Compounds for treating genetic diseases

Abstract

Provided are 13-membered ribosome targeting compounds that can be used to treat genetic diseases, including genetic diseases associated with premature stop codon mutations or other nonsense mutations.These compounds can induce and / or promote the read-through of premature stop codon mutations.Also provided are pharmaceutical compositions containing the compounds, methods of using the compounds, and processes for producing the compounds.

Description

Background Art

[0001] Background Nonsense mutations are mutations in which a stop codon (UAA, UAG, or UGA) replaces an amino acid-coding codon, resulting in premature termination of translation and ultimately a truncated, inactive protein. The Human Gene Mutation Database reports the occurrence of mutations that cause thousands of diseases, approximately 12% of which are single-point (nonsense) mutations that lead to premature stop codons (Krawczak M, et al., Hum Mutat. 2000, 15, 45-51.; Mort, et al., M. Hum. Mutat. 2008, 29, 1037-47). Nonsense mutations that result in truncated proteins have been shown to account for many forms of genetic diseases, including cancer, hemophilia, Tay-Sachs, lysosomal storage diseases or mucopolysaccharidoses, such as Hurler syndrome, Duchenne muscular dystrophy, ataxia telangiectasia, Rett syndrome, various hereditary retinopathies, cystic fibrosis, recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), and familial adenomatous polyposis (FAP).

Summary of the Invention

Problems to be Solved by the Invention

[0002] Effective treatments for genetic diseases caused by nonsense mutations remain elusive. As a result, there is an urgent need to discover and develop new compounds that are effective against nonsense and / or frameshift mutations that result in premature stop codons and are thus useful for the treatment of genetic diseases and disorders caused by nonsense mutations.

Means for Solving the Problems

[0003] Summary These and other needs are met by the present invention relating to compounds that can be used for the treatment of genetic diseases, including genetic diseases associated with premature stop codon mutations or other nonsense and / or frameshift mutations. The compounds can induce and / or facilitate readthrough of premature stop codon mutations.

[0004] In one aspect, a method of treating a subject having a genetic disease, the method comprising administering a therapeutically effective amount of Formula I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0005] A pharmaceutical composition containing the compound is also described herein, similar to the method for producing the compound.

Mode for Carrying Out the Invention

[0006] 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. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references cited herein, including U.S. Patent Publication 2013 / 0090326, are hereby incorporated by reference in their entirety. In case of conflict, the present specification, including these definitions, will control.

[0007] As used herein, the singular forms "a", "an", and "the" include aspects of more than one member as well as aspects of only one member.

[0008] As used herein, the term "about" means "approximately" and is used to modify a numerical value to indicate a range around that value. If "X" is a certain value, then "about X" generally indicates a range of 0.95X to 1.05X. Any recitation of "about X" shall specifically disclose 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 provide support for the teaching and written description requirements for limitations of claims such as, for example, "0.98X". If the quantity "X" includes only integer values (e.g., "X carbons"), then "about X" indicates (X - 1) to (X + 1). In this case, "about X" as used herein specifically discloses at least the values X, X - 1, and X + 1.

[0009] When "about" is placed before a numerical range, it applies to both ends of the range. Thus, "about 5 - 20%" is equivalent to "about 5% - about 20%". When "about" is placed before the first value of a series of values, it applies to all values in that series. Thus, "about 7%, 9% or 11%" is equivalent to "about 7%, about 9% or about 11%".

[0010] The following abbreviations and terms have the meanings indicated throughout this specification.

Table 1

Table 2

[0011] The symbol “-” means a single bond, “=” means a double bond, “≡” means a triple bond, and “ --- ” means a single or double bond. The symbol

Chemical formula

[0012] When a chemical structure is depicted or described, unless otherwise explicitly stated, all carbons are assumed to have hydrogen substitutions to conform to a valence of 4. For example, in the structure on the left-hand side of the following schematic diagram, 9 hydrogens are implied. In the structure on the right-hand side, 9 hydrogens are described. A specific atom in a structure is described by a letter formula, for example, -CH 2 CH 2 -, as having one or more hydrogens (explicitly defined hydrogens) as a substitution. It is understood by those skilled in the art that the said notation technique is common in the chemical field for the concise and simple description of otherwise complex structures.

Chemical formula

[0013] The group “R” is, for example, the following formula

Chemical formula

[0014] If the group "R" is, for example, of the following formula

Chemical formula

[0015] If the group "R" is, for example, of the following formula

Chemical formula

Chemical formula

[0016] 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.

[0017] As used herein, the term "alkanoyl" includes alkyl-C(O)- groups (wherein the alkyl group is as defined herein). Examples of alkanoyl groups include, but are not limited to, acetyl and propanoyl.

[0018] As used herein, the term "agent" includes a compound or mixture of compounds that, when added to a composition, tends to produce a specific 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.

[0019] As used herein, the term "alkenyl" includes straight-chain or branched-chain hydrocarbons containing at least one carbon-carbon double bond. The chain may contain the indicated number of carbon atoms. For example, "C 1 -C 12 alkenyl" indicates that the group may have from 1 to 12 (inclusive) carbon atoms and at least one carbon-carbon double bond. If the number shown for the carbon is 1, C i alkenyl is bonded to the carbon by a double bond (i.e., a carbon equivalent to an oxo group). In certain embodiments, the chain contains from 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 may preferably be 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, arylenyl, butadienyl, pentadienyl, 3-(1,4-pentadienyl) and hexadienyl.

[0020] The alkenyl group may 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 alkenyl group may be substituted with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, provided that a hydrogen atom substituent on a carbon-carbon double bond is not replaced with a hydroxy, amino, or thio group. In certain embodiments, the alkenyl group is unsubstituted or not optionally substituted.

[0021] As used herein, "alkenylene" includes an alkenyl group substituted at two points. Examples are but-2-enylene (-CH 2 CH=CHCH 2 -), etc.

[0022] As used herein, the term "alkyl" includes an aliphatic hydrocarbon chain which may be straight or branched. The chain may contain the indicated number of carbon atoms: e.g., C 1 -C 10 indicates that the group may have 1 to 10 (inclusive) carbon atoms therein. Unless otherwise indicated, an alkyl group contains 1 to about 20 carbon atoms. In certain embodiments, the alkyl group has 1 to about 10 carbon atoms. In certain embodiments, an alkyl group ("lower alkyl") has 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain. Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1-butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopentyl, or cyclohexyl.

[0023] The alkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) may be substituted with a moiety independently selected from the group consisting of chloro, fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In certain embodiments, the alkyl group is unsubstituted or not optionally substituted.

[0024] As used herein, "alkylene" includes an alkyl group substituted at two points. Examples are methylene (-CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and the like.

[0025] As used herein, the term "alkoxy" includes a straight-chain or branched-chain saturated or unsaturated hydrocarbon containing at least one oxygen atom in an ether group (e.g., EtO-). The chain may contain the indicated number of carbon atoms. For example, "C 1 -C 12 alkoxy" indicates that the group may have 1 to 12 (including both ends) carbon atoms and at least one oxygen atom. Examples of C 1 -C 12 alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexyloxy.

[0026] The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be substituted with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, provided that the hydrogen atom alpha to the ether oxygen is not substituted with a hydroxy, amino, or thio group. In certain embodiments, the alkoxy group is unsubstituted or not optionally substituted.

[0027] As used herein, the term "alkynyl" 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.

[0028] As used herein, "alkynylene" includes an alkynyl group substituted at two points. An example is 2-butynylene (-CH 2 CCCH 2 -), etc.

[0029] The alkynyl group may 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 alkynyl group may be substituted with a moiety independently selected from the group consisting of 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 certain embodiments, the alkynyl group is unsubstituted or not optionally substituted.

[0030] As used herein, the term "aryl" includes cyclic aromatic carbocyclic systems containing 6 to 18 carbons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl and phenanthrenyl.

[0031] The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 5, 1 to 2 or 1) of the aryl group may be substituted with a moiety independently selected from the group consisting of alkyl, cyano, acyl, halo, haloalkyl, hydroxy, alkoxy, amino, alkylamino, acylamino, thio and alkylthio. In certain embodiments, the alkoxy group is unsubstituted or not optionally substituted.

[0032] As used herein, the term "arylalkyl" or "aralkyl" includes an alkyl group as defined herein, wherein 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.

[0033] An arylalkyl or aralkyl group may be unsubstituted or optionally substituted depending on its component groups. By way of example, but not limitation, the aryl group of an arylalkyl group may be substituted as in 4-methylbenzyl. In certain embodiments, the group is unsubstituted or optionally substituted if it contains defined substituents such as, in particular, hydroxyalkyl or alkylaminoalkoxy groups.

[0034] As used herein, the term "cycloalkyl" includes non-aromatic saturated monocyclic or polycyclic ring systems that may contain the indicated number of carbon atoms. For example, C 3 -C 12 indicates that the group may have from 3 to 12 (inclusive) carbon atoms therein. Unless otherwise indicated, cycloalkyl groups contain from about 3 to about 20 carbon atoms. In certain embodiments, the cycloalkyl group has from 3 to about 12 carbon atoms in the group. In certain embodiments, the cycloalkyl group has from 3 to about 7 carbon atoms in the group. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.

[0035] The cycloalkyl group may 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 cycloalkyl group may be substituted with a moiety independently selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, oxo, amino, alkylamino, acylamino, thio, and alkylthio. In certain embodiments, the substituted cycloalkyl group may incorporate an exocyclic or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In certain embodiments, the cycloalkyl group is unsubstituted or not optionally substituted.

[0036] As used herein, "fluoroalkyl" includes an alkyl group, where the alkyl group includes one or more fluoro substituents. Examples include, but are not limited to, trifluoromethyl.

[0037] As used herein, "geminal" substitution includes two or more substituents directly bonded to the same atom. Examples include 3,3-dimethyl substitution of a cyclohexyl or spirocyclohexyl ring.

[0038] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

[0039] As used herein, the term "heteroaryl" or "heterocycloaryl" includes monocyclic and bicyclic groups that are fully unsaturated or partially unsaturated and contain from about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms), including at least one heteroatom. The heteroatoms referred to in the term heteroaryl are oxygen, sulfur, and nitrogen. The nitrogen atoms of heteroaryl are optionally oxidized to the corresponding N-oxides. 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. Other examples include [Chemical Formula] including.

[0040] The term "heteroarylene" or "heterocycloarylene" includes heteroaryl groups substituted at two points.

[0041] Heteroaryl groups may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 5, 1 to 2, or 1) of the heteroaryl group may be substituted with moieties independently selected from the group consisting of alkyl, cyano, acyl, halo, haloalkyl, hydroxy, oxo, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In certain embodiments, the heteroaryl group is unsubstituted or optionally unsubstituted.

[0042] As used herein, the term "heteroaroyl" includes a heteroaryl-C(O)-group (wherein heteroaryl is as defined herein). Heteroaroyl groups include, but are not limited to, thiophenoyl, nicotinoyl, pyrrole-2-ylcarbonyl and pyridinoyl.

[0043] As used herein, the term "heterocycloalkyl" can be used interchangeably with a heterocyclyl-C(O)-group (wherein heterocyclyl is as defined herein) and includes it as used herein. Examples include, but are not limited to, N-methylprolinoyl and tetrahydrofuranyl.

[0044] 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), wherein one or more of the atoms in the ring system is one or more elements other than carbon, such as nitrogen, oxygen or sulfur. The heterocyclyl group may optionally have at least one sp 2Containing hybrid atoms (e.g., a ring incorporating a carbonyl, an internal olefin or an external 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. A monocyclic heterocycle means a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered ring containing a heteroatom independently selected from the group consisting of at least one O, N and S. A 3-membered or 4-membered ring contains 0 or 1 double bond and a heteroatom selected from the group consisting of O, N and S. A 5-membered ring contains 0 or 1 double bond and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. A 6-membered ring contains 0, 1 or 2 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. A 7-membered and 8-membered ring contains 0, 1, 2 or 3 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and trithianyl.

[0045] The term "heterocycloalkylene" includes a heterocyclyl (heterocycle; heterocyclic) group substituted at two points.

[0046] The term "heterocyclyl" also includes polycyclic rings such as bicyclic or tricyclic heterocycles which may be in fused, bridged or spiro orientation. 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 where 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 are 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, 3-azabicyclo[3.2.0]heptane, (3aR,6aS)-hexahydro-1H-2λ 2 -cyclopenta[c]pyrrole, (3aR,7aS)-octahydro-2λ 2 -isoindole, including but not limited to these.

[0047] 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 where 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.

[0048] The heterocyclyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2 or 1) may be substituted with a moiety independently selected from the group consisting of alkyl, halo, haloalkyl, oxo, acetyl, hydroxy, alkoxy, amino, alkylamino, acylamino, thio and alkylthio. In certain embodiments, a substituted heterocyclyl group may incorporate an exocyclic or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In certain embodiments, the heterocyclyl group is unsubstituted or not optionally substituted.

[0049] The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety via any carbon atom or any nitrogen atom contained in the ring, which can be unsubstituted or substituted.

[0050] As used herein, the term "hydrophilic moiety" or "hydrophilic group" includes a moiety or functional group having 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 groups or amine groups.

[0051] As used herein, the term "hydroxyalkyl" includes an alkyl group in which at least one hydrogen substituent is replaced by an alcohol (-OH) group. In certain embodiments, the hydroxyalkyl group has one alcohol group. In certain embodiments, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain 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.

[0052] Any two substituents or any two instances of the same substituent are "independently selected" from the list of options, and the groups can be the same or different. For example, if R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule having two R a groups and two R b groups can have all alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a is alkyl, the second R a is fluoro, the first R b is hydroxyalkyl, and the second R b is amino (or any other substituent from the group). Alternatively, both R a and the first R b are fluoro, while the second R bis alkyl (i.e., some pairs of substituents may be the same while other pairs may be different).

[0053] An "amino protecting group" is a protecting group suitable for preventing unwanted reactions of amino nitrogen. Representative amino protecting groups include, but are not limited to, formyl; acyl groups such as alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS), etc.

[0054] A "hydroxyl protecting group" is a protecting group suitable for preventing unwanted reactions of hydroxyl oxygen. Representative hydroxyl protecting groups include, but are not limited to, acyl groups such as acetyl; arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); ethers such as methoxymethyl (MOM), tetrahydropyranyl (THP), and benzyl (Bn), etc.

[0055] The "yield" of each of the reactions described herein is expressed as a percentage of the theoretical yield.

[0056] "Subject" and "patient" are used interchangeably. The "subject" or "patient" for the purposes of the present invention includes humans and other animals, particularly mammals and other organisms. Thus, the method is applicable to both human therapy and veterinary applications. In certain embodiments, the patient is a mammal, and in a more specific embodiment, the patient is a human.

[0057] The "pharmaceutically acceptable salts" of a compound mean salts that are pharmaceutically acceptable and have 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 is incorporated herein by reference in Remington’s Pharmaceutical Sciences, 17 th th ed., Mack Publishing Company, Easton, PA, 1985 or can be found in S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference.

