for 25-35 minutes. The organic and aqueous layers were separated. The combined organic layers were concentrated to 2-4 volumes under reduced pressure in a reactor (3000 L) at 25-35°C. 241.5 kg EtOH was added to the reactor. The mixture was concentrated to 2-4 volumes under reduced pressure at 25-35°C, thereby obtaining a white suspension. 161.4 kg EtOH was added to the mixture. The mixture was concentrated to 2-4 volumes under reduced pressure at 25-35°C, thereby obtaining a white suspension. 40.6 kg EtOH was added to the suspension, which was then stirred at 55-65°C for 10-40 minutes. 349.2 kg n-hexane was then added to the white suspension. The temperature was adjusted to 55-65°C for 2-3 hours.The internal temperature was adjusted to 5-15°C, and the mixture was stirred for 2-3 hours. The white suspension was filtered to obtain a wet cake. The cake was washed with 349.5 kg of n-hexane. The filtrate was discarded. The cake was dried under reduced pressure at 35-45°C for 15-24 hours to obtain S5-10 as a white solid, 54.05 kg.

[0243] [ka] (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-dioxoundecan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-11). Prepared by the method of S5-5 starting from S5-10 (1.6 g, 1.9 mmol). Purification on a silica gel column (0-100% gradient of 0.5% aqueous NH4OH in 80% DCM / 20% MeOH / DCM) afforded the title compound (1.0 g, 57%) as a white foam. MS (ESI+) m / z: 948.23 [M + H] + ; 1H 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, 1H), 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, 3H), 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).

[0244] S5-10 (24.5 g, 28.5 mmol) was dissolved in DMF (anhydrous, 100 mL), followed by the addition of KCO (4.72 g, 34.2 mmol) and BnCl (3.92 mL, 34.2 mmol). The mixture was heated at 40 °C under nitrogen for 16 h. In a separate flask, 75 mL of brine was diluted with 425 mL of deionized water. To this aqueous solution, the DMF solution was slowly added at rt with vigorous stirring. The resulting mixture was stirred for an additional 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 (26.5 g, 98.1%).

[0245] S5-10 (65 g) was dissolved in DCM (650 mL) in a 5 L jacketed reactor and stirred at 24–25 °C under nitrogen. EtN (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 then diluted with MTBE (975 mL). The organic phase was washed with aqueous NaOH (1 N, 2 × 264 mL), aqueous NaHPO (50%, 325 mL), and aqueous 13% NaCl (325 mL). The organic phase was concentrated under reduced pressure at 35-36° C. to give the title compound as a white foam (75.7 g), which was used in the next step without purification.

[0246] S5-11 Large-Scale Procedure 53.5 kg S5-10, 201.9 kg DMF, and 11.3 kg K2CO3 were placed in 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. 540.0 kg HO was then 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 in portions with 1080.0 kg HO. The filtrate was discarded. The filtrate was dried in a filter dryer at 0-5°C. 44.0 kg S5-11, containing approximately 7% DMF, was obtained as a white solid. 44.0 kg S5-11 and 220 kg HO were placed in a glass-lined reactor (300 L). The mixture was stirred at 15-25 °C and 0-5 °C. The mixture was filtered to remove the aqueous layer. The cake was washed in portions with 1080.0 kg HO. The solid was dried under reduced pressure with a nitrogen flow in a filter drier at 0-5 °C for 98 hours. 41.3 kg S5-11 was obtained as a white solid.

[0247] [ka] (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-dioxononan-3-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate (S5-6). Prepared by the method of S4-12 starting from S5-5 or S5-11 to afford the title compound as a white foam. MS (ESI+) m / z: 904.11 [M + H] + ; 1 H NMR (400 MHz, chloroform-d) δ 9.27 (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).

[0248] In a 5 L jacketed reaction bottle, S5-11 (75.70 g) was dissolved in toluene (1.51 L) and stirred at 24–25 °C. NaIO / SiO 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 (SiO, 100 g, eluted with EtOAc (227 mL)). The organic phase was washed with NaSO (60.33 g, 6.0 equiv., in 200 mL water), and aqueous NaCl (150 mL, wt = 13% in HO) was added. NaSO (45 g) was added to the organic phase. After 1 h, the organic phase was separated and concentrated under reduced pressure below 30 °C to give a yellowish liquid. The yellowish liquid was dissolved in DCM (4 x 50 mL), concentrated under reduced pressure four times, and then dried under high vacuum at rt for 4 h to give the title compound as a white foam (72.3 g) which was used in the next step without further purification.

[0249] [ka] (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-yl benzoate (S5-7). Prepared using the method of S3-6 (from S4-12 in Scheme 4) starting from S5-6 (7.3 g, 8.1 mmol) to afford the title compound (7.1 g) as a white foam. MS (ESI+) m / z: 906.13 [M + H] + .