[0058] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids such as 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, 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, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid and salicylic acid, etc.

[0059] Examples of pharmaceutically acceptable base addition salts include those formed when the acidic protons present in the parent compound are replaced with metal ions such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Specific salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucosamine, polyamine resins, etc. Examples of organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0060] "Therapeutically effective amount" is the amount of the compound of the present invention that, when administered to a patient, reduces the symptoms of the disease. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the age of the patient being treated, etc. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art, taking into account the knowledge of one of ordinary skill in the art and the present disclosure.

[0061] As used herein, the term "genetic disease" means a genetic disorder, genetic disease, genetic condition or genetic syndrome.

[0062] "Prevention" or "prevent" of a disease, disorder or syndrome means preventing the occurrence of the disease in a human, 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 manifested the symptoms of the disease, disorder or syndrome.

[0063] As used herein, "treatment" or "treat" 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 regression of the disease, disorder or syndrome. As is known in the art, modulation of systemic to local delivery may require adjustment for age, weight, general health, sex, eating habits, administration time, drug interactions and disease severity and can be confirmed by routine experimentation by one of ordinary skill in the art.

[0064] A CFTR modulator is a drug or compound that targets a fundamental defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The two main types of modulators are potentiators and corrector drugs [accessed May 24, 2022, Cystic Fibrosis Foundation https: / / www.cff.org / Research / Developing-New-Treatments / CFTR-Modulator-Types / ].

[0065] Embodiments In one aspect, a method of treating a subject having a genetic disease, the method comprising administering to the subject a therapeutically effective amount of Formula I

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0066] or a pharmaceutically acceptable salt thereof. In an embodiment of the method, the compound is of formula IA

Chemical formula

[0067]

Chemical formula

Chemical formula

[0068]

Chemical formula

Chemical formula

[0069]

Chemical formula

Chemical formula

[0070] In this and other embodiments of the method, R of the compound of formula 6D 6b is -H, C 1 -C 10 alkyl optionally substituted, C optionally substituted 1 -C 10 hydroxyalkyl and allyl optionally substituted, and is selected from the group consisting of. In this and other embodiments of the method, R of the compound of formula 6D 6b is methyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, -CH 2 CHOHCH 2 OH and allyl, and is selected from the group consisting of.

[0071] In other embodiments of the method, the compound is of formula IE

Chemical formula

[0072] In other embodiments of the method, the compound is of formula IF

Chemical formula

[0073] In other embodiments of the method, the compound is of formula IG

Chemical formula

[0074] In this and other embodiments of the method, R of the described compound 9a is -H, C 1-4 alkyl or C 1-4 alkylene-OH.

[0075] In this and other embodiments of the method, R of the described compound 11a and R 11b are -H. In this and other embodiments of the method, R of the described compound 11a and R 11b One of them is -H and the other is optionally substituted C 1-10 alkyl. In this and other embodiments of the method, R of the described compound 11a and R 11b One of them is -H and the other is methyl. In this and other embodiments of the method, R of the described compound 11a and R 11b are each independently optionally substituted C 1-10 alkyl. In this and other embodiments of the method, R of the described compound 11a and R 11b are each methyl.

[0076] In this and other embodiments of the method, R of the described compound 2a and R 2b One of them is optionally substituted C 1-10 alkyl. In this and other embodiments of the method, R of the described compound 2a and R 2b One of them is methyl, and R 2a and R 2b The other is H or both R 2a and R 2b are both methyl. In this and other embodiments of the method, R of the described compound 2a and R 2b One of them is methyl and the other is halo, more specifically fluoro or chloro.

[0077] In this and other embodiments of the method, R of the described compound 2a and R 2b One of them is methyl and the other is optionally substituted C 1-10 alkyl. In this and other embodiments of the method, R of the described compound 2a and R2b One of them is methyl and the other is C which is optionally substituted 1-10 alkyl, C which is optionally substituted 1-10 alkoxy and C which is optionally substituted 1-10 alkenyl, selected from the group consisting of, wherein C which is optionally substituted 1-10 alkyl, C which is optionally substituted 1-10 alkoxy and C which is optionally substituted 1-10 alkenyl is optionally substituted with one or more selected from the group consisting of halo, aryl and heteroaryl.

[0078] In another embodiment, the compound is of formula IH

Chemical formula

[0079] In this and other embodiments of the method, R of the compounds of formula I and thus formula IA - IH 9a is -H or C 1-4 alkyl, and R of the described compounds 10a and R 10b one of them is -H or C which is optionally substituted 1-10 alkyl.

[0080] In this and other embodiments of the method, R of the compounds of formula I and thus formula IA - IH 9a is -H.

[0081] In this and other embodiments of the method, R of the compounds of formula I and thus formula IA - IH 9a is C which is optionally substituted 1-10 alkyl.

[0082] In this and other embodiments of the method, R of the compounds of formula I and thus formula IA - IH 9a is methyl.

[0083] In other embodiments, the compound is of formula IIA, IIB, IIC or IID [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0084] In other embodiments, the compound is of formula IIA-1, IIA-2, IIB-1, IIB-2, IIC-1, IIC-2, IID-1 or IID-2: [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0085] In other embodiments, the compound is of formula IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a or IID-2a [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0086] In other embodiments, the compound is of formula IIA-1b, IIA-2b, IIB-1b, IIB-2b, IIC-1b, IIC-2b, IID-1b or IID-2b [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0087] In the compounds of formula I and II for use in the method, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH2 OMe or CH 2 CH 2 is OH. In certain embodiments, R 9a is -H, methyl, ethyl, propyl, isobutyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 is OH. In certain embodiments, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl. In other embodiments, R 9a is acetyl, C(=O)-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 is OH.

[0088] R in the compounds of Formulas I-II 10a : 1. L a is C 2-6 alkenylene In embodiments of the compounds of Formulas I and II, -L a -L b -L c -L d for L a is C 2-6 alkenylene. In other embodiments, -L a -L b -L c -L d for L a is C 2-6 alkenylene, L b and L c are absent, and L d is H. In other embodiments, La is -CH 2 =CH 2 -, and L b and L c do not exist, and L d is H.

[0089] 2. L a is C 1-6 alkylene or oxo In certain embodiments, L a is C 1-6 alkylene. In a further embodiment, L a is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 -. In a further embodiment of L a one of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - can be replaced by oxo (C=O).

[0090] 3. L a is -CH 2 - or oxo In certain embodiments, L a is CH 2 or oxo (C=O).

[0091] In other embodiments, L a is CH 2 or C(=O); and L b does not exist.

[0092] In other embodiments, L a is CH2 and L b does not exist. In other embodiments, L a is CH 2 ; L b does not exist; L c is CO, C(=O)NH-C 1-6 alkylene, -NH-C 1-6 alkylene, N(C 1-6 alkyl)-C 1-6 alkylene, and L d is H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or N(C 1-6 alkyl) 2 . In other embodiments, L a is CH 2 ; L b does not exist; L c is -NH-CH 2 , N(C 1-6 alkyl)-C 1-6 alkylene, and L d is H, C 1-6 alkyl or optionally substituted heteroaryl. In a further embodiment, -L a -L b -L c -L d is CH 2 -NHMe, CH 2 -N(Me)-imidazolyl, CH 2 -N(iPr)(Me), CH 2 -N(Me) 2 , CH 2 -N(Et) 2 , CH 2 -N(iPr)(Me), CH 2 -N(Me)(Et), CH 2 -N(Me)(tBu), CH 2 -N(H)(iPr), CH 2 -N(Me)(cyclopropyl) or CH 2 -N(Me)(CO)-CH 2 -N(Me) 2 .

[0093] 3a. L b is cycloalkyl or heterocycloalkyl which is optionally substituted In other embodiments, L a is CH 2 or oxo; and L b is cycloalkyl or heterocycloalkyl which is optionally substituted. In other embodiments, L a is CH 2 or oxo; and L b is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, any of which may be optionally substituted. In other embodiments, L a is CH 2 or oxo; and L b is cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, any of which may be optionally substituted.

[0094] In other embodiments, L a is CH 2 or oxo; and L b is cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, any of which may be optionally substituted. In these and other embodiments, L c is absent or C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl, N-C 1-6Alkylene - heteroaryl, C(=O), C(=O)O, C(=O)NH, C(=O)N - alkyl, C(=O)NH - C 1-6 Alkylene, C(=O)N(C 1-6 Alkyl)-C 1-6 Alkylene, SO 2 、SO 2 NH, SO 2 N - C 1-6 Alkyl, OC(=O)-NH, OC(=O)-N - alkyl, N(C 1-6 Alkyl)-C(=O)-C 1-6 Alkylene, SO 2 、SO 2 C 1-6 Alkylene, SO 2 NH, SO 2 N(C 1-6 Alkyl), SO 2 NH-(C 1-6 Alkylene), SO 2 N(C 1-6 Alkyl)-(C 1-6 Alkylene), SO 2 N(C 1-6 Alkylene - aryl), SO 2 N(C 1-6 Alkylene - heteroaryl),

Chemical formula

[0095] In other embodiments, L a is CH 2 or oxo; and L b is cyclobutyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl; L c does not exist, L d is H, -OH, C 1-6 alkyl, aryl, heteroaryl. In a further embodiment, L a is CH 2 and L b is piperidinyl, piperazinyl or morpholinyl; L c does not exist, L dis H, OH, methyl, trifluoromethyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-tolyl, 4-tolyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, [Chemical formula] and so on.

[0096] In other embodiments, L a is CH 2 or oxo; and L b is heterocycloalkyl or cycloalkyl. In a further embodiment, L a is CH 2 or C(=O); L b is piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl; L c is absent or C 1-6 alkylene, C(=O), C(=O)O, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-6 alkylene, C(=O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, -OH, C 1-6 alkyl, C 1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0097] In a further embodiment, L a is CH 2 or C(=O); L b is azetidinyl, piperidinyl, piperazinyl or morpholinyl; L c is absent or C1-6 alkylene, C(=O), C(=O)O, C(=O)NH, C(=O)N(C 1-6 alkyl)-, C(=O)NH-C 1-6 alkylene, C(=O)N(C 1-6 alkyl)-C 1-6 alkylene, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH or SO 2 N(C 1-6 alkyl); and L d is H, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 6-12 aryl or optionally substituted 5- to 10-membered heteroaryl.

[0098] In a further embodiment, L a is CH 2 or oxo; L b is cyclobutyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl; L c is C(=O), C(=O)NH, C(=O)N-alkyl, C(=O)NH-CHCH 3 , C(=O)N(C 1-6 alkyl)-C 1-6 alkylene; and L dis H, methyl, ethyl, isopropyl, isobutyl, t-butyl, hydroxy, methoxy, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,

Chemical formula

[0099] In other embodiments, L a L b is

Chemical formula

[0100] In other embodiments, L a L b is

Chemical formula

[0101] In other embodiments, L a L b is

Chemical formula

[0102] In other embodiments, L a L b is

Chemical formula

Chemical formula

[0103] In other embodiments, L a L b is

Chemical formula

Chemical formula

[0104] In other embodiments, L a L b is

Chemical formula

[0105] In other embodiments, L a L b is [Chemical formula] ; L c does not exist or is C 1-6 alkylene, C(=O), C(=O)O, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-6 alkylene, C(=O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. In a further embodiment, L c does not exist or is C 1-6 alkylene, C(=O), C(=O)NH, C(=O)O, C(=O)N-alkyl, C(=O)NH-CH 2 , C(=O)NH-CHCH 3 , C(=O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, methyl, ethyl, isopropyl, hydroxyl, methoxy, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, [Chemistry] is.

[0106] In other embodiments, L a is CH 2 or oxo; L b is cyclobutyl, L c is absent or -NH-C 1-6 alkylene, N(C 1-6 alkyl)-C 1-6 alkylene, and L d is H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In a further embodiment, L a is CH 2 or C(=O); L b is cyclobutyl; L c is absent or CH 2 CH 2 CH 2 or oxo; and L d is H, methyl, ethyl, isopropyl, cyclopropyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, [Chemistry] is. In a further embodiment, L a L b is [Chemistry] is; L c is NHCH 2 -, N(Me)CH 2 -, N(Et)CH 2 -, N(iPr)CH 2 -, N(isobutyl)CH 2 -; and L d is H or cyclopropyl. In a further embodiment, L a L b is [Chemical formula] is; L c is NHCH 2 -, N(Me)CH 2 -, N(Et)CH 2 -, N(iPr)CH 2 -, N(isobutyl)CH 2 -; and L d is H or cyclopropyl.

[0107] In other embodiments, the compound has the formula A: [Chemical formula] [wherein, X is H 2 or O; Y is N, CH, C-(C 1-6 alkyl) or O; R 9a is H, optionally substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O-C 1-6 alkyl, C(=O)C 1-6 alkyl, C 1-6 alkylene-cycloalkyl or C(=O)cycloalkyl, selected from the group consisting of; L c is absent or C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N-C 1-4 alkyl, N-C 1-4 cycloalkyl, -NH-C 1-4 alkylene, -N(C 1-4 alkyl)-C 1-4 alkylene, -N-C 1-4 alkylene-cycloalkyl, N-C 1-4 alkylene-heterocycloalkyl, N-C 1-4 alkylene-aryl, N-C 1-4Alkylene - heteroaryl, C(=O), C(=O)O - C(=O)NH, C(=O)N - alkyl, C(=O)NH - C 1-4 Alkylene, C(=O)N(C 1-4 alkyl)-C 1-4 Alkylene SO 2 , SO 2 NH, SO 2 N - C 1-4 alkyl, SO 2 N-(C 1-4 alkyl)-(C 1-4 alkylene), OC(=O)-NH, OC(=O)-N - C 1-4 alkyl, N(C 1-6 alkyl)-C(=O)-C 1-6 alkylene, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), SO 2 NH-(C 1-4 alkylene, SO 2 N(C 1-4 alkyl)-(C 1-4 alkylene), SO 2 N(C 1-4 alkylene - aryl), SO 2 N(C 1-4 alkylene - heteroaryl),

Chem.

[0108] In a further embodiment of formula A, R 9a , R 11a , L c and L d have any of the definitions defined in Section 3a when L b is optionally substituted heterocycloalkyl.

[0109] In a further embodiment of formula A, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or C 1-4 alkylene, NH, N-C 1-4 alkyl, -N(C 1-4 alkyl)-C 1-4 alkylene, C(=O), C(=O)O-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-4 alkylene, OC(=O)-NH, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl) or

Chemical formula

[0110] In a further embodiment of formula A: X is H 2 or O; Y is N, CH or O; and R 11a is H or methyl.

[0111] In another embodiment, formula A1 [Chemical formula] [wherein, X is H 2 or O; R 9a is H or C 1-4 alkyl; R 11a is H or C 1-4 alkyl; L c is absent or C 1-3 alkylene, C(=O), C(=O)NH, C(=O)NH-C 1-3 alkylene or SO 2 C 1-3 alkylene; and Ld is NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, where cycloalkyl, aryl and heteroaryl are each independently and optionally halo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy substituted. ]] There is provided a compound of formula A1 or a pharmaceutically acceptable salt thereof.