[0250] 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 equiv.) and isobutyl chloroformate (5.44 g, 0.5 equiv.) were added and stirred at 0–3 °C for 30 min. MeOH (360 mL) was added to the reaction mixture at 0–3 °C. Then, NaBH (6.03 g, 2.0 equiv.) was added slowly over 30 min at 0–10 °C. 3N aqueous HCl was added slowly to the reaction mixture to adjust the pH to approximately 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% aqueous NaCl (144 mL). NaSO (40.0 g) was added to the organic phase. After 2 h, the organic phase was separated and concentrated under reduced pressure at 30 °C to give an oil, which was dried under high vacuum at rt to give 73.12 g of a white foam. The product was further purified by column chromatography (silica gel, 813 g, 200-300 mesh) using EtOAc / n-hexane / EtN (1 / 2 / 0.03) as eluent to give the title product (44.31 g, 61% yield).

[0251] Synthesis of azalides via S3-6 (Schemes 3 and 4) Scheme 6 describes an approach to preparing azalides from S3-6. The approach involves oxidation of S3-6 to give S6-1. Reductive amination of S6-1 with S6-2, followed by ring closure, gives S6-3. Further elaboration of S6-3 can be achieved by: N-substitution of N-9a under reductive amination conditions using R5-CHO or a similar ketone, C-2 alkylation, and deprotection of the C-5 desosamine hydroxyl group to give azalide S6-4 (where R 9a is R5-CH2-, and R 2b is as defined for compounds of formula I). [ka]

[0252] [ka] A solution of compound S3-6 (20 mg, 32.7 μmol) in DCM (1 mL) was stirred with Dess-Martin reagent (34.6 mg, 81.7 μmol) for 30 min at RT. The mixture was diluted with MTBE (15 mL) and filtered through Celite®. The filtrate was concentrated, and the residue was dried under reduced pressure to give crude S6-1, which was used directly in the next step. MS (ESI+) m / z: 606.19 [M + H]+

[0253] [ka] To a solution of crude S6-1 (20 mg, 0.033 mmol) in DCM was added S6-2-1 (7 mg, 0.0395 mmol), AcOH (2 drops), and NaBH(OAc) (13.9 mg, 0.066 mmol). The mixture was stirred at RT for 30 min, and then formaldehyde (27 mg, 37% aqueous solution, 0.12 mmol) and NaBH(OAc) (28 mg, 0.13 mmol) were added. After stirring for 40 min, the solution was diluted with DCM, washed with saturated NaHCO and water, and dried over NaSO. 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) was rotary evaporated with anhydrous toluene (5 mL) and dried under reduced pressure. The residue was dissolved in m-xylene (5.5 mL) and N was bubbled through for 5 minutes. The solution was refluxed for 3 hours to give S6-3-1. MS(ESI+) m / z: 702.22 [M + H] + Another general method is further illustrated in Scheme 7. Starting from S4-6, coupling of S4-6 with S7-1 under reductive amination conditions gives S7-2. N-substitution at the N-9a position using an aldehyde R5-CHO or similar ketone under reductive amination conditions gives S7-2, where R 9ais R5-CH2-. Conversion of S7-3 to the acid S7-4, followed by mixed anhydride formation and cyclization, gives S7-5. Removal of the C-5 cladinose from S7-5 gives S7-6. Oxidation of S7-6 gives S7-7. The method is C-2 alkylation (where R 2b is as defined for compounds of Formula I) and concludes with deprotection of the C-5 desosamine to give azalide S7-8. [ka]

[0254] [ka] General procedure: A solution of S7-1 (1.2 equiv.) in DCM (0.2 M) was stirred with acetic acid (2 equiv.) and Na(OAc)3BH (2 equiv.) at 0 °C for 10 min, and S3-2 or S4-6 (1 equiv.) was added. The reaction mixture was warmed to rt and stirred until completion (30 min to overnight). This solution was used directly in the next step.

[0255] [ka] A solution of compound S7-1-1 (377 mg, 2.19 mmol) in DCM (20 mL) was cooled to an internal temperature of −17° C. in an acetone-dry ice bath. Acetic acid (0.436 mL, 7.64 mmol) was added under nitrogen, raising the temperature to −13° C., and then Na(OAc)3BH (606 mg, 2.86 mmol) was added in one portion. A solution of compound S3-2 (1.52 g, 1.91 mmol) in DCM (13 mL) was added while maintaining the internal temperature below −10° C. The reaction mixture was allowed to warm slowly to 11° C. over 2 h. Additional Na(OAc)3BH (606 mg, 2.86 mmol) was added at this temperature and stirred for 30 min to allow complete conversion to S7-2-1. MS (ESI+) m / z: 950.36 [M + H] +

[0256] [ka] General procedure: To the above solution was added R5CHO (3 equiv.) and Na(OAc)3BH (2 equiv.). 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 give the desired compound.

[0257] [ka] The reaction mixture of S7-2-1 was treated with formaldehyde (37% aqueous solution, 0.62 mL, 8.29 mmol) and Na(OAc)BH (606 mg, 2.86 mmol). The reaction mixture was stirred at RT for 1.5 h. After adding saturated NaHCO (30 mL) to 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 NaSO, filtered, and concentrated. The crude material was purified by ISCO (A: DCM, B: 20% MeOH in DCM with 0.5% NHOH), and the product eluted at 100% B. This afforded 1.47 g (79.8%) of compound S7-3-1 as a white foam. MS (ESI+) m / z: 964.29 [M + H] + . 1H NMR (400 MHz, chloroform-d) δ 8.04 - 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).