[0112] In a further embodiment of formula A1: R 9a is H, Me, Et or Pr; R 11a is H or Me; L c is CH 2 , CH 2 CH 2 , C(=O)NH, C(=O), C(=O)NHCH 2 or SO 2 CH 2 ; and L d is N(CH 3 ) 2 , NHCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, phenyl, naphthalenyl, imidazolyl, pyrimidinyl or pyridinyl, where phenyl, imidazolyl, pyrimidinyl and pyridinyl are each independently and optionally F, Cl, Br, Me, OMe or CF 3 substituted.

[0113] In another embodiment, the compound of formula A1 is

Chemical formula

[0114] In another embodiment, formula A2 [Chemical formula] [wherein, R 9a is H or C 1-4 alkyl; L c is C 1-3 alkylene, C(=O), C(=O)NH, C(=O)NH-C 1-3 alkylene, SO 2 or SO 2 C 1-3 alkylene; and L d is OH, NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein aryl and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy. ] There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0115] In a further embodiment of formula A2: R 9a is H, Me, Et, Pr, butyl or isopropyl; L c is CH 2 , CH 2 CH 2 , C(=O), C(=O)NH, C(=O)NHCH 2 , SO 2 or SO 2 CH 2 ; and L d is OH, N(CH 3 ) 2 , NHCH(CH 3 ) 2 , phenyl or pyridinyl, wherein phenyl and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe or CF 3 .

[0116] In a further embodiment of formula A2: R 9a is H, Me, Et or Pr; L c is CH 2 or C(=O); and L d is phenyl or pyridinyl, where phenyl and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe or CF 3 respectively.

[0117] In other embodiments, the compound is of formula B:

Chemical formula

Chemical formula

[0118] In a further embodiment of formula B, R 9a and R 11a and L c and L d are each as defined in Section 3a when L b is cycloalkyl optionally substituted.

[0119] In a further embodiment of formula B, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or is C 1-4 alkylene, NH, N-C 1-4 alkyl or -N(C 1-4 alkyl)-C 1-4 alkylene; and L d is H, C 1-6 alkyl or cycloalkyl optionally substituted.

[0120] In a further embodiment of formula B: X is H 2 or O; R 9a is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkylene-OH, C 1-4 alkylene-OMe; and R 11a is H or methyl.

[0121] In other embodiments, R 10a is

Chem.

[0122] In other embodiments, R 10a is

Chem.

[0123] In other embodiments, R 10a is

Chem.

[0124] In other embodiments, R 10a is

Chem.

[0125] In other embodiments, R 10a is -CH 2 NHME, -CH 2 N(ME) 2 ,

Chem.

[0126] 4. L a is CH 2 CH 2 or CH 2 CH 2 CH 2 In one embodiment, L a is CH 2 CH 2or CH 2 CH 2 CH 2 is. In other embodiments, one methylene unit of L a may be replaced by oxo. In other embodiments, L a is COCH 2 COCH 2 CH 2 CH 2 COCH 2 . In other embodiments, L a is CH 2 CH 2 CH 2 CH 2 CH 2 COCH 2 COCH 2 CH 2 CH 2 COCH 2 ; L b is cycloalkyl which is absent or optionally substituted or heterocycloalkyl which is optionally substituted; L c is absent or C 1-6 alkylene, C 1-6 alkylene - N(C 1-6 alkyl), NH, N - C 1-6 alkyl, N - C 1-6 cycloalkyl, - NH - C 1-6 alkylene, - NH - C 1-6 alkylene - heteroarylene, - N(C 1-6 alkyl) - C 1-6 alkylene, - N - C 1-6 alkylene - cycloalkyl, N - C 1-6 alkylene - heterocycloalkyl, N - C 1-6 alkylene - aryl, N - C 1-6 alkylene - heteroarylene, C(=O), C(=O)O -, C(=O)NH, C(=O)N - alkyl, C(=O)NH - C 1-6 alkylene, C(=O)N(C 1-6 alkyl) - C 1-6 alkylene SO 2 SO 2 C 1-6 alkylene, SO 2NH, SO 2 N-C 1-6 Alkyl, OC(=O)-NH, OC(=O)-N-alkyl, SO 2 , SO 2 C 1-6 Alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH-(C 1-6 alkylene, SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl), [Chemical formula] and L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0127] In another embodiment, L a is CH 2 CH 2 CH 2 and L b and L c do not exist.

[0128] In a certain embodiment, L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2CH 2 、 and CH 2 COCH 2 ; L b does not exist, and L c is N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl or N-C 1-6 alkylene-heteroaryl; and L d is H, OH, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl. In other embodiments, L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 , CH 2 COCH 2 ; L b does not exist; L c is N(Me), N(Et), N(Me)(CH 2 ), NH; and L d is H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0129] In other embodiments, La is CH 2 CH 2 、CH 2 CH 2 CH 2 、COCH 2 、COCH 2 CH 2 、CH 2 COCH 2 ; L b does not exist; L c does not exist; and L d is pyrrolidinyl, oxazolyl,

Chem.

Chem.

[0130] In certain embodiments, L a is CH 2 CH 2 、CH 2 CH 2 CH 2 、COCH 2 、COCH 2 CH 2 、CH 2 COCH 2 ; L b does not exist, L c is N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -NH-C 1-6 alkylene - heteroarylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene - cycloalkyl, N-C 1-6 alkylene - heterocycloalkyl, N-C 1-6 alkylene - aryl or N-C 1-6 alkylene - heteroarylene; and L d is H, OH, C 1-6Alkyl, OH, alkoxy, NH 2 , NHC 1-6 Alkyl, N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0131] In other embodiments, L a is CH 2 CH 2 CH 2 and L b is absent; L c is N(Me), N(Et), N(Me)(CH 2 ), NH; and L d is H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, imidazolyl. In other embodiments, L a L b is CH 2 CH 2 CH 2 and L c L d is NH 2 , NH-Me, NH-Et, NH-isopropyl, NH-cyclopropyl, NH-cyclobutyl, NH-cyclopentyl, N(Me) 2 , N(Et) 2 , N(Me)(Et), N(Me)-cyclopropyl, N(Me)-cyclobutyl, N(Me)-cyclopentyl, N(Me)CH 2 -imidazolyl, N(Me)(iPr), N(Me)(tBu), NH-cyclopropyl, NH-oxazolyl, NH-pyrimidinyl, NH-pyridyl, NHCH 2 -cyclopropyl, NHCH 2 -oxazolyl, NHCH 2 -pyrimidinyl, NHCH 2 -pyridyl, NHCH 2 -quinazolinyl, NHCH2 -quinolinyl or NHCH 2 -oxadiazolen-phenyl.

[0132] In other embodiments, L a is CH 2 CH 2 CH 2 and L b is absent; L c is absent; and L d is OH or alkoxy.

[0133] In other embodiments, L a is CH 2 CH 2 CH 2 and L b is absent; L c is N(Me), N(Et), N(Me)(CH 2 ), NH; and L d is H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, imidazolyl. In other embodiments, L a L b is CH 2 CH 2 CH 2 and L c L d is NH 2 , NHMe, NHEt, NH cyclopropyl, N(H) cyclobutyl, N(H) cyclopentyl, N(Me) 2 , N(Et) 2 , N(Me)(Et), N(Me) cyclopropyl, N(Me) cyclobutyl, N(Me) cyclopentyl, N(Me)CH 2 -imidazolyl, N(Me)(iPr), N(Me)(tBu), NH-cyclopropyl, NH-oxazolyl, NH-pyrimidinyl, NH-pyridyl, NHCH 2 -cyclopropyl, NHCH 2 -oxazolyl, NHCH 2 -pyrimidinyl, NHCH 2 -pyridyl.

[0134] In one embodiment, L a is CH 2 CH 2 CH 2 ; L b is absent; L c is CO, C(=O)O-, OC(=O)-NH, C(=O)NH or C(=O)NHCH 2 ; and L d is H, C 1-6 alkyl or optionally substituted aryl or heteroaryl. In other embodiments, L a is CH 2 CH 2 CH 2 ; L b is absent; L c is CO, and L d is methyl. In other embodiments, L a L b is CH 2 CH 2 CH 2 ; and L c L d is O-C(=O)NH-phenyl or

Chemical formula

[0135] a is CH 2 CH 2 CH 2 ; L b is optionally substituted cycloalkyl or heterocycloalkyl; L c is absent; and L d is H, OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0136] In other embodiments, L a is CH 2 CH 2 CH2 and; L b does not exist; L c does not exist; and L d is optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl; in other embodiments, L d is H, methyl, trifluoromethyl, phenyl, pyridyl, pyrimidinyl or OH. In other embodiments, L a is CH 2 CH 2 CH 2 and L b does not exist; L c does not exist; and L d is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

Chemical formula

[0137] In other embodiments, L a is CH 2 CH 2 CH 2 and L b does not exist; L c does not exist; and L d is H, methyl, trifluoromethyl, phenyl, pyridyl, pyrimidinyl, OH,

Chemical formula

Chemical formula

[0138] In other embodiments, L a is COCH 2 CH 2 and L b does not exist; L c does not exist; and L dis phenyl, pyridyl, pyrimidinyl, OH,

Chem.

Chem.

[0139] In certain embodiments, L a is COCH 2 CH 2 ; L b is absent; L c is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl, N-C 1-6 alkylene-heteroaryl, C(=O), C(=O)O-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-6 alkylene, C(=O)N(C 1-6 alkyl)-C 1-6 alkyleneSO 2 、SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N-C 1-6 alkyl, OC(=O)-NH, OC(=O)-N-alkyl, SO 2 、SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH-(C 1-6 alkylene, SO2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl),

Chemical formula

[0140] In certain embodiments, L a is COCH 2 CH 2 ; L b is absent; L c is NH or NHCH 2 ; L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl.

[0141] In certain embodiments, L a is COCH 2 CH 2 ; L b is absent; L cis NH or NHCH 2 ; and L d is pyrimidinyl optionally substituted, quinolinyl optionally substituted, oxazolyl optionally substituted, cyclobutyl optionally substituted.

[0142] In other embodiments, R 10a is HO-CH 2 -CH 2 -CH 2 -, (Me) 2 N-CH 2 -CH 2 -CH 2 -, (Me)N-CH 2 -CH 2 -CH 2 -, (Et) 2 N-CH 2 -CH 2 -CH 2 -

Chemical formula

[0143] In other embodiments, R 10a is

Chemical formula

Chemical formula

[0144] In other embodiments, the compound is of formula C:

Chemical formula

Chemical formula

[0145] In a further embodiment of formula C, R 9a , R 11a , L c and L d have any of the definitions defined in Section 4.

[0146] In a further embodiment of formula C, R 9a is C 1-6 alkylene-O-C 1-6 alkyl, C(=O)C 1-6 alkyl, C 1-6 alkylene-cycloalkyl, C(=O)cycloalkyl or C(=O)NH-aryl. In other embodiments, R 9a is C 1-6 alkylene-O-C 1-6 alkyl, C(=O)C 1-6 alkyl, C 1-6 alkylene-C 1-6 cycloalkyl, C(=O)C 3-6is cycloalkyl or C(=O)NH-aryl. In other embodiments, R 9a is C 1-6 alkylene-OMe, C(=O)C 1-3 alkyl, C(=O)C 3-6 cycloalkyl or C(=O)NH-phenyl.

[0147] In a further embodiment of Formula C, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N-C 1-4 alkyl, N-C 1-4 cycloalkyl, -NH-C 1-4 alkylene, -N(C 1-4 alkyl)-C 1-4 alkylene, -N-C 1-4 alkylene-cycloalkyl, N-C 1-4 alkylene-heterocycloalkyl, N-C 1-4 alkylene-aryl, N-C 1-4 alkylene-heteroaryl, C(=O), C(=O)O-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-4 alkylene, C(=O)N(C 1-4 alkyl)-C 1-4 alkylene or OC(=O)-NH; L d is H, C 1-6 alkyl, OH, alkoxy, C1-6 It is haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0148] In a further embodiment of Formula C: Z is H 2 or O; R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl or CH 2 CH 2 OH; and R 11a is H or methyl.

[0149] In other embodiments, the compound is of Formula C1:

Chemical formula

[0150] In a further embodiment of Formula C1: R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is NH, NH-CH 2 , NH-CH 2 -(5- to 6-membered heteroarylene), C(=O)O-, C(=O)NH or OC(=O)-NH; and L d is C 3-6 cycloalkyl, phenyl or 5- to 10-membered heteroaryl.

[0151] In another embodiment, the compound is of Formula C2:

Chemical formula

[0152] In a further embodiment of formula C2: R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is absent or is NH or NH-CH 2 ; and L d is OH, C 3-6 is cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl or 6- to 10-membered nitrogen-containing heteroaryl.

[0153] In another embodiment, R 10a is

Chemical formula

Chemical formula

[0154] In certain embodiments, R 10a is

Chemical formula

[0155] In other embodiments, the compounds of Formula I and Formula II used in the method are selected from the compounds described in the following table or pharmaceutically acceptable salts thereof.

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

[0156] In other embodiments, compounds described in Table B are provided.

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

[0157] In these or other embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered alone or in any combination with a drug selected from the group consisting of aminoglycosides, potentiators, correctors, amplifiers, and any combination of these.

[0158] Method for producing the compound The compounds disclosed herein can be produced as described in the following paragraphs.

[0159] The compound can be produced via two intermediates. The east half intermediate has the formula P-1: [Chemical formula] is a compound of formula P-1 or a salt thereof. In the compound of formula P-1, R 3 , R 4a , R 4b , R 5 , R 6a , R 6b , R 8a and R 8b are as defined herein; and G 4 is of the formula:

Chemical formula

[0160] The acyclic eastern half intermediate is of formula P-2:

Chemical formula

Chem.

[0161] In certain embodiments, -OPG is -OBz.

[0162] Also of formula P-3:

Chem.

[0163] Coupling and Macrolactonization In certain embodiments, the compounds of the invention are as shown in the following scheme, wherein R s is a sugar residue

Chem.

[0164] Formula P-5 is cyclized after deprotection of the sugar residue as described in the following scheme to obtain the compound of formula I. [Chemical formula]

[0165] Alternatively, as shown in the following scheme, the compound precursor of formula P-5 in which R 9a is hydrogen is cyclized to obtain the compound of formula I, which is subjected to reductive amination to obtain the compound of formula I in which R 9a is other than H. [Chemical formula]

[0166] R 2b The late-stage installation of the group can be achieved by treatment of the compound of formula P-6 above with a base and a suitable electrophilic substance group (for example, a halogenating agent or R 2 -LG (where LG is a leaving group). In this method, the sugar residue in P-6 is protected and R 9a is H or alkyl. [Chemical formula]

[0167] For all intermediates, the variable groups are as defined herein for the compound of formula I.