[0258] [ka] General procedure: A solution of S7-3 (1 equiv.) in THF / HO (3:1, 0.1 M) was stirred with LiOH (5 equiv.) at rt for 2 h. Water and formic acid (approximately 8 equiv.) were added to adjust the pH to approximately 6. The mixture was extracted twice with DCM, and the aqueous layer was treated with excess saturated aqueous NaHCO solution.

[0259] For water-soluble compounds, the aqueous solution was concentrated and the residue was evaporated under reduced pressure. The solid was triturated with DCM three times. The combined DCM solution was concentrated and the residue was dried under reduced pressure to give the desired compound, S7-4.

[0260] For non-water-soluble compounds, the aqueous layer was extracted with DCM three times. The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dried under reduced pressure to give the desired compound, S7-4.

[0261] [ka] A solution of compound S7-3-1 (1.2 g, 1.24 mmol) in THF (9 mL) / HO (3 mL) was stirred with LiOH (148 mg, 6.19 mmol) at RT for 2 h. The pH was adjusted to 8-9 by slow addition of HCl (6 mL, 1 M, 6 mmol). The mixture was concentrated to dryness under reduced pressure, 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% yield. 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, 3H), 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).

[0262] [ka] General procedure: To a solution of S7-4 (1 equiv.) in dry DCM (38V) was added EtN (2 equiv.) and 1,3,5-trichlorobenzoyl chloride (1.2 equiv.). After 30 min, DMAP (0.02 equiv.) was added. The mixture was stirred at rt for 30 min. The solution was washed with saturated aqueous NaHCO (3×) and brine (1×). The DCM layer was concentrated, and the residue was dried under reduced pressure to give the desired compound, S7-5.

[0263] [ka] To a solution of compound S7-4-1 (500 mg, 0.568 mmol) in dry DCM (19 mL) was added EtN (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 major product peak (>90%) and minor 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 RT for 30 min. The reaction solution was washed with saturated NaHCO (3 × 20 mL) and brine (20 mL) and dried over NaSO. Concentration and drying under reduced pressure gave crude compound S7-5- as a yellowish foam, approximately 530 mg, 108% yield. The main impurity was 1,3,5-trichlorobenzoic acid. A portion of the crude was purified by HPLC to give the pure product. MS (ESI+) m / z: 862.29 [M + H] + . 1H NMR (formic salt, 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), 1.75 - 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).

[0264] [ka] General method: A solution of S7-5 (where R is cladinose) (1 equiv.) in DCM (0.12 M) was stirred with a solution of HCl in dioxane (4 M, 6 equiv.) for 20 min. Water (same volume as DCM) was added. The DCM layer was separated, and the aqueous layer was extracted with DCM (1×). The aqueous layer was treated with saturated aqueous NaHCO3, and the aqueous solution was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dried under reduced pressure to give the desired compound, S7-6.

[0265] [ka] A solution of crude compound S7-5-1 (300 mg, 0.347 mmol) in DCM (3 mL) was stirred with a solution of 4 M HCl in dioxane (0.52 mL) 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 treated with saturated NaHCO3 until effervescence ceased (pH 8–9). This aqueous solution was extracted with DCM (3 × 10 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound S7-6-1 as a white foam, 223 mg (91%). MS (ESI+) m / z: 704.32 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.14 - 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).

[0266] [ka] General procedure: N-chlorosuccinimide (2 equiv.) in anhydrous DCM (0.2 M) was stirred at -15 to -20 °C for 10 min. A solution of dimethyl sulfide (2 equiv.) was added to the solution. After stirring for 20 min, a solution of S7-6 (1 equiv.) 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 point triethylamine (2.5 equiv.) was added. The mixture was stirred at -10 °C for 40 min. Saturated aqueous 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.

[0267] [ka] A solution of N-chlorosuccinimide (300 mg, 0.226 mmol) in anhydrous DCM (1 mL) was stirred at -15 to -20 °C for 10 min. Then, dimethyl sulfide (0.2 mL of DCM, 16.5 μL) was added. After stirring at the same temperature for 20 min, a solution of S7-6-1 (80 mg, 0.113 mmol) in DCM (0.5 mL) was added dropwise to the suspension over 5 min, and the resulting mixture was stirred at -15 to -20 °C for an additional 30 min. 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 the addition of saturated aqueous NaHCO3, 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 using 20% MeOH in DCM containing 0.5% NH4OH to give compound S7-7-1 as a white foam, 52 mg (65.5%). MS (ESI+) m / z: 702.3 [M + H] + . 11H NMR (400 MHz, CDCl3) δ 8.10 - 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), 1.42 (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).

[0268] [Chemical formula] 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 N. The solution was then cooled to -72 °C (internal) 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), and the mixture was stirred for 10 min at -72 °C. Dimethyl sulfate (75 μL, 0.79 mmol) was added, and the reaction mixture was slowly warmed and placed at -15 °C for 1.5 h. The reaction mixture was cooled to -40 °C, stirred, and quenched with MeN (1.21 mL, 40% aqueous solution, 7.9 mmol) and NHOAc (saturated, aqueous, 10 mL), warmed to 10 °C, and stirred for 5 min. The mixture was diluted with EtOAc (20 mL), and the organic layer was separated and washed with water (2 × 10 mL) and brine (10 mL). After drying over NaSO, the solvent was removed and the residue was purified by ISCO (A: DCM, B: 20% MeOH in DCM containing 0.5% NHOH) to give product S7-8-1a as a white solid, 270 mg, 72%, at 100% B. (ESI+) m / z: 716.36 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.10 - 7.94 (m, 2H), 7.62 - 7.48 (m, 1H), 7.43 (t, 2H), 5.03 (dd, 1H), 4.61 (d, 1H), 4.05 (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).

[0269] A solution of compound S7-8-1a (200 mg, 0.28 mmol) in MeOH (5 mL) was heated at 50° C. for 16 hours. HPLC purification afforded S7-8-1 in a 0.1% formic acid / water / CH3CN solution. 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 under reduced pressure, and the residue was evaporated under reduced pressure to afford S7-8-1 as a white foam, 120 mg, 70%. (ESI+) m / z: 612.37 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 4.45 (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).

[0270] Alternative azalide synthesis from S5-6 (Scheme 5) Another azalide synthesis is described in Scheme 8. Coupling of S5-6 with S7-1 under reductive amination conditions gives S8-1. N-substitution at the N-9a position using an aldehyde R5-CHO or similar ketone under reductive amination conditions gives S8-2, where R 9a is R5-CH2-. Conversion of S8-2 to the acid S8-3, followed by mixed anhydride formation and cyclization, gives S8-4. Removal of the C-5 cladinose from S8-4 gives S8-5. Oxidation, C-2 alkylation (where R 2b is as defined for compounds of Formula I), deprotection of the C-5 desosamine completes the process to give azalide S8-6. [ka]

[0271] [ka] To a solution of NaBH4 (19.7 g, 521 mmol) in THF (200 mL) was added 4-amino-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (53.00 g, 216 mmol) in one portion at 20-25 °C. The reaction mixture was cooled to 0 °C under N2, and then a solution of I2 (55 g, 216 mmol) in THF (500 mL) was added slowly. The mixture was then stirred at 80 °C for 16 h. TLC (dichloromethane:methanol = 10:1, R f =0.13) indicated complete consumption of the starting material and the formation of one new spot. The reaction mixture was cooled to 25 °C, and MeOH (500 mL) was carefully added until the mixture became clear. After stirring for 1 h at RT, the solvent was removed to give a white residue, which was dissolved in 20% aqueous KOH (500 mL) and stirred at 20-30 °C for 1 h. The reaction was extracted with CHCl (300 mL, 3×), and the combined organic extracts were dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40-30 / 1, 0.5% NHHO). Product S7-1-2 tert-butyl 4-amino-4-(hydroxymethyl)-piperidine-1-carboxylate (R f =0.30, dichloromethane / methanol = 10 / 1, 0.5% NH3H2O) as a white solid (33.5 g, 144 mmol, 66.7% yield, 99.5% purity). 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).

[0272] [ka] General procedure: A solution of S7-1 (1.2 equiv.) in DCM (0.2 M) was stirred with acetic acid (2 equiv.) and Na(OAc)3BH (2 equiv.) at 0 °C for 10 min. S5-6 (1 equiv.) was added. The reaction mixture was stirred at rt until complete (30 min to overnight). The solution was used directly in the next step.

[0273] [ka] General procedure: To the above solution was added R5CHO (3 equiv.) and Na(OAc)3BH (2 equiv.). 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 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 desired compound, S8-2.

[0274] [ka] To a solution of compound S7-1-2 (23 g, 100 mmol) in CHCl (600 mL), AcOH (20 g, 333 mmol, 19 mL) and NaBH(OAc) (35.3 g, 166 mmol) were added at 25 °C. After cooling the solution to -10 °C, a solution of S5-6 (75.4 g, 83.4 mmol) in CHCl (150 mL) was slowly added under N. The reaction solution was slowly warmed and stirred at 20-25 °C for 2 h. S8-1-1 was observed as the main peak in the solution LCMS, MS (ESI) m / z: 1118.6 [M+H]. +After cooling to 5-10°C, NaBH(OAc)3 (35.3 g, 166 mmol) and HCHO (135 g, 1670 mmol, 124 mL, 37% aqueous solution) were added to the mixture. The reaction mixture was slowly warmed and stirred at 20-25°C for 12 hours. The reaction mixture was cooled to 0°C, and then saturated aqueous NaHCO3 (900 mL) was slowly added. The mixture was extracted with CHCl2 (2 x 1.5 L). The combined extracts were dried over NaSO4, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 to 40:1; Plate 1; R f =0.24) to give compound S8-2-1 (80 g, 63.8 mmol, 76.6% yield, 96% purity) as a white solid. MS (ESI) m / z: 1132.7 [M+H] + , 567.0 [M / 2+H] + . 1 H NMR (400 MHz, 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 - 5.19 (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).

[0275] [ka] General procedure: To a solution of S8-2 in DCM (10 mM) was added 10% Pd / C (10-50 mol%). The reaction vessel was evacuated and backfilled with hydrogen. Hydrogen was bubbled 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 evaporated under reduced pressure.

[0276] [ka] 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 wt % of S8-2-1) under a N atmosphere. The mixture was stirred under H (15 psi) at 25 °C for 2 h. The reaction mixture was filtered under reduced pressure, 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 (400 MHz, chloroform-d) δ 8.10 - 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 (br s, 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).