[0168] Other variable groups described for the intermediates and precursors are defined as follows: LG is a leaving group; G 4 is of the formula:

Chemical formula

[0169] As described above, R s is a sugar moiety

Chemical formula

[0170] Method In one aspect, there is provided a method of treating a genetic disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I. There is also provided a method of treating a genetic disorder characterized by a premature stop codon mutation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I.

[0171] Genetic disorders characterized by premature stop codon mutations can be treated by inducing and / or promoting complete read-through of the mutations, which are transcripts (mRNAs) that are otherwise lacking. That is, genetic disorders characterized by premature stop codon mutations can be treated by inducing and / or promoting suppression of nonsense mutations (premature stop codon mutations). Thus, as disclosed herein, genetic disorders that can be treated by the methods disclosed and claimed herein are responsive to read-through inducing and / or promoting compounds.

[0172] Methods for identifying genetic disorders characterized by premature stop codon mutations are available to those of skill in the art and can include whole or partial genomic analysis, genetic biomarker detection, phenotypic classification, and genetic information analysis. These methods often result in pairs of mutant / wild-type (WT) sequences. The WT sequence pairs can be used to identify whether a genetic disease is characterized by a premature stop codon mutation. Similarly, determination of the ability of a compound or composition to induce or promote read-through is also known in the art.

[0173] For this purpose, a plasmid containing two reporter genes interrupted by the sequence of a mutant gene (disease-causing gene) is transfected in a protein expression platform of a complete cell or cell-free system, and the ratio between the expression levels of the two genes in the presence of a test compound is typically measured at a series of concentrations and duplications and compared to the wild-type gene expression level ratio and / or the expression level ratio measured in a control sample without the test compound.

[0174] It should be noted that the experimental model of readthrough activity (i.e., the nucleotide sequence of a gene containing a premature stop codon mutation) is a byproduct of the process of identifying genetic disorders associated with premature stop codon mutations and / or protein truncation phenotypes. Furthermore, it should also be noted that with the great progress in genomic data collection, this process is now well within the capabilities of those skilled in the art.

[0175] Methods for testing the readthrough of premature stop codon mutations are known. Experimental methods designed for the evaluation of the ability of a compound to induce or promote readthrough are provided herein.

[0176] Some in vitro methods for testing the readthrough-inducing ability of the compounds provided herein and the safety as potential drugs are used by those skilled in the art.

[0177] Non-limiting examples of genetic diseases associated with the presence of at least one premature stop codon mutation or other nonsense mutation include cystic fibrosis (CF), muscular dystrophy (Duchenne type (DMD), Becker type (BMD), congenital, spinal muscular atrophy), ataxia telangiectasia, mucopolysaccharidosis type I (Hurler syndrome), hemophilia (A and B), Usher syndrome (retinitis pigmentosa, X-linked retinitis pigmentosa), Tay-Sachs, factor VII deficiency, familial atrial fibrillation, Hailey disease, McArdle disease, mucopolysaccharidosis, nephropathic cystinosis, polycystic kidney disease, Rett syndrome, cystinosis, severe epidermolysis bullosa, Draber syndrome, X-linked nephrogenic diabetes insipidus (XNDI), cancer, beta-thalassemia, epidermolysis bullosa (EB), familial adenomatous polyposis (FAP), and obesity.

[0178] In certain embodiments, the genetic disorder is EB.

[0179] In certain embodiments, the genetic disorder is severe EB.

[0180] In certain embodiments, the genetic disorder is dystrophic epidermolysis bullosa (DEB), recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), epidermolysis bullosa simplex (EBS) and / or Kindler syndrome.

[0181] In certain embodiments, the genetic disorder is RDEB, JEB and / or FAP.

[0182] Additional genetic diseases associated with the presence of at least one premature stop codon or other nonsense mutation are disclosed, for example, in “Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases,” Kim M. Keeling, K. M Bedwell, D.M., Wiley Interdisciplinary Reviews: RNA, 2011, 2 (6), p. 837-852; “Cancer syndromes and therapy by stop-codon readthrough,” Bordeira-Carrico, R. et al., Trends in Molecular Medicine, 2012, 18 (11), p. 667-678 and the references cited therein.

[0183] In one aspect, compounds or compositions are provided herein for use in treating genetic diseases associated with premature stop codon mutations.

[0184] In another aspect, provided is the use of a compound or composition disclosed herein in the manufacture of a medicament for treating genetic diseases associated with premature stop codon mutations. The genetic diseases in this and other aspects and embodiments include cystic fibrosis (CF), muscular dystrophy (Duchenne (DMD), Becker, congenital, spinal), ataxia telangiectasia, Hurler syndrome, hemophilia (A and B), Usher syndrome (retinitis pigmentosa, X-linked retinitis pigmentosa), Tay-Sachs, factor VII deficiency, familial atrial fibrillation, Hailey disease, McArdle disease, mucopolysaccharidosis, nephropathic cystinosis, polycystic kidney disease, Rett syndrome, cystinosis, severe epidermolysis bullosa, Draber syndrome, X-linked nephrogenic diabetes insipidus (XNDI), cancer, beta-thalassemia, EB, severe EB, DEB, RDEB, JEB, FAP, EBS, Kindler syndrome, and obesity, and are selected from the group consisting of.

[0185] In another aspect, provided is a method of increasing the expression level of a gene having a premature stop codon mutation, the method comprising translating the gene into a protein in the presence of a compound or composition disclosed herein in any of each embodiment and any combination thereof. In one embodiment, provided is a compound or composition disclosed herein for use in increasing the expression level of a gene having a premature stop codon mutation. In a further embodiment, provided is the use of a disclosed compound or composition in the manufacture of a medicament for increasing the expression level of a gene having a premature stop codon mutation. By these and other aspects and embodiments, the premature stop codon mutation has an RNA code selected from the group consisting of UGA, UAG, and UAA. By these and other aspects and embodiments, the protein is translated in a cytoplasmic translation system. By these and other aspects and embodiments, the compound or composition disclosed herein is used in a mutation-suppressing amount. By these and other aspects and embodiments, the translation inhibition IC of the compound or composition in the eukaryotic cytoplasmic translation system 50 is greater than the translation inhibition IC of the compound in the ribosomal translation system. 50 By these and other aspects and embodiments, the translation inhibition IC of the compound in the eukaryotic cytoplasmic translation system50 is greater than the translational inhibition IC of the compound in the prokaryotic translation system 50 than.

[0186] Pharmaceutical Compositions and Administration The present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable additive. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0187] Pharmaceutically acceptable additives include any and all solvents, diluents or other liquid media, dispersants, suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. suitable for the particular dosage form desired. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0188] The pharmaceutical compositions described herein can be manufactured by any method known in the art of pharmacology. Generally, such manufacturing methods include combining the compound of the present invention (the "active ingredient") with a carrier and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dosage units.

[0189] The pharmaceutical composition can be manufactured, packaged and / or sold in bulk as a single unit dose and / or multiple single unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition that contains a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient administered to the subject and / or a convenient fraction of such dosage, such as half or one third of such dosage.

[0190] The relative amounts of the active ingredient, pharmaceutically acceptable additives and / or any additional ingredients in the pharmaceutical composition of the present invention depend on the identity, physical build and / or condition of the subject to be treated and further depend on the route by which the composition is administered and vary. By way of example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0191] Pharmaceutically acceptable additives used in the manufacture of the provided pharmaceutical composition include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Additives such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavors and fragrances may also be present in the composition.

[0192] Examples of diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, corn starch, powdered sugar and mixtures thereof.

[0193] Examples of granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicic acid, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, aluminum magnesium silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds and mixtures thereof.

[0194] Examples of surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [aluminum magnesium silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymer and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68. It contains Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, sodium docusate and / or mixtures thereof.

[0195] Examples of binders include starch (such as corn starch and starch paste), gelatin, sugars (such as sucrose, glucose, dextrose, dextrin, sugar solution, lactose, lactitol, mannitol, etc.), natural and synthetic gums (such as acacia, sodium alginate, Irish moss extract, panwar gum, gatti gum, mucilage of isapol husk, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), aluminum magnesium silicate (Veegum) and arabinogalactan of the genus Larix), alginic acid, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylic acid, wax, water, alcohol and / or mixtures thereof.

[0196] Examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives and other preservatives.

[0197] Examples of antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite.

[0198] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, calcium disodium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates; malic acid and its salts and hydrates: phosphoric acid and its salts and hydrates: and tartaric acid and its salts and hydrates. Examples of antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0199] Examples of antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0200] Examples of alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoic acid, and phenylethyl alcohol.

[0201] Examples of acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0202] Other preservatives include tocopherol, tocopherol acetate, detroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0203] Examples of buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0204] Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0205] Examples of natural oils include almond, apricot, avocado, babassu, bergamot, croton seed, borrage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, lemongrass, macadamia nut, meadowfoam seed, mink, nutmeg, olive, orange, orange raffia, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasanqua, seaberry, sage, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut and wheat germ oil. Synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil and mixtures thereof.

[0206] Examples of liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may include inert diluents commonly used in the art such as water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, peanut, corn germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments of parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymers, and mixtures thereof.

[0207] Injectable formulations, for example, sterile aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable formulations may be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Acceptable media and solvents that can be used include, inter alia, water, Ringer's solution, United States Pharmacopeia, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the manufacture of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by the inclusion of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0208] Sterile injectable compositions, such as sterile aqueous or oily suspensions, can be formulated by techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. Sterile injectable formulations can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Acceptable media and solvents that can be used are, inter alia, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Further, sterile, fixed oils can be used as a solvent or suspending medium (such as synthetic mono- or diglycerides). Natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms, fatty acids such as oleic acid and their glyceride derivatives are useful in the manufacture of injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants, such as Tween or Span or other similar emulsifying agents or bioavailability enhancers commonly used in the manufacture of solid, liquid, or other dosage forms of pharmaceutically acceptable drugs can also be used for the purpose of formulation.

[0209] To extend the effect of a drug, it is often desirable to delay drug absorption from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The rate of drug absorption then depends on its dissolution rate, which can depend on crystal size and crystal form. Alternatively, the absorption delay of a parenterally administered drug is achieved by dissolution or suspension of the drug in an oily medium.

[0210] Compositions for rectal or vaginal administration are typically suppositories that can be manufactured by mixing the conjugate of the present invention with a suitable non-irritating additive or carrier such as cocoa butter, polyethylene glycol, or suppository wax that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active ingredient.

[0211] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable additive or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicas, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0212] Similar types of solid compositions can be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be provided with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in a particular part of the intestinal tract, optionally in a delayed form. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0213] Oral pharmaceutical compositions include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain a bulking agent such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and, if desired, an active ingredient mixed with a stabilizer. In soft capsules, the compounds shown herein may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol. Further, a stabilizer may be added. The total formulation for oral administration must be in a dosage suitable for the chosen route of administration.

[0214] The tablet cores are provided with a suitable coating. For this purpose, a concentrated sugar solution can be used which may contain, if desired, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or tablet coatings for identification purposes or for the characterization of different combinations of active aminoglycoside compound dosages.

[0215] The active ingredient can be in microencapsulated form with one or more of the above additives. Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be provided with coatings and shells such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can, as is customary, contain additional substances other than the inert diluent, for example tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can contain buffering agents. Optionally, they can contain opacifying agents and can be compositions which release the active ingredient only or preferentially in a particular part of the intestinal tract, optionally in a delayed form. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0216] Dosage forms for topical and / or transdermal administration of the compounds of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Generally, the active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffer as required. Further, the present invention contemplates the use of transdermal patches which often have the additional advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be controlled, for example, by dissolution and / or dispersion of the active ingredient in a suitable medium. Alternatively or in addition thereto, the rate can be controlled by providing a rate controlling membrane and / or by dispersion of the active ingredient in a polymeric matrix and / or gel.

[0217] Suitable devices for use in intradermal delivery of the pharmaceutical compositions described herein include short needle devices such as those disclosed in U.S. Patent Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. The intradermal composition can be administered by a device that limits the effective penetration length of the needle into the skin, such as those described in PCT Publication WO99 / 34850 and its functional equivalents. A jet injection device that delivers a liquid vaccine to the dermis through a liquid jet syringe and / or a needle that produces a jet that penetrates the stratum corneum and reaches the dermis is suitable. Jet injection devices are described, for example, in U.S. Patent Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT Publications WO97 / 37705 and WO97 / 13537. A ballistic powder / particle delivery device that uses a compressed gas to accelerate a vaccine in powder form into the dermis through the outer layer of the skin is suitable. Alternatively or in addition thereto, a conventional syringe can be used in the classical Mantoux method of intradermal administration.

[0218] The pharmaceutical composition of the present invention can be manufactured, packaged and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may contain an active ingredient and may contain dry particles having a diameter in the range of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. Such a composition may be in the form of a dry powder for administration using a device that uses a dry powder reservoir where an aerosol stream can support the dispersion of the powder and / or a self-propelling solvent / powder dispersion container such as a device containing an active ingredient dissolved and / or suspended in a low-boiling aerosol in a sealed container. Such powders contain particles where at least 98% by weight of the particles have a diameter greater than 0.5 nanometers and at least 95% by number of the particles have a diameter less than 7 nanometers. Alternatively, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by number of the particles have a diameter less than 6 nanometers. The dry powder composition may contain a solid fine powder diluent such as sugar and is conveniently provided in unit dosage form.

[0219] Low-boiling aerosols generally include liquid aerosols having a boiling point of less than 65°F at atmospheric pressure. Generally, the aerosol may occupy 50 to 99.9% (w / w) of the composition and the active ingredient may occupy 0.1 to 20% (w / w) of the composition. The aerosol may further contain additional ingredients such as liquid non-ionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size comparable to that of the particles containing the active ingredient).

[0220] The pharmaceutical composition of the present invention formulated for pulmonary delivery provides the active ingredient in the form of droplets of a solution and / or a suspension. Such a formulation can be manufactured, packaged and / or sold as an aqueous and / or dilute alcoholic solution and / or suspension, optionally sterile, containing the active ingredient, and can be easily administered using any spraying and / or atomizing device. Such a formulation may further contain one or more additional ingredients including, but not limited to, flavoring agents such as sodium saccharin, volatile oils, buffering agents, surfactants and / or preservatives such as methyl hydroxybenzoate. The droplets provided by this route of administration can have an average diameter in the range of about 0.1 to about 200 nanometers.

[0221] The formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical composition of the present invention. Other formulations suitable for intranasal administration are coarse powders containing the active ingredient and having an average particle of about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal cavity from a powder container held near the nose.

[0222] Formulations for nasal administration can contain, for example, from a minimum of about 0.1% (w / w) to a maximum of 100% (w / w) of the active ingredient and can contain one or more of the additional ingredients described herein. The pharmaceutical composition of the present invention can be manufactured, packaged and / or sold in a formulation for buccal administration. Such a formulation can be manufactured, for example, using conventional methods and can be in the form of tablets and / or lozenges containing, for example, from 0.1 to 20% (w / w) of the active ingredient, the remainder being a composition that is orally soluble and / or degradable and optionally containing one or more of the additional ingredients described herein. Alternatively, the formulation for buccal administration can contain a powder and / or an aerosolized and / or atomized solution and / or suspension containing the active ingredient. Such powdered, aerosolized and / or atomized formulations can have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers when dispersed and can further contain one or more of the additional ingredients described herein.