[0277] [ka] General method: To a solution of S9-3 (1 eq.) in dry DCM (38V) was added EtN (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 rt for 30 min. The solution was washed with saturated aqueous NaHCO (3×) and brine (1×). The DCM solution was dried over NaSO, filtered, and concentrated. The residue was evaporated under reduced pressure to give the desired compound, S8-4.

[0278] [ka] In a 5 L three-neck flask, EtN (17.9 g, 177 mmol, 24.7 mL) and DMAP (5.43 g, 44.4 mmol) were added to a solution of 2,4,6-trichlorobenzoyl chloride (16.2 g, 66.6 mmol, 10.4 mL) in CHCl (3900 mL) at 20-25 °C. Then, a solution of compound S8-3-1 (26 g, 22.2 mmol) in CHCl (260 mL) was slowly added to the mixture over 48 h via a syringe pump. After the addition, the reaction was stirred at 20-25 °C for 2 h. The reaction solution was washed with saturated NaHCO (3 × 600 mL). The solvent was dried over NaSO and removed under reduced pressure, and the residue was purified by column chromatography (SiO, dichloromethane:methanol = 100:1 to 30:1; plate 1; R f =0.24) to give compound S8-4-1 (2 batches, 31.9 g, 27 mmol, 50.6% yield, 86.7% purity) as a white solid. MS (ESI) m / z: 512.9 [M / 2+H] + . 1H NMR (400MHz, chloroform-d) δ 8.02 - 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).

[0279] [ka] General method: A solution of S8-4 (1 equiv.) in DCM (0.12 M) was stirred with a solution of HCl in dioxane (4 M, 6 equiv.) for 20 min. Water was added, the DCM layer was separated, and the aqueous layer was extracted with DCM (1×). The aqueous layer was saturated, treated with aqueous NaHCO3, and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was evaporated under reduced pressure to give the desired product, S8-5.

[0280] [ka] To a solution of compound S8-4-1 (31.9 g, 27 mmol) in CHCl (320 mL) was added trifluoroacetic acid (92.3 g, 810 mmol, 59.9 mL) at 0-5°C. The mixture was stirred at 20-25°C for 3 hours. Water (300 mL) was added to the reaction, and the aqueous layer was separated. After extraction with CHCl (2 × 80 mL), the aqueous layer was adjusted to pH 8-9 with solid NaCO. The water was extracted with CHCl (4 × 100 mL). The combined extracts were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, dichloromethane:methanol = 60:1 to 10:1; Plate 1; R f =0.24) to give compound S8-5-1 (21 g, 26.4 mmol, 98.1% yield) 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 (br d, 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).

[0281] [ka] To a solution of 3-methoxybenzaldehyde (5.41 g, 39.7 mmol) in CHCl (100 mL) was added AcOH (6.36 g, 105 mmol, 6.06 mL) and NaBH(OAc) (11.2 g, 52.9 mmol) at 0 °C. Then, a solution of compound S8-5-1 (21.0 g, 26.4 mmol) in CHCl (100 mL) was added slowly at 0–10 °C. The mixture was warmed to 20–25 °C and stirred for 6 h. To the reaction mixture was added saturated aqueous NaHCO (400 mL) and CHCl (100 mL) at 0 °C, and the mixture was extracted with CHCl (2 × 100 mL). The combined extracts were washed with brine (200 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified using a MEGA Series LC Pump (A: 0.1% NHOH in DCM, B: MeOH) on a 0.50 kg column cartridge (SiO: 0.50 kg). The majority of the product eluted at approximately 2% B, with some eluting up to 4% B. Compound S8-6-1a (11.8 g, 14.9 mmol, 56.3% yield, 98.9% purity) was obtained as a brown foam. MS (ESI) m / z: 782.6 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.01 - 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).

[0282] [ka] [ka] A solution of NCS (13 g, 97 mmol) in CHCl (118 mL) was stirred at -15 to -20 °C for 10 min under N. MeS (6.03 g, 97 mmol, 7.12 mL) was added dropwise to this solution. The mixture was stirred at the same temperature for 30 min. A solution of compound S8-6-1a (11.8 g, 14.9 mmol) in CHCl (118 mL) was added dropwise to the suspension at -15 to -20 °C, and the resulting mixture was stirred for an additional 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 the addition of saturated aqueous NaHCO (224 mL) at 0 to 10 °C. The organic layer was separated. The aqueous layer was extracted with CHCl (2×160 mL). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified using a 0.25 kg column cartridge (SiO: 0.25 kg) with a MEGA Series LC Pump (A: 0.2% NHOH in DCM, B: MeOH). The majority of the product eluted at approximately 2% B, with some elution up to 4% B. Compound 8-6-1b (8.55 g, 10.4 mmol, 69.7% yield, 94.9% purity) was obtained as a brown foam. MS (ESI) m / z: 780.4 [M+H] + , 390.9 [M / 2+H] + . 11H NMR (400 MHz, methanol-d4) δ 8.04 (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 - 2.78 (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).

[0283]

Chem.

[0284] [ka] A solution of compound S8-6-1c (6.55 g, 8.18 mmol) in EtOH (66 mL) was stirred at 80 °C for 36 hours. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm; mobile phase: [water (TFA)-ACN]; B%: 2% to 27%, 20 min). Compound S8-6-1 (3.23 g, 4.66 mmol, 56.9% yield, 99.5% purity) was obtained as a light yellow solid. (MS (ESI) m / z: 690.4 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.22 (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).

[0285] Equivalence and Scope In the claims, the terms "a," "an," "the ...

[0286] Furthermore, the present invention encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms from the enumerated claims that are introduced into a further claim. For example, any claim that depends from a further claim may be modified to include one or more limitations found in any further claim that depends from the same base claim. When elements are listed, such as in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. In general, when the invention or aspects of the invention are described as including particular elements and / or features, it should be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, these embodiments are not specified verbatim herein. We also note that the terms "comprise" and "comprises" are open and allow for the inclusion of additional elements or steps.

[0287] When ranges are given, the endpoints are included. Furthermore, unless otherwise stated or evidenced otherwise by the context and the understanding of one of ordinary skill in the art, values given as ranges can take any particular value or subrange within the ranges set forth in various embodiments of the invention, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0288] This specification cites various published patents, published patent applications, articles, and further publications, all of which are incorporated herein by reference. In the event of any inconsistency between the incorporated references and this specification, this specification will control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein because such embodiments are deemed to be known to those of skill in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not it relates to existing prior art.

[0289] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above, but rather as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications of this description can be made without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

1. Formula I or Formula I': 【Chemical 1】 or a pharmaceutically acceptable salt thereof, comprising: (a1) Intramolecularly cyclizing 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: 【Chemistry 2】 (b1) Intramolecularly cyclizing a compound of formula B (wherein PG is a protecting group) to form a compound of formula I': 【Chemistry 3】 [In the ceremony: R ２ａ and R ２ｂ one of which is H, halo, optionally substituted C １－１０ Alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R ２ａ and R ２ｂ the other is halo, optionally substituted C １－１０ Alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ The alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R ３ is a suitable protecting group selected from H, acyl, carbamoyl, alkyl ether or silyl ether protecting groups, or 【Chemistry 4】 where R ３ｃ is H or a protecting group; R ４ａ and R ４ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; R ６ａ is an optionally substituted C １－１０ is alkyl; R ６ｂ is —H, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ hydroxyalkyl and optionally substituted aryl; R ８ａ and R ８ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; R ９ａ is —H and optionally substituted C １－１０ selected from the group consisting of alkyl; R １２ is C １－６ is alkyl; and L is an optionally substituted C ２－５ It is alkylene. A method comprising:

2. 10. The process of claim 1, wherein the intramolecular cyclization of the compound of formula B proceeds under neutral conditions in the presence of a solvent.

3. 3. The method of claim 1 or claim 2, wherein the intramolecular cyclization of the compound of formula B proceeds at a temperature of from about 50°C to about 175°C.

4. 4. The process of any of claims 1 to 3, wherein the intramolecular cyclization of the compound of formula B proceeds in the presence of m-xylene at a temperature of from about 60°C to about 150°C.

5. The method of claim 1, comprising the steps of: 【Chemistry 5】

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

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

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

9. The bases were 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 9. The method of claim 8, wherein the amine base is selected from the group consisting of quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine (PMP), tributylamine, triethylamine, diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (TED), collidine, and 2,6-lutidine (2,6-dimethylpyridine).

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

11. Compounds of formula A-2 (wherein R ｘ If desired, C １－４ Alkyl, hydroxyl, oxo, COOH, COO(C １－６ C substituted with alkyl), amino, alkylamino, halo or cyano １－６ 11. The method of any of claims 5 to 10, further comprising the step of converting the compound of formula A-1, wherein the compound is an alkyl group. 【Chemistry 6】

12. The method of claim 11, further comprising converting the compound of formula A-3 to a compound of formula A-2: 【Chemistry 7】

13. The method of claim 12, further comprising converting the compound of formula A-4 to a compound of formula A-3: 【Chemistry 8】

14. 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: 【Chemistry 9】

15. The method of claim 14, further comprising converting the compound of formula A-4A1 to a compound of formula A-4A: 【Chemistry 10】

16. The method of claim 15, further comprising converting the compound of formula A-4A2 to a compound of formula A-4A1: 【Chemistry 11】

17. The method of claim 16, further comprising converting the compound of formula A-4A3 to a compound of formula A-4A2: 【Chemistry 12】

18. 18. The method of claim 17, further comprising converting the compound of formula II to a compound of formula A-4A3: 【Chemistry 13】

19. 20. The method of claim 18, comprising the step of reacting a compound of formula III with a compound of formula II: 【Chemistry 14】

20. The method of claim 13, further comprising converting the compound of formula A-4B to a compound of formula A-4: 【Chemistry 15】

21. The method of claim 20, further comprising converting the compound of formula A-4B1 to a compound of formula A-4B: 【Chemistry 16】

22. The method of claim 21, comprising the step of reacting a compound of formula A-4B2 with a compound of formula A-4B1: 【Chemistry 17】 。

23. The method of claim 22, comprising the step of reacting a compound of formula A-4B3 with a compound of formula A-4B2: 【Chemistry 18】