[0223] The description of the pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to all types of animals. Modifications for making a pharmaceutical composition suitable for administration to humans into a composition suitable for administration to various animals are well understood, and those skilled in the veterinary pharmacology art can design and / or effect such modifications by routine experimentation.

[0224] The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. However, it is understood that the total daily usage of the compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular subject or organism depends upon a variety of factors including the disease, disorder or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and eating habits of the subject; the time of administration, route of administration and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination with or concurrently with the specific active ingredient employed; and like factors well known in the medical arts.

[0225] To practice the methods of the present invention, the above compounds or pharmaceutical compositions thereof can be administered by intravenous, intravitreal, intradermal, transdermal, intrathecal, intraarterial, intraperitoneal, intranasal, intravaginal, rectal, interosseous, periprosthetic, topical, intramuscular, subcutaneous, mucosal, intraosseous, periprosthetic, intrauterine, oral, topical, local, inhalation (e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion immersion directly into target cells, catheter, lavage, cream, lipid composition (e.g., liposome) or other methods or any combination of the foregoing (see, e.g., Remington’s Pharmaceutical Sciences, 2003, incorporated herein by reference). Generally, the most appropriate route of administration depends upon various factors including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0226] In certain embodiments, the pharmaceutical composition and / or additional agent is formulated for administration via the digestive route. The digestive route includes all possible routes of administration by which the composition comes into direct contact with the digestive tract. In particular, the pharmaceutical compositions disclosed herein can be administered orally, buccally, rectally or sublingually. That is, these compositions can be formulated with an inert diluent or an assimilable edible carrier or encapsulated in hard or soft shell gelatin capsules, compressed into tablets or sold as being directly incorporated into foods included in the diet.

[0227] In a further embodiment, the compositions described herein can be administered via a parenteral route. As used herein, the term "parenteral" includes routes that bypass the digestive tract. In particular, the pharmaceutical compositions disclosed herein can be administered, for example, intravenously, intradermally, intramuscularly, intraarterially, intrathecally, subcutaneously or intraperitoneally, but are not limited thereto.

[0228] According to one embodiment, administration is carried out orally. For oral administration, the compounds shown herein can be readily formulated by combining the compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compounds shown herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a patient. Pharmacological formulations for oral use can be manufactured by using solid additives, pulverizing the obtained mixture if desired, and treating the mixture of granules, if desired after addition of suitable auxiliaries, to obtain tablets or dragee cores. Suitable additives include, in particular, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrants such as crosslinked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0229] For buccal administration, the composition can take the form of tablets or lozenges formulated by conventional methods.

[0230] For inhaled administration, the compounds shown herein are conveniently delivered in the form of an aerosol spray presentation (typically containing a powdered, liquefied and / or gaseous carrier) from a pressurized pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be determined by the provision of a valve to deliver a metered amount. Gelatin capsules and cartridges for use in, for example, inhalers or insufflators can be formulated containing a powder mixture of the compounds shown herein and a suitable powder base, such as, but not limited to, lactose or starch.

[0231] For administration by injection, the compounds shown herein can be formulated in an aqueous solution, such as Hank's solution, Ringer's solution or physiological saline buffer, with or without an organic solvent such as propylene glycol, polyethylene glycol, preferably in a physiologically compatible buffer.

[0232] The pharmaceutical composition for topical administration may include compositions formulated for pharmaceutical applications such as ointments, pastes, creams or powders. Ointments include all oily, adsorptive, emulsion and water-soluble base compositions for topical application, while creams and lotions can be compositions containing only an emulsion base. Topical pharmaceutical agents may include penetration enhancers to promote the adsorption of active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohol, alkyl methyl sulfoxide, pyrrolidone and laurocapram. Possible bases for the composition for topical application include polyethylene glycol, lanolin, cold cream and petrolatum and any other suitable absorbent, emulsion or water-soluble ointment base. Topical formulations may also include emulsifiers, gelling agents and antimicrobial preservatives as needed to protect the composition and provide a homogeneous mixture. Transdermal administration of the composition may also include a "patch". For example, the patch may supply one or more compositions continuously at a predetermined rate for a certain period of time.

[0233] In certain embodiments, the composition may be delivered by eye drops, intranasal sprays, inhalation and / or other aerosol delivery media. Methods for delivering the composition directly to the lungs via a nasal aerosol spray are described in U.S. Patents 5,756,353 and 5,804,212 (each incorporated herein by reference in its entirety). Similarly, drug delivery using intranasal microparticle resins (Takenaga et al., 1998) and lysophosphatidyl-glycerol compounds (U.S. Patent 5,725,871, incorporated herein by reference in its entirety) is also well known in the pharmaceutical art and can be used for the delivery of the compositions described herein. Similarly, transmucosal drug delivery in the form of a polytetrafluoroethylene support matrix is described in U.S. Patent 5,780,045 (incorporated herein by reference in its entirety) and can be used for the delivery of the compositions described herein.

[0234] It is further contemplated that the compositions disclosed herein can be delivered via an aerosol. The term aerosol refers to a colloidal system of micronized solid or liquid particles dispersed in a liquefied or pressurized gas propellant. Typical inhalation aerosols consist of a suspension of the active ingredient in a liquid propellant or a mixture of a liquid propellant and a suitable solvent. Suitable propellants include hydrocarbons and hydrocarbon ethers. Suitable containers vary with the pressure required by the propellant. Administration of the aerosol varies depending on the age, weight of the subject, as well as the severity and response of the symptoms.

[0235] For transmucosal administration, penetration enhancers are used in the formulation. Such penetration enhancers are generally known in the art.

[0236] The compounds shown herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Injectable formulations can be provided, for example, in unit dosage forms in ampoules or in multiple-dose containers with added preservatives as desired. The composition can be a suspension, solution or emulsion in an oily or aqueous medium and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.

[0237] Alternatively, the compounds shown herein can be in powder form for constitution with a suitable medium, for example, sterile, pyrogen-free water, before use.

[0238] The exact amount of the compound required to achieve an effective amount varies for each subject depending on, for example, the species, age and general condition of the subject, the severity of side effects or disorders, the identity of the particular compound, the method of administration, etc. The desired dosage can be delivered once daily, twice daily, three times daily, every other day, every three days, weekly, every two weeks, every three weeks or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0239] In certain embodiments, the effective amount of the compound for once-daily or more administration to a 70 kg adult may range from about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg per unit dosage form.

[0240] In certain embodiments, the compounds of the invention may be administered orally or parenterally once-daily or more at dosage levels sufficient to deliver to the subject body weight from about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg per day to obtain the desired therapeutic effect.

[0241] It is recognized that the dosage ranges described herein provide guidance for the administration of pharmaceutical compositions provided to adults. For example, the amount administered to a pediatric or adolescent can be determined by a healthcare provider or one of ordinary skill in the art and can be lower than or the same as that administered to an adult.

[0242] It is also recognized that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents. The compounds or compositions can be administered in combination with additional therapeutically active agents that improve bioavailability, decrease and / or modify metabolism, block excretion, and / or modify body distribution. It is also recognized that the treatments used can exert desired effects and / or different effects on the same disorder.

[0243] A compound or composition can be administered simultaneously with, before, or after one or more additional therapeutic agents. Generally, each agent is administered at the dosage and / or time schedule determined for that agent. Further, it is recognized that the additional therapeutic agents utilized in this combination can be administered together as a single composition or separately in different compositions. The particular combination used in a regimen takes into account the compatibility of the compounds of the invention with the additional therapeutic agents and / or the desired therapeutic effect to be achieved. Generally, it is expected that the additional therapeutic agents used in combination are used at levels that do not exceed those at which they are used individually. In certain embodiments, the levels used in combination are lower than those used individually. The additional therapeutic agents include antibiotics, for example, antibiotics useful in the treatment of tuberculosis. Examples of antibiotics include, but are not limited to, isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

[0244] The present invention also includes kits (e.g., pharmaceutical packs). The kits provided can include a pharmaceutical composition or compound of the present invention and a container (e.g., vial, ampule, bottle, syringe, and / or dispenser package or other suitable container). In certain embodiments, the kits provided can further optionally include a second container containing pharmaceutical additives for dilution or suspension of the pharmaceutical composition or compound of the present invention. In certain embodiments, the pharmaceutical composition or compound of the present invention provided in the container and the second container together form one unit dosage form.

Examples

[0245] The following examples are provided so that the present invention described herein can be more fully understood. The synthetic and biological examples described in this specification are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting the scope in any way.

[0246] Table 1 is a list of the intermediates used in the preparation of the example compounds.

Table 78

Table 79

[0247] Intermediate Scheme 1

Chem.

[0248]

Chem.

[0249]

Chem.

[0250] tert-Butyl 4-(D-threonyl)piperazine-1-carboxylate (I4). IS1-1 (766 mg, 1.03 mmol) was dissolved in anhydrous EtOH (12 mL), and the reaction mixture was evacuated and backfilled with nitrogen (3 times). 5% Pd / C (109 mg, 0.05 mmol) was added, and the reaction mixture was evacuated and backfilled with nitrogen (3 times). Then, the reaction mixture was evacuated and backfilled with hydrogen (3 times), and stirred at room temperature (rt) for 1.5 h under a hydrogen atmosphere (balloon). The reaction mixture was evacuated and backfilled with nitrogen (5 times). Celite® was added to the reaction mixture, stirred for 5 min, filtered through a Celite® pad moistened with MeOH and rinsed with MeOH, and concentrated. The crude material was dissolved in dichloromethane and filtered through a syringe filter to give the crude product. MS (ESI+) m / z: 288.03 [M + H]+, 1 1H NMR (400 MHz, chloroform-d) δ 3.86 (td, 1H), 3.79 (s, 10H), 1.47 (s, 9H), 1.18 (d, 3H).

[0251]

Chem.

[0252] tert-Butyl 4-((2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutyl)piperazine-1-carboxylate (IS1-2). In an oven-dried three-necked flask equipped with a reflux condenser, IS1-1 (1.25 g, 2.96 mmol) was dissolved in dry THF (29 mL, 0.1 M) and cooled to 0 °C under nitrogen. 1 M borane·THF complex (8.8 mL, 8.8 mmol) was added dropwise over 11.5 minutes while maintaining a temperature below 3.5 °C. A slight evolution of gas was observed. The reaction mixture was stirred for 6 minutes, the ice bath was removed, then the reaction mixture was warmed to 16.5 °C and then heated at 65 °C for 2 hours. The reaction mixture was cooled in an ice bath and quenched slowly by the addition of MeOH (7 mL). The reaction mixture was diluted with additional MeOH and concentrated (3 times). The residue was dissolved in MeOH (50 mL) and heated for about 1 hour until gently refluxing, and then concentrated. The crude product was purified by silica gel chromatography eluting with 20% MeOH in dichloromethane + 0.5% NH 4 OH / CH 2 Cl 2 (0 - 60% gradient) to give a white foam (766 mg). MS (ESI+) m / z: 408.13 [M + H]+, 1 H NMR (400 MHz, chloroform-d) δ 7.44 - 7.29 (m, 5H), 5.24 (d, 1H), 5.11 (s, 2H), 4.05 (qd, 1H), 3.65 (d, 1H), 3.48 - 3.31 (m, 4H), 2.71 (dd, 1H), 2.56 - 2.46 (m, 3H), 2.42 (dt, 2H), 1.45 (s, 9H), 1.18 (d, 3H). [Chemical Structure] I5

[0253] tert-Butyl 4-((2S,3S)-2-amino-3-hydroxybutyl)piperazine-1-carboxylate (I5).

[0254] IS1-2 (766 mg, 1.87 mmol) was dissolved in anhydrous EtOH (20 mL), and the reaction mixture was evacuated and backfilled with nitrogen (3 times). 5% Pd / C (200 mg, 0.94) was added, and the reaction mixture was evacuated and backfilled with nitrogen (3 times). The reaction mixture was evacuated and backfilled with hydrogen (3 times), and stirred at rt under a hydrogen atmosphere (balloon) for 1.5 h and heated at 45 °C for 1 h. The reaction mixture was cooled to rt, evacuated, and backfilled with nitrogen (5 times). Celite® was added to the reaction mixture, stirred for 5 min, filtered through a Celite® pad moistened with MeOH and rinsed with MeOH, and concentrated to obtain the crude product. MS (ESI+) m / z: 274.08 [M + H]+, 1 H NMR (400 MHz, chloroform-d) δ 7.41 - 7.33 (m, 0H), 3.56 (qd, 1H), 3.50 - 3.34 (m, 4H), 2.93 - 2.78 (m, 1H), 2.48 (d, 3H), 2.43 - 2.28 (m, 3H), 1.45 (s, 10H), 1.17 (d, 3H).

[0255] Intermediate Scheme 2

Chemical Structure

Chemical Structure

[0256] (R)-2-((tert-Butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid (IS2-2). The oven-dried flask was evacuated and backfilled with nitrogen (twice), then cooled to rt. 10% Pd / C (50% wet, 7.96 g, 3.74 mmol) was added to the flask, which was evacuated and backfilled with nitrogen (twice). Glacial acetic acid (32 mL) was added to the reaction mixture, which was evacuated and backfilled with nitrogen (twice). N-Boc-D-pyridylalanine (5 g, 18.7 mmol) was added, followed by glacial acetic acid (5 mL). The reaction mixture was evacuated and backfilled with nitrogen (twice), then evacuated and backfilled with hydrogen (four times). The reaction mixture was heated to 60 °C and stirred under a hydrogen balloon for 15 h. The reaction mixture was cooled to rt, evacuated, and backfilled with nitrogen (four times). Celite® was added, and the reaction mixture was stirred for about 15 min, then filtered through a Celite® pad while washing with MeOH. The reaction mixture was concentrated and then reconcentrated from MTBE to give a clear gum. The material was used without further purification. MS (ESI+) m / z: 273.07 [M + H]+.