24. The method of claim 23, comprising the step of reacting a compound of formula II with a compound of formula A-4B3: 【Chemistry 19】

25. R ３ but 【Chemistry 20】 and further comprising converting the compound of formula I to a compound of formula IA: 【Chemical Formula 21】

26. 26. The method of claim 25, further comprising converting the compound of formula IA to a compound of formula I': 【Chemical 22】

27. 27. The method of claim 26, further comprising converting the compound of formula I' to a compound of formula IC: 【Chemical 23】

28. (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: 【Chemistry 24】 The method of claim 1, comprising the steps of:

29. 29. The method of claim 28, further comprising converting the compound of formula B-1 to a compound of formula B: 【Chemistry 25】

30. 30. The method of claim 29, further comprising converting the compound of formula B-2 to a compound of formula B-1: 【Chemical 26】

31. The method of claim 30, further comprising converting the compound of formula B-3 to a compound of formula B-2: 【Chemical 27】

32. Compounds of formula B-4 (wherein R ３ but 【Chemical Formula 28】 32. The method of claim 31, further comprising converting a compound of formula B-3 into a compound of formula B-3: 【Chemical 29】

33. The method of claim 32, further comprising converting the compound of formula B-5 to a compound of formula B-4: 【Chemistry 30】

34. The method of claim 33, further comprising converting the compound of formula B-6 to a compound of formula B-5: 【Chemical 31】

35. The method of claim 34, further comprising converting the compound of formula B-7 to a compound of formula B-6: 【Chemical 32】

36. 36. The method of claim 35, further comprising converting the compound of formula B-8 to a compound of formula B-7: 【Chemical 33】

37. Compounds of formula B-7 (wherein R １０ａ is OH and R １０ｂ is H or R １０ａ and R １０ｂ The method of claim 36, further comprising converting (wherein C═O forms C═O) to a compound of formula B-6: 【Chemical 34】

38. A compound of formula IV, where R １０ａ is OH and R １０ｂ is H or R １０ａ and R １０ｂ The method of claim 37, further comprising converting (wherein C═O forms C═O) to a compound of formula B-9: 【Chemistry 35】

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

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

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

42. R ６ａ and R ６ｂ The method of any of claims 1 to 41, wherein each is methyl.

43. R ３ is H or 【Chemical 36】 and R ３ｃ 43. The method of any of claims 1 to 42, wherein is H or a benzoyl group.

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

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

46. R ２ａ and R ２ｂ one of which is H, And R ２ａ and R ２ｂ the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. １－１０ is alkyl, 46. The method of any one of claims 1 to 45.

47. R ２ａ and R ２ｂ one of which is H, And R ２ａ and R ２ｂ The method of any one of claims 1 to 46, wherein the other of the groups is methyl.

48. 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: 【Chemical 37】 [In the ceremony: R １０ａ and R １０ｂ one of which is OH and the other is H or R １０ａ and R １０ｂ together form C=O; R ２ａ and R ２ｂ one of which is H, halo, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R ２ａ and R ２ｂ the other is halo, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R ３ is a suitable protecting group selected from H, an acyl, carbamoyl, alkyl ether or silyl ether protecting group, or 【Chemical 38】 where R ３ｃ is H or a protecting group; R ４ａ and R ４ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; R ６ａ is optionally substituted C １－１０ is alkyl; R ６ｂ is —H, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ hydroxyalkyl and optionally substituted aryl; R ８ａ and R ８ｂ each independently represents —H and optionally substituted C １－１０ alkyl; and PG is a suitable protecting group. A method comprising:

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

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

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

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

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

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

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

56. R ３ is H or 【Chemical Formula 39】 and R ３ｃ 56. The method of any of claims 48-55, wherein is H or a benzoyl group.

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

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

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

60. R ２ａ and R ２ｂ one of which is H, And R ２ａ and R ２ｂ the other is methyl, ethyl, propyl or isopropyl; 60. The method of any one of claims 48 to 59.

61. R ２ａ and R ２ｂ is H, and R ２ａ and R ２ｂ The method of any of claims 48 to 60, wherein the other is methyl.

62. A method for preparing a compound of formula A-3 from a compound of formula A-4, comprising reacting a compound of formula A-4 with a compound of formula NH ２ An amine bearing -L-OH is contacted under reductive amination conditions to form a compound of formula A-3: 【Chemistry 40】 [In the ceremony: R ２ａ and R ２ｂ one of which is H, halo, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; And R ２ａ and R ２ｂ the other is halo, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ Alkoxy and optionally substituted C ２－１０ alkenyl, wherein C １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R ３ is a suitable protecting group selected from H, an acyl, carbamoyl, alkyl ether or silyl ether protecting group, or 【Chemistry 41】 where R ３ｃ is H or a protecting group; R ４ａ and R ４ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; R ６ａ is optionally substituted C １－１０ is alkyl; R ６ｂ is —H, optionally substituted C １－１０ alkyl, optionally substituted C １－１０ hydroxyalkyl and optionally substituted aryl; R ８ａ and R ８ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; PG is a suitable protecting group; and L is optionally substituted C ２－５ It is alkylene. A method comprising:

63. A compound of formula A-4 and a compound of formula NH ２ 63. The method of claim 62, wherein the coupling of the amine with -L-OH is carried out in the presence of a solvent.