[0257] [Chemical formula] IS2-3

[0258] (R)-3-(1-((Benzyloxy)carbonyl)piperidin-4-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (IS2-3). Crude IS2-2 (4.15 g, 15.2 mmol) was dissolved in THF (30 mL), and saturated NaHCO 3 aqueous solution (20 mL) was added. The reaction mixture was cooled to 0 °C, and N-(benzyloxycarbonyloxy)succinimide (4.16 g, 16.7 mmol) was added. The reaction mixture was stirred for 11 min, the ice bath was removed, and the reaction mixture was stirred at room temperature. When complete, the reaction mixture was cooled in an ice bath, and 1N HCl (about 50 mL) was slowly added until the foaming ceased, and the solution was adjusted to pH 2 - 3. The reaction mixture was extracted with MTBE (25 mL × 3). The combined extracts were washed with 1N HCl (20 mL × 2), water (40 mL), and brine (40 mL), and MgSO 4It was dried, filtered, and concentrated. The substance was purified by 80 g of silica gel (dichloromethane / EtOAc + 1% AcOH gradient: 0 - 100%) to obtain the title compound (2.3 g, 37%, 2 steps). MS (ESI+) m / z: 429.09 [M + Na]+. 1 H NMR (400 MHz, chloroform - d) δ 7.42 - 7.28 (m, 5H), 5.14 (s, 2H), 4.95 (d, 1H), 4.44 - 4.32 (m, 1H), 4.30 - 4.07 (m, 2H), 2.89 - 2.66 (m, 2H), 1.91 - 1.51 (m, 5H), 1.46 (s, 9H), 1.27 - 1.06 (m, 2H).

[0259] [Chemical formula] I7

[0260] Benzyl (R)-4-(2 - amino - 3 - hydroxypropyl)piperidine - 1 - carboxylate (I7). In an oven - dried flask, the crude IS2 - 3 (2.3 g, 5.65 mmol) was concentrated from dry toluene (10 mL), and dry THF (12 mL) was added to N 2It was dissolved below and cooled to 0 °C. Trimethyl borate (1.37 mL, 12.4 mmol) was added and the reaction mixture was stirred for about 7 minutes. Borane dimethyl sulfide complex (0.80 mL, 8.47 mmol) was added dropwise via syringe over about 4 minutes such that the temperature did not exceed 3 °C. The reaction mixture was stirred for 10 minutes, the ice bath was removed, and the reaction mixture was stirred at rt for 5.5 hours. The reaction mixture was cooled to 0 °C, additional trimethyl borate (0.7 mL) and borane dimethyl sulfide (0.4 mL) were added, and the reaction mixture was warmed to rt over 1.5 h. The reaction mixture was cooled to 0 °C and methanol (10 mL) was added dropwise over 15 minutes while maintaining a temperature below 10 °C. The ice bath was removed, the reaction mixture was stirred for 30 minutes and concentrated. The resulting clear oil was dissolved in methanol again (about 50 mL), concentrated (twice), and then placed under high vacuum for about 20 minutes. The residue was partitioned between 1N HCl (30 mL) and MTBE (25 mL). The aqueous layer was extracted with MTBE (25 mL × 2). The aqueous layer was basified with saturated NaHCO 3 aqueous solution (pH about 8.5) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated. MS (ESI+) m / z: 293.01 [M + H]+. 1 H NMR (400 MHz, chloroform-d) δ 7.31 - 7.24 (m, 2H), 7.24 - 7.20 (m, 1H), 7.20 - 7.11 (m, 1H), 7.11 - 7.01 (m, 1H), 5.03 (s, 2H), 4.18 - 3.96 (m, 2H), 3.47 (dd, 1H), 3.16 (ddd, 1H), 2.84 (tt, 1H), 2.78 - 2.57 (m, 2H), 1.67 - 1.41 (m, 3H), 1.27 - 0.88 (m, 4H).

[0261] Intermediate Scheme 3.

Chemical Structure

[0262] [Chemical formula] IS3-2

[0263] tert-Butyl ((1r,3r)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclobutyl)carbamate (IS3-2). To a solution of 2-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)acetic acid (IS3-1, 1.1 g, 4.8 mmol) in dichloromethane (20 mL) were added methyloxy(methyl)amine hydrochloride (0.70 g, 7.2 mmol), N,N-diisopropylethylamine (4.15 mL, 24.0 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (2.73 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into 1 M NaOH and stirred vigorously for 10 min. The organic layer was separated and washed with 2 N HCl (twice), water (once), and brine (once). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (80 g silica gel column, 0 - 50% EtOAC / Hex) to give the title compound as a white powder (1.19 g, 4.4 mmol, 92%). MS (ESI+) m / z: [M + Na]+ 295.2.

[0264] [Chemical formula] IS3-4

[0265] tert-Butyl ((1R,3r)-3-((E)-2-(((R)-tert-butylsulfinyl)imino)propyl)cyclobutyl)carbamate (IS3-4). A solution of IS3-2 (1.19 g, 4.4 mmol) in THF (20 mL) was cooled to -40 °C, and Red-Al (1.83 mL, 70 wt% in toluene, 5.7 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 h. Ethyl acetate and saturated aqueous potassium sodium tartrate solution (Rochelle salt) were added, and the mixture was stirred vigorously for 2 h. The organic layer was separated, washed with brine (once), dried over sodium sulfate, filtered, and concentrated to give anhydrous IS3-3 as a clear oil. IS3-3 (0.96 g, 4.5 mmol) was dissolved in toluene (9 mL), (S)-2-methylpropane-2-sulfinamide (0.545 g, 4.5 mmol) was added, followed by copper(II) sulfate (2.15 g, 13.5 mmol). The reaction mixture was stirred at rt for 18 h, filtered through Celite® and eluted with ethyl acetate. The filtrate was concentrated and purified by column silica gel chromatography (24 g, 0 - 70% EtOAc / Hex) to give the title compound (0.53 g, 1.67 mmol, 37%). 1 H NMR (400 MHz, chloroform-d) δ 7.99 (t, 1H), 4.71 (s, 1H), 4.24 (s, 1H), 2.70 (dd, 2H), 2.65 - 2.51 (m, 1H), 2.23 - 1.98 (m, 4H), 1.43 (d, 10H), 1.18 (d, 9H).

[0266]

Chemical Structure

[0267] tert-Butyl ((1S,3R)-3-((R)-2-(((S)-tert-butylsulfinyl)amino)but-3-en-1-yl)cyclobutyl)carbamate (IS3-5). ZnCl 2A solution (2.63 mL, 1.9 M in MeTHF, 5.01 mmol) was added to dry THF (3.34 mL) and cooled to -78 °C. A methyl lithium solution (3.22 mL, 3.1 M in DME, 10 mmol) was slowly added while maintaining the internal reaction temperature at -65 °C. The mixture was stirred for 10 minutes, and a vinyl magnesium chloride solution (3.22 mL, 1.6 M in THF, 3.13 mmol) was slowly added while maintaining the internal reaction temperature at -65 °C. The mixture was stirred for 5 minutes. A solution of IS3-4 (0.53 g, 1.67 mmol) in THF (1 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes. Acetic acid (0.5 mL) was slowly added, the bath was removed, and the reaction mixture was warmed to rt over 20 minutes. Half-saturated (sat.) NH 4 Cl aqueous solution was added, followed by MTBE. The layers were separated, the aqueous layer was extracted with MTBE (twice), and the combined extracts were dried over Na 2 SO 4 filtered, and concentrated. The crude material was purified by column chromatography (12 g silica gel column, 0 - 50% EtOAC / Hex) to give the title compound as a white powder (0.366 g, 1.06 mmol, 64%). 1 H NMR (400 MHz, chloroform-d) δ 5.61 (dddd, 1H), 5.22 - 5.08 (m, 2H), 4.73 (s, 1H), 4.10 (s, 1H), 3.76 - 3.67 (m, 1H), 3.06 (d, 1H), 2.41 - 2.26 (m, 1H), 2.13 - 1.92 (m, 4H), 1.74 (td, 2H), 1.42 (s, 9H), 1.19 (d, 9H).

[0268]

Chemical Structure

[0269] Benzyl ((R)-1-((1r,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)but-3-en-2-yl)carbamate (IS3-7). Concentrated HCl (0.1 mL, 1.27 mmol) was added to a solution of IS3-5 (0.366 g, 1.06 mmol) in THF / water (5:2, 2.8 mL), and the reaction mixture was stirred at room temperature for 18 h. Saturated NaHCO 3 aqueous solution (3 mL) was added, followed by N-(benzyloxycarbonyloxy)succinimide (0.276 g, 1.11 mmol). The reaction mixture was stirred at room temperature for 1 h and extracted with EtOAc (twice). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by column silica gel chromatography (12 g, 0 - 70% EtOAc / Hex) to give the title compound as a white powder (0.31 g, 0.83 mmol, 78%). MS (ESI+) m / z: 397.31 [M + Na]+; 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.30 (m, 5H), 5.73 (ddd, 1H), 5.18 - 5.04 (m, 4H), 4.63 (d, 2H), 4.12 (s, 2H), 2.28 (s, 1H), 2.06 (s, 2H), 1.97 (s, 2H), 1.74 - 1.59 (m, 2H), 1.43 (s, 9H).

[0270]

Chemical Structure

[0271] Benzyl ((R)-1-((1r,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-hydroxypropan-2-yl)carbamate (IS3-8). IS3-7 (0.31 g, 0.827 mmol) was dissolved in methanol (16.5 mL) and cooled to -78 °C. An ozone stream (7 PSI, 2 LPM) was bubbled through the reaction for 8 min, at which point a slight blue coloration was observed. The ozone stream was removed, and then nitrogen was bubbled through the solution for 5 min (blue color disappeared). Sodium borohydride (77.1 mg, 2.04 mmol) was added, the reaction mixture was removed from the bath, and warmed to room temperature for 30 min. Saturated NH4 The reaction was quenched with an aqueous Cl solution and extracted with dichloromethane (3 times). The combined extracts were dried over Na 2 SO 4 and filtered, then concentrated under reduced pressure. The substance was purified by column silica gel chromatography (12 g, 0 - 70% EtOAc / Hex) to obtain the title compound as a white foam (0.265 g, 0.7 mmol, 85%). MS (ESI+) m / z: 401.09 [M + Na]+; 1 1H NMR (400 MHz, chloroform - d) δ 7.44 - 7.30 (m, 5H), 5.09 (s, 2H), 4.82 (s, 1H), 4.69 (s, 1H), 4.22 - 4.09 (m, 1H), 3.67 (s, 2H), 3.55 (s, 1H), 2.28 (s, 1H), 2.06 (d, 2H), 1.99 (s, 3H), 1.74 - 1.60 (m, 2H), 1.43 (s, 9H).

[0272]

Chemical Structure

[0273] tert - Butyl ((1S,3r)-3-((R)-2 - amino - 3 - hydroxypropyl)cyclobutyl)carbamate (I8). The IS3 - 8 solution (265 mg, 0.7 mmol) was dissolved in methanol (3 mL), and Pd / C (74.3 mg, 5 wt% on carbon, 0.5 mol%) was added. A hydrogen balloon was bubbled through the reaction mixture for 0.5 h. The reaction mixture was filtered through Celite® and eluted with methanol, and the filtrate was concentrated under reduced pressure to obtain I8 as a transparent oil (171 mg, 0.7 mmol, 100%). MS (ESI+) m / z: 245.08 [M + Na]+; 1 1H NMR (400 MHz, methanol - d 4) δ 4.13 - 4.01 (m, 1H), 3.64 (dd, 1H), 3.42 (dd, 1H), 2.97 (dt, 1H), 2.39 - 2.23 (m, 1H), 2.16 - 1.95 (m, 4H), 1.69 (ddt, 2H), 1.43 (s, 9H).

[0274] Intermediate Scheme 4

Chem.

[0275]

Chem.

[0276]

Chem.

[0277] A solution of compound IS4-1 (4.5 g, 11.5 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (100 mL) was added dropwise to a suspension of LiAlH 4 (1.0 M solution in THF, 48.3 mL, 48.3 mmol, 4.2 equiv) in anhydrous THF (57.4 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 0.5 h and then warmed to rt for 1 h. The mixture was quenched by careful addition of water (2 mL), 3 N NaOH solution (2.5 mL), and then water (5.5 mL). The mixture was dried over MgSO 4 and the precipitate was removed by filtration. The precipitate was washed with EtOAc and the combined filtrates were concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0.5% NH 4 OH-containing DCM solution of 0 - 20% MeOH. This gave 2.81 g (89%) of compound IS4-2. 1 1H NMR (400 MHz, chloroform-d) δ 5.29 (s, 1H), 3.61 - 3.50 (m, 3H), 3.45 (t, 2H), 3.39 (t, 2H), 2.44 - 2.24 (m, 2H), 2.01 - 1.90 (m, 3H), 1.90 - 1.76 (m, 3H), 1.42 (s, 9H).

[0278]

Chem.

[0279] (R)-2-Amino-5-(pyrrolidin-1-yl)pentan-1-ol hydrochloride (IS4-3) Compound IS4-2 (2.98 g, 10.9 mmol, 1.0 equiv) was dissolved in MeOH (20 mL), and HCl (4 M solution in dioxane, 8.15 mL, 32.6 mmol, 3.0 equiv) was added at rt. The reaction mixture was stirred at rt for 2 h, at which point UPLC indicated completion of the conversion. The reaction mixture was concentrated under reduced pressure to give 2.85 g (108% crude yield) of IS4-3. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.99 (s, 2H), 5.33 (s, 1H), 3.63 - 3.54 (m, 1H), 3.54 - 3.41 (m, 3H), 3.15 - 3.02 (m, 3H), 3.02 - 2.86 (m, 2H), 2.04 - 1.93 (m, 2H), 1.93 - 1.81 (m, 2H), 1.81 - 1.68 (m, 2H), 1.67 - 1.47 (m, 2H).

[0280]

Chem.

[0281] (R)-2-Amino-5-(pyrrolidin-1-yl)pentan-1-ol (I-10). MeOH (1 L) was added to Amberlyst A26(OH) (1 kg, >0.8 eq / L) under a mechanical stirrer, and the mixture was stirred for 30 minutes. The solvent was removed by filtration, and the same series of operations was repeated 4 times. Compound 3 (117.8 g, 483 mmol, 1.0 equiv) was dissolved in MeOH (700 mL) and added to the washed resin at rt. The reaction mixture was stirred at rt for 30 minutes. The solution was collected, and after filtration, the resin was washed 3 times with MeOH (700 mL) as before until it was shown by UPLC that no desired product was present in the solution. The organic solutions were combined and concentrated under reduced pressure to give 81.1 g (97% crude yield) of the free base of I-10 as a yellow oil. 1 H NMR (400 MHz, CDCl 3 -d) δ 3.57 (dd, 1H), 3.30 (dd, 1H), 2.84 (dtd, 1H), 2.58 - 2.41 (m, 6H), 1.78 (h, 5H), 1.70 - 1.41 (m, 3H), 1.40 - 1.26 (m, 1H).

[0282] Intermediate Scheme 5

Chem.

[0283]

Chem.

[0284] [Chemical formula] IS5-2

[0285] tert-Butyl ((1r,3r)-3-(2-oxopropyl)cyclobutyl)carbamate (IS5-2). At -30 °C, a solution of methylmagnesium chloride (1 M in THF, 17.1 mL, 51.4 mmol) was added to a solution of Weinreb amide IS5-1 (5.9 g, 21.6 mmol) in THF (51.4 mL). The reaction mixture was stirred at -10 °C for 30 min. Quenched with NH 4 Cl and the crude mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO 4 and concentrated. The crude mixture was purified by ISCO to give IS5-2 (3.07 g, 13.5 mmol, 64%). MS (ESI+) m / z: 250.04 [M + Na]+; 1 H NMR (400 MHz, chloroform-d) δ 4.71 (s, 1H), 4.19 (s, 1H), 2.64 (s, 2H), 2.59 (m, 1H), 2.11 (s, 3H), 2.06 (m, 4H), 1.43 (s, 9H).

[0286] [Chemical formula] IS5-3

[0287] tert-Butyl ((1R,3r)-3-((E)-2-(((R)-tert-butylsulfinyl)imino)propyl)cyclobutyl)carbamate (IS5-3). To a solution of ketone IS5-2 (2.9 g, 12.7 mmol) and (R)-2-methylpropan-2-sulfinamide (3.07 g, 25.4 mmol) in THF (25.4 mL) was added titanium ethoxide (5.32 mL, 25.4 mmol). The reaction mixture was heated at 70 °C for 24 h. THEED (8.97 g, 38 mmol) was added and the mixture was allowed to cool freely to 20 °C. The reaction mixture was partitioned between 1N ammonium hydroxide (150 mL) and ethyl acetate (150 mL). Some solids were removed by filtration through a small pad of Celite®. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by ISCO to give IS5-3 (3 g, 9.07 mmol, 71%). MS (ESI+) m / z: 353.02 [M + Na]+.

[0288] [Chemical formula] IS5-4

[0289] tert-Butyl ((1R,3r)-3-((S)-2-(((R)-tert-butylsulfinyl)amino)-2-methylpent-4-en-1-yl)cyclobutyl)carbamate (IS5-4). To a solution of imine IS5-3 (3g, 9.07 mmol) in dichloromethane (18.1 mL) was slowly added allylmagnesium bromide (1 M in diethyl ether, 18.1 mL, 18.1 mmol) at -20 °C at a rate such that the precipitation of salts was not hindered by stirring. The mixture was warmed to 0 °C for 1 h and then quenched with saturated aqueous ammonium chloride (50 mL). The organics were separated and concentrated. The residue was purified by ISCO to give IS5-4 (2.14 g, 5.74 mmol, 64%). MS (ESI+) m / z: 395.08 [M + Na]+. 1 H NMR (400 MHz, chloroform-d) δ 5.80 (ddt, 1H), 5.18 - 5.05 (m, 2H), 4.74 (s, 1H), 3.17 (s, 1H), 2.52 - 2.39 (m, 1H), 2.35 - 2.23 (m, 2H), 2.06 (s, 2H), 1.73 (dd, 2H), 1.59 (s, 3H), 1.43 (s, 9H), 1.22 (s, 3H), 1.18 (s, 9H).

[0290]

Chemical formula

[0291] tert-Butyl ((1R,3r)-3-((S)-2-(((benzyloxy)carbonyl)amino)-2-methylpent-4-en-1-yl)cyclobutyl)carbamate (IS5-5). A solution of sulfinamide IS5-4 (2.14 g, 5.74 mmol) in THF / water (5:2 vol / vol, 14.5 mL) was added to concentrated HCl (0.56 mL, 6.88 mmol), and the reaction mixture was stirred at room temperature for 18 h. Saturated NaHCO 3An aqueous solution (10 mL) was added, followed by N-(benzyloxycarbonyloxy)succinimide (1.5 g, 6.02 mmol). The reaction mixture was stirred at room temperature for 1 hour and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO to give IS5-5 (1.94 g, 84%, 4.81 mmol) as a white powder. MS (ESI+) m / z: 425.14 [M + Na]+; 1 H NMR (400 MHz, chloroform-d) δ 7.42 - 7.29 (m, 5H), 5.75 (ddt, 1H), 5.10 (dd, 2H), 5.04 (s, 2H), 4.78 - 4.69 (m, 1H), 4.56 (s, 1H), 4.09 (s, 1H), 2.46 (m, 2H), 2.26 (dd, 1H), 2.07 (d, 4H), 1.78 (dd, 1H), 1.45 (s, 9H), 1.20 (s, 3H).

[0292]

Chemical Structure

[0293] tert-Butyl ((1S,3R)-3-((R,E)-2-(((benzyloxy)carbonyl)amino)-2-methylpent-3-en-1-yl)cyclobutyl)carbamate (IS5-6). To a solution of alkene IS5-5 (1.85 g, 4.59 mmol) in EtOH / water (9:1 vol / vol, 18.5 mL) was added rhodium(III) chloride hydrate (181 mg, 0.688 mmol). The reaction mixture was heated at 50 °C for 2.5 hours, 1 and 1H NMR confirmed complete conversion to the desired product. The reaction was concentrated and purified by ISCO to give IS5-6 (0.64 g, 1.58 mmol, 35%). MS (ESI+) m / z: 425.14 [M + Na]+; 11H NMR (400 MHz, chloroform-d) δ 7.44 - 7.29 (m, 5H), 5.49 (s, 1H), 5.05 (s, 2H), 4.72 (d, 2H), 4.07 (s, 1H), 2.36 (p, 1H), 2.09 - 1.87 (m, 4H), 1.69 (t, 2H), 1.60 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H).

[0294]

Chem.

[0295] tert-Butyl ((1S,3R)-3-((R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxy-2-methylpropyl)cyclobutyl)carbamate (IS5-7). To a solution of alkene IS5-6 (0.64 g, 1.58 mmol) in methanol (32 mL) under stirring, ozone gas was passed at -78 °C until the color of the reaction turned blue. Then, it was purged with nitrogen for 5 minutes until the color became colorless. Sodium borohydride (119 mg, 3.16 mmol) was added and the reaction was stirred at -78 °C. After 60 minutes, the reaction was considered complete by TLC (a certain amount was quenched with NH 4 Cl and extracted with MTBE). The reaction was quenched with saturated NH 4 Cl aqueous solution at about -70 to 50 °C. MTBE was added and the reaction mixture was warmed to room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by ISCO to obtain IS5-7 (0.28 g, 45%). MS (ESI+) m / z: 415.12 [M + Na]+.

[0296]

Chem.

[0297] tert-Butyl ((1S,3R)-3-((R)-2-amino-3-hydroxy-2-methylpropyl)cyclobutyl)carbamate (I-11). The reaction mixture, which is a solution of Cbz-amino alcohol IS5-7 (278 mg, 0.71 mmol) in methanol (2 mL) and Pd / C (10% wt, 75.3 mg, 0.071 mmol), was bubbled with hydrogen for 15 minutes and stirred for 1 hour under a hydrogen atmosphere. Upon completion, the mixture was filtered through Celite® using ethyl acetate, and the filtrate was concentrated to obtain amino alcohol I-11 (180 mg, 0.7 mmol, 99%) as a clear oil. The crude material was used in the next step without further purification. MS (ESI+) m / z: 259.13 [M + H]+.

[0298] Intermediate Scheme 6

Chemical Structure

[0299]

Chemical Structure

[0300]

Chem.

[0301] tert-Butyl (R)-4-(3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (IS6-2). A solution of compound IS6-1 (41.6 g, 189 mmol, 1.0 equiv) in anhydrous methylene chloride (240 mL) was added to 2,2-dimethoxypropane (231 mL, 1.89 mol, 10 equiv) at 25 °C. Then, TsOH·H 2 O (3.59 g, 18.9 mmol, 0.1 equiv) was added all at once. The reaction mixture was stirred at 25 °C for 4 h. The mixture was partitioned between EtOAc and saturated NaHCO 3 aqueous solution. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The mixture was purified by silica gel chromatography (40% EtOAc in heptane solution) to give 20.13 g (41% over 2 steps) of compound IS6-2. 1 1H NMR (400 MHz, chloroform-d) δ 4.04 - 3.91 (m, 2H), 3.79 - 3.63 (m, 4H), 1.68 - 1.54 (m, 4H), 1.49 (s, 15H).

[0302]

Chem.

[0303] tert-Butyl (R)-2,2-dimethyl-4-(3-oxopropyl)oxazolidine-3-carboxylate (IS6-3). To a solution of compound IS6-2 (20.13 g, 77.5 mmol, 1.0 equiv) in DCM (155 mL), DMSO (44.0 mL, 620 mmol, 8.0 equiv) was added, followed by Hunig's base (53.9 mL, 310 mmol, 4.0 equiv), and the mixture was cooled to 0 °C. To this mixture, SO 3· Pyr (24.6 g, 155 mmol, 2.0 eq) was added portionwise while maintaining the internal temperature below 5 °C. The reaction mixture was stirred at 0 - 5 °C for 1 h. MTBE and brine (500 mL + 500 mL) were added to this batch and each was shaken for about 10 - 15 min. The organic layer was separated and washed with brine (4 times). The final organic layer was dried over sodium sulfate and concentrated to obtain the crude product IS6-3, which was used in the next step without further purification.

[0304]

Chem.

[0305] tert-Butyl (R)-4-(3-(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propyl)-2,2-dimethyloxazolidine-3-carboxylate (IS6-4). To a solution of compound IS6-3 (19.9 g, 77.3 mmol, 1.0 eq) in DCM (154 mL) was added compound A (12.5 g, 92.7 mmol, 1.2 eq), followed by AcOH (4.85 mL, 85.0 mmol, 1.1 eq), and the mixture was cooled to 0 °C. To this mixture, NaBH(OAc) 3 (24.3 g, 115 mmol, 1.5 eq) was added portionwise while maintaining the internal temperature below 5 °C. The reaction mixture was stirred at 25 °C for 16 h. Saturated NaHCO 3 aqueous solution was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with DCM (3 times). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The mixture was purified by silica gel chromatography (0 - 3 - 5% MeOH in 0.5% NH 4 OH-containing DCM solution) to obtain 28.32 g (97.2% yield) of compound IS6-4.

[0306]

Chem.

[0307] (R)-2-Amino-5-(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pentan-1-ol hydrochloride (IS6-5). Compound IS6-4 (28.32 g, 75.1 mmol, 1.0 equiv) was dissolved in MeOH (150 mL), and HCl (4 M solution in dioxane, 93.7 mL, 375 mmol, 5.0 equiv) was added at rt. The reaction mixture was stirred at rt for 4 h, at which point UPLC indicated completion of the conversion. The reaction mixture was concentrated under reduced pressure to afford 22.9 g (100% crude yield) of compound IS6-5.

[0308] [Chemical formula] I-12

[0309] (R)-2-Amino-5-(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pentan-1-ol (I-12). Amberlyst A26(OH) (200 g, >0.8 eq / L) was added to MeOH (500 mL) under a mechanical stirrer, and the mixture was stirred for 30 min. The solvent was removed by filtration, and the same series of operations was repeated 4 times. Compound 5 (22.9 g, 1.0 equiv) was dissolved in MeOH (500 mL) and added to the washed resin at rt. The reaction mixture was stirred at rt for 30 min. The solution was collected and, after filtration, the resin was washed 3 times with MeOH (500 mL) as before until UPLC indicated that the desired product was not present in the solution. The organic solutions were combined and concentrated under reduced pressure to afford the free base (16.97 g, 96.0% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (s, 1H), 8.41 (s, 1H), 3.66 - 3.57 (m, 3H), 3.51 (s, 2H), 3.32 (dd, 1H), 3.03 (t, 2H), 2.93 - 2.81 (m, 3H), 2.64 - 2.54 (m, 2H), 1.80 - 1.43 (m, 4H).

[0310] Intermediate Scheme 7: [Chemistry]

[0311] [Chemistry] IS8-1 Benzyl (S)-(1-(4-(tert-butyl)piperazin-1-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate (IS8-1). To a solution of ((benzyloxy)carbonyl)-L-serine (3.1 g, 12.9 mmol, 1 equiv) in DMF (16.5 mL) were added N,N-diisopropylethylamine (6.71 mL, 38.6 mmol, 3 equiv) and 1-t-butyl-piperazine (2 g, 14.1 mmol, 1.1 equiv). HATU (5.85 g, 15.4 mmol, 1.2 equiv) was added portionwise. The mixture was stirred at RT for 2 h. The mixture was diluted with DCM (40 mL) and washed with water (4 × 80 mL) and brine (30 mL). The DCM solution was dried over Na 2 SO 4 and concentrated. The residue was purified by column silica gel chromatography eluting with a gradient of 0.5% NH 4 OH in 100% DCM to 0.5% NH 4 OH in DCM solution. This gave 3.9 g (83%) of the title compound as a white foam. MS (ESI+) m / z: 363.74 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.41 - 7.27 (m, 5H), 5.97 (d, J = 8.3 Hz, 1H), 5.12 (q, J = 12.2 Hz, 2H), 4.70 (dt, J = 8.4, 4.2 Hz, 1H), 3.89 - 3.40 (m, 6H), 3.24 (s, 1H), 2.54 (qd, J = 11.8, 11.2, 4.8 Hz, 4H), 1.06 (s, 9H).

[0312] [Chemistry] IS8-2

[0313] Benzyl (R)-(1-(4-(tert-butyl)piperazin-1-yl)-3-hydroxypropan-2-yl)carbamate (IS8-2). A solution of benzyl (S)-(1-(4-(tert-butyl)piperazin-1-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate (3.9 g, 10.7 mmol, 1 equivalent) in THF (22 mL) was cooled in an ice bath, and BH3-THF complex (33.3 mL, 1 M, 33.3 mmol, 3 equivalents) was added dropwise while maintaining the internal temperature below 10 °C. The ice-bath was removed and the mixture was heated to reflux for 3 h. After cooling to rt, the mixture was slowly (foaming!) quenched with MeOH (10 mL). When the foaming stopped, the solution was concentrated by rotary evaporation. The residue was dissolved in MeOH (25 mL) and the solution was heated to reflux for 1.5 h. After cooling to rt and concentrating by rotary evaporation, the residue was purified by column chromatography eluting with a gradient of 0.5% NH 4 OH-containing 100% DCM~% MeOH 0.5% NH 4 OH-containing DCM solution) to give 2 g (54%) of the title compound as a thick oil. MS (ESI+) m / z: 349.24 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.27 (m, 5H), 5.28 (d, J = 13.2 Hz, 1H), 5.15 - 5.03 (m, 2H), 3.93 - 3.73 (m, 2H), 3.71 - 3.61 (m, 1H), 2.71 - 2.23 (m, 11H), 1.05 (s, 9H).

[0314] [Chemistry] I15

[0315] (R)-2-Amino-3-(4-(tert-butyl)piperazin-1-yl)propan-1-ol (I15). To a solution of benzyl (R)-(1-(4-(tert-butyl)piperazin-1-yl)-3-hydroxypropan-2-yl)carbamate (2 g, 5.72 mmol) in MeOH (19 mL) was added 10% Pd / C (600 mg). After evacuation and backfilling with H 2 H was bubbled through the mixture for 3 h. The mixture was filtered through celite, washed with MeOH, and concentrated by rotary evaporation. The residue was dried under reduced pressure to afford 1.23 g (100%) of the title compound as a semi-solid. MS (ESI+) m / z: 201.18 [M + H] 2 . + 1 H NMR (400 MHz, chloroform-d) δ 3.69 - 3.54 (m, 2H), 3.43 (d, J = 10.2 Hz, 4H), 3.19 (h, J = 6.4, 5.9 Hz, 1H), 2.58 (ddd, J = 31.2, 11.3, 5.9 Hz, 8H), 2.38 (dd, J = 12.4, 7.3 Hz, 1H), 1.08 (s, 9H).