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

65. A compound of formula A-4 and a compound of formula NH ２ Coupling of amines bearing -L-OH was carried out using NaB(OAc) ３ 65. The process of any of claims 62 to 64, carried out in the presence of H and acetic acid.

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

67. NH ２ L in -L-OH is optionally up to three halo, CN, NO ２ , amino, amido, carboxy, alkylcarbonyl, alkoxycarbonyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with halo or alkyl.

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

69. NH ２ -L-OH is NH ２ -CH ２ -L １ -OH, NH ２ -CH(C １－６ alkyl)-L １ -OH, NH ２ -L １ -CH ２ —OH or NH ２ -L １ -CH(C １－６ alkyl)-OH, wherein L １ is CR １４ａ R １４ｂ and R １４ｂ is H or C １－６ is alkyl; R １４ａ is an optionally substituted R １０１ -CH ２ -, R １０１ -CH ２ CH ２ -, R １０１ -CH ２ CH ２ CH ２ -, optionally substituted R １０１ -CH ２ CH ２ CH—OH— and optionally substituted R １０１ -CH ２ CH ２ CH—OMe—; or R １４ａ is an optionally substituted saturated or partially unsaturated cycloalkyl, an optionally substituted saturated or partially unsaturated heterocycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl containing at least one double bond; or R １４ａ and R １４ｂ together with the carbon atoms to which they are attached 【Chemistry 42】 where Q is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocyclic ring, 【Chemistry 43】 indicates the attachment point, and R １１ａ and R １１ｂ each independently represents H, halo, and optionally substituted C １－１０ 68. The method of claim 67, wherein the alkyl is selected from the group consisting of alkyl.

70. NH ２ -L-OH is NH ２ -L １ -CH ２ 70. The method of claim 69, wherein the alkyl group is -OH.

71. L １ is CR １４ａ R １４ｂ where R １４ｂ is H or C １－６ alkyl, and R １４ａ is an optionally substituted R １０１ -CH ２ -, R １０１ -CH ２ CH ２ -, R １０１ -CH ２ CH ２ CH ２ -, optionally substituted R １０１ -CH ２ CH ２ CH—OH— and optionally substituted R １０１ -CH ２ CH ２ 71. The method of claim 70, wherein the aryl group is selected from the group consisting of CH-OMe-.

72. R １０１ but 【Chemical 44】 wherein: 【Chemistry 45】 72. The method of claim 71, wherein indicates a point of attachment.

73. L １ is CR １４ａ R １４ｂ where R １４ｂ is H or C １－６ alkyl, and R １４ａ is an 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. R １４ａ but 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 where: 【Chemistry 49】 74. The method of claim 73, wherein indicates a point of attachment.

75. L １ is CR １４ａ R １４ｂ where R １４ａ and R １４ｂ together with the carbon atoms to which they are attached 【Chemistry 50】 where Q is a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocyclic ring, 【Chemistry 51】 71. The method of claim 70, wherein indicates a point of attachment.

76. Each R ｑ are independently H, —CH ２ Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, 【Chemistry 52】 【Chemistry 53】 or two R ｑ together with the atom to which they are attached, [Chemical 54] (as a salt) (e.g., a formate salt), wherein: 【Chemistry 55】 76. The method of claim 75, wherein indicates a point of attachment. 【Request 77】 【Chemical 56】 but 【Chemical 57】 76. The method of claim 75, wherein: 【Chemistry 58】 but 【Chemical Formula 59】 and each R ｑ are independently H, —CH ２ Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, 【Chemistry 60】 【Hua 61】 or two R ｑ together with the atom to which they are attached, 【Hua 62】 (as a salt) (e.g., a formate salt), wherein: 【Chemistry 63】 indicates the attachment point. 【Request 78】 【Chemical 64】 but 【Chemistry 65】 and R ｑ is H, -CH ２ Cl, carboxybenzyl, acetyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, —C(═O)-Me, 【Hua 66】 【Hua 67】 wherein: 【Chemistry 68】 76. The method of claim 75, wherein indicates a point of attachment.

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

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

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

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

83. R ３ｃ 83. The method of any of claims 62-82, wherein is a protecting group selected from benzoyl, p-nitrobenzoyl, TMS, TES IPDMS, TBS, or methoxymethyl.

84. R ３ｃ The method of any of claims 62 to 82, wherein is a benzoyl group.

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

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

87. R ２ａ and R ２ｂ one of which is H, And R ２ａ and R ２ｂ the other of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl. １－１０ is alkyl, 87. The method of any one of claims 62 to 86.

88. R ２ａ and R ２ｂ one of which is H, And R ２ａ and R ２ｂ the other is methyl, ethyl, propyl or isopropyl; 88. The method of any one of claims 62 to 87.

89. R ２ａ and R ２ｂ is H, and R ２ａ and R ２ｂ The method of any of claims 62 to 88, wherein the other is methyl.

90. L is CH ２ CR １４ａ R １４ｂ where R １４ａ and R １４ｂ Compounds of formula A, B, A-1, A-2, A-3 and B1, wherein:

91. Compounds 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. Compounds listed in Table 1.

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