[0316] Scheme 1

Chemical Structure

[0317]

Chemical Structure

[0318] [Chemical Structure] S1-3-I1-1

[0319] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3R,4R,6R)-7-(((S)-1-Hydroxypent-4-en-2-yl)(methyl)amino)-4-methoxy-4,6-dimethyl-2-(2,2,5-trimethyl-4-oxo-4H-1,3-dioxin-6-yl)heptan-3-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S1-3-I1-1). S1-2-I1 (1.53 g, 2.26 mmol) was dissolved in dichloromethane (10 mL), and Na(OAc) 3BH (957 mg; 4.52 mmol) was added. Formaldehyde (37 wt% aqueous solution, 1.82 mL, 22.5 mmol) was added. After 15 minutes, further Na(OAc) 3 BH (475 mg; 2.24 mmol) and formaldehyde (37 wt% aqueous solution, 0.30 mL, 3.7 mmol) were added. After 20 minutes, the reaction mixture was quenched by the addition of NaHCO 3 (saturated, aqueous solution). The layers were separated and the aqueous layer was extracted with dichloromethane (3 times). The combined dichloromethane extracts were dried over Na 2 SO 4 and filtered and concentrated. The material was purified by elution through 40 g of silica gel (eluted with a 2 - 10% MeOH - dichloromethane gradient containing 0.5% NH 4 OH aqueous solution) to give the title compound (1.20 g, 76%, 2 steps) as a thick oil. MS (ESI+) m / z: 689.26 [M + H]+. 1 1H NMR (400 MHz, chloroform - d) δ 8.04 (dt, 2H), 7.61 - 7.51 (m, 1H), 7.44 (t, 2H), 5.82 - 5.66 (m, 1H), 5.16 - 4.95 (m, 3H), 4.70 (d, 1H), 3.87 (d, 1H), 3.55 (dq, 1H), 3.47 (dd, 1H), 3.33 - 3.18 (m, 2H), 3.06 (s, 3H), 2.88 (td, 1H), 2.81 - 2.66 (m, 1H), 2.49 (dd, 1H), 2.38 - 2.23 (m, 7H), 2.16 (s, 3H), 2.10 (dd, 1H), 1.92 - 1.75 (m, 5H), 1.73 (s, 3H), 1.68 (s, 3H), 1.64 - 1.55 (m, 1H), 1.55 - 1.42 (m, 1H), 1.38 (dd, 1H), 1.34 - 1.18 (m, 7H), 0.95 (d, 3H), 0.83 (d, 3H).

[0320]

Chemical Structure

[0321] (2S,3R,4S,6R)-2-(((3S,6R,8R,9R,10R)-3-allyl-8-methoxy-4,6,8,10,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoic acid (S1-5-I1-1). S1-3-I1-1 (1.19 g, 1.72 mmol) was concentrated from toluene three times. The substance was dissolved in chlorobenzene (357 mL), and a nitrogen stream was bubbled through the solution for 10 minutes. The mixture was heated overnight at a bath temperature of 145 °C (internal temperature of about 130 - 135 °C). The reaction was cooled to rt and concentrated. The residue was purified by elution with 40 g of silica gel (eluted with a 2 - 10% MeOH-dichloromethane gradient containing 0.5% NH 4 OH aqueous solution) to give the title compound (835 mg, 77%). A mixture of C2 epimers. MS (ESI+) m / z: 631.23 [M + H]+. Scheme 2.

[0322]

Chemical Structure

[0323]

Chemical Structure

[0324]

Chemical Structure

[0325] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-vinyl-1-oxa-4-azacyclotridecane-11,13-dione (S2-2-I3-1). S2-1-I3-1 (18 mg, 0.029 mmol, prepared according to the method of S2-1-I1-1) was dissolved in MeOH (2 mL), and the reaction mixture was heated at 65 °C (external temperature) for 3 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The substance was purified by HPLC (Atlantis T3 column, 5 - 30% MeCN - water - 0.1% HCO 2 H) to give 6.35 mg of the title compound (6.35 mg) as the formate. MS (ESI+) m / z: 176.1 [M + 3H]3+, 263.7 [M + 2H]2+, 526.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ 8.54 (s, 2H), 5.97 (dt, 1H), 5.68 (s, 2H), 4.46 (d, 1H), 4.29 - 4.17 (m, 2H), 3.72 (dtt, 1H), 3.48 - 3.37 (m, 2H), 3.31 (tq, 2H), 3.06 (s, 3H), 2.95 (d, 1H), 2.82 (s, 1H), 2.75 (s, 6H), 2.00 (ddd, 1H), 1.53 - 1.25 (m, 16H), 1.05 (d, 3H).

[0326] Compound 2

Chemical Structure

[0327] tert-Butyl 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)piperazine-1-carboxylate (S2-2-I5-1). Prepared from I5 by the methods of S2-1-I1-1 and S2-2-I3-1 to give the title compound as the formate. MS (ESI+) m / z: 713.6 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.34 (s, 3H), 5.43 (dd, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.87 (ddd, 1H), 3.73 (ddd, 1H), 3.55 - 3.37 (m, 7H), 3.17 (s, 3H), 3.11 - 3.03 (m, 1H), 3.02 (s, 3H), 2.96 - 2.85 (m, 2H), 2.82 (s, 6H), 2.62 - 2.52 (m, 3H), 2.52 - 2.40 (m, 2H), 2.26 (d, 1H), 2.08 - 1.97 (m, 1H), 1.82 (d, 1H), 1.57 - 1.48 (m, 4H), 1.44 (s, 9H), 1.38 (d, 4H), 1.37 - 1.33 (m, 9H), 1.31 (d, 3H), 1.06 (d, 3H).

[0328] Scheme 3 [Chemical formula]

[0329] [Chemical formula] S3-1-I5-1 (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2S,3S,6R,8R,9R,10R)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-3-(piperazin-1-ylmethyl)-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-1-I5-1). S2-2-I5-1 (430 mg, 0.526 mmol) was dissolved in dichloromethane (4.4 mL) and cooled in an ice / water bath. Trifluoroacetic acid (0.5 mL, 6.52 mmol) was added, the ice / water bath was removed, and the reaction mixture was stirred at rt for 5.5 h. The reaction mixture was concentrated to give a pale yellow gum, which was slowly treated with NaHCO 3 (saturated, aqueous, 10 mL) and extracted with EtOAc (9 mL × 4). The combined extracts were dried over Na 2 SO 4 and filtered and concentrated to give the crude title compound. MS (ESI+) m / z: 717.13 [M + H]+.

[0330]

Chemical Structure

[0331] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2S,3R,6R,8R,9R,10R)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-3-(piperazine-1-carbonyl)-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-1-I4-1). Prepared according to the method of S3-1-I5-1, replacing S2-2-I4-1 therewith. The title compound was thus obtained and used without further purification. MS (ESI+) m / z: 731.04 [M + H]+.

[0332] Compound 3

Chemical Structure

[0333] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-1). S3-1-I4-1 (35 mg, 0.048 mmol) was dissolved in MeOH (1 mL), and the reaction mixture was heated at 40 °C (external temperature) overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. The substance was purified by HPLC (Atlantis T3 column, 5 - 30% MeCN - water - 0.1% HCO 2 H) to give 1.83 mg of the title compound as the formate. MS (ESI+) m / z: 627.42 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.29 (s, 4H), 5.27 (s, 1H), 4.46 (d, 1H), 4.30 (s, 1H), 4.14 - 3.87 (m, 4H), 3.81 - 3.63 (m, 2H), 3.62 - 3.50 (m, 2H), 3.46 - 3.35 (m, 2H), 3.31 - 3.12 (m, 3H), 2.92 (s, 3H), 2.74 (d, 10H), 2.35 (d, 1H), 2.08 - 1.84 (m, 2H), 1.62 (dd, 1H), 1.55 - 1.23 (m, 18H), 1.19 (d, 3H), 0.89 (d, 3H).

[0334] Compound 4

Chemical Structure

[0335] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-methylpiperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-2). S3-1-I4-1 (36.4 mg, 0.0497 mmol) was dissolved in dichloromethane (0.5 mL), and Na(OAc) 3 BH (20 mg, 0.094 mmol) was added, followed by formaldehyde (37 wt% aqueous solution, 20.1 mg, 0.248 mmol). After 14 h, the reaction mixture was quenched with NaHCO 3 (saturated, aqueous solution) and extracted with EtOAc (3 times). The combined extracts were dried over Na 2 SO 4 and filtered, and concentrated. The crude material was dissolved in methanol (1 mL), and the reaction mixture was heated at an external temperature of 40 °C overnight. The reaction was cooled to rt and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5–50% MeCN–water–0.1% HCO 2 H) to give 9.45 mg of the title compound as the formate. MS (ESI+) m / z: 641.36 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.33 (s, 3H), 5.30 (s, 1H), 4.48 (d, 1H), 4.31 (s, 1H), 4.03 (d, 1H), 3.94 - 3.80 (m, 2H), 3.80 - 3.68 (m, 2H), 3.67 - 3.54 (m, 2H), 3.49 - 3.36 (m, 2H), 2.95 (s, 3H), 2.82 (s, 6H), 2.76 - 2.65 (m, 6H), 2.65 - 2.52 (m, 2H), 2.44 (s, 3H), 2.42 - 2.31 (m, 1H), 2.06 - 1.98 (m, 1H), 1.92 (s, 1H), 1.71 - 1.62 (m, 1H), 1.52 (q, 1H), 1.47 (s, 3H), 1.42 - 1.35 (m, 4H), 1.35 - 1.29 (m, 9H), 1.20 (d, 3H), 0.92 (d, 3H).

[0336] Compound 5 [Chemical formula] S3-2-I4-1-3

[0337] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(4-isopropylpiperazine-1-carbonyl)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-3). Prepared from S3-1-I4-1 and acetone by the method of S3-2-I4-1-2 to obtain the title compound as formate. MS (ESI+) m / z: 669.44 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.50 (s, 2H), 5.08 (s, 1H), 4.48 (d, 1H), 4.09 - 3.89 (m, 2H), 3.87 - 3.54 (m, 6H), 3.50 - 3.35 (m, 3H), 2.91 (s, 3H), 2.80 (s, 6H), 2.79 - 2.72 (m, 1H), 2.71 - 2.44 (m, 8H), 2.15 - 1.93 (m, 2H), 1.75 (d, 2H), 1.52 (q, 1H), 1.42 (s, 3H), 1.39 (s, 3H), 1.31 (dd, 9H), 1.17 (d, 3H), 1.10 (d, 6H), 0.85 (d, 3H).

[0338] Compound 6

Chem.

[0339] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-4). Prepared from S3-1-I4-1 and 2,2,2-trifluoroacetaldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 709.29 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.49 (s, 1H), 5.27 (s, 1H), 4.49 (d, 1H), 4.23 (s, 1H), 4.03 (d, 1H), 3.90 - 3.66 (m, 4H), 3.66 - 3.54 (m, 2H), 3.49 - 3.37 (m, 2H), 3.14 (q, 2H), 2.95 (s, 3H), 2.82 (s, 6H), 2.80 - 2.62 (m, 8H), 2.33 (s, 1H), 2.09 - 1.98 (m, 1H), 1.95 - 1.81 (m, 1H), 1.70 (d, 1H), 1.54 (q, 1H), 1.50 - 1.41 (m, 4H), 1.41 - 1.23 (m, 13H), 1.20 (d, 3H), 0.91 (d, 3H).

[0340] Compound 7

Chem.

[0341] (2S,3R,6R,8R,9R,10R)-3-(4-Benzylpiperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-5). Prepared from S3-1-I4-1 and benzaldehyde by the method of S3-2-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 717.5 [M + H]+; 1 1H NMR (400 MHz, methanol-d 4) δ = 7.42 - 7.22 (m, 5H), 5.13 - 5.01 (m, 1H), 4.63 - 4.51 (m, 1H), 4.38 (d, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.76 - 3.50 (m, 9H), 3.29 - 3.21 (m, 1H), 2.89 (s, 3H), 2.80 - 2.64 (m, 2H), 2.55 - 2.44 (m, 7H), 2.39 (s, 6H), 2.35 - 2.25 (m, 1H), 2.16 (s, 1H), 2.06 (br d, 1H), 1.85 - 1.6 (m, 3H), 1.39 (d, 6H), 1.33 - 1.22 (m, 10H), 1.18 - 1.05 (m, 4H), 0.84 (d, 3H).

[0342] Compound 8 [Chem.] S3-2-I4-1-6

[0343] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-(4-(3-methoxybenzyl)piperazine-1-carbonyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-6). Prepared from S3-1-I4-1 and 3-methoxybenzaldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 747.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.55 (br s, 0.2H), 7.23 (t, 1H), 6.97 - 6.88 (m, 2H), 6.84 (br d, 1H), 5.12 - 5.00 (m, 1H), 4.39 (d, 1H), 4.04 - 3.96 (m, 1H), 3.89 (br d, 1H), 3.82 - 3.47 (m, 12H), 2.94 - 2.73 (m, 4H), 2.55 - 2.37 (m, 14H), 2.30 (br t, 1H), 2.04 (br d, 1H), 1.86 - 1.64 (m, 3H), 1.39 (d, 6H), 1.32 - 1.21 (m, 10H), 1.19 - 1.04 (m, 4H), 0.84 (br d, 3H).

[0344] Compound 9 [Chem.] S3-2-I4-1-7

[0345] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-phenethylpiperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-7). Prepared from S3-1-I4-1 and phenylacetaldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 731.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.30 - 7.14 (m, 5H), 5.15 - 5.02 (m, 1H), 4.38 (d, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.81 - 3.48 (m, 7H), 3.29 - 3.23 (m, 1H), 2.93 - 2.80 (m, 5H), 2.76 - 2.65 (m, 1H), 2.67 - 2.46 (m, 10H), 2.40 (s, 6H), 2.31 (s, 1H), 2.09 - 2.00 (m, 1H), 1.85 - 1.60 (m, 3H), 1.43 - 1.21 (m, 17H), 1.19 - 1.05 (m, 4H), 0.85 (d, 3H).

[0346] Compound 10 [Chem.] S3-2-I4-1-8

[0347] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(4-isobutylpiperazine-1-carbonyl)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-8). Prepared from S3-1-I4-1 and isobutyl aldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 683.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 5.07 (br dd, 1H), 4.40 (d, 1H), 4.04 - 3.84 (m, 2H), 3.75 - 3.49 (m, 6H), 2.90 (s, 4H), 2.57 - 2.44 (m, 11H), 2.43 - 2.24 (m, 4H), 2.18 - 1.99 (m, 3H), 1.90 - 1.63 (m, 4H), 1.39 (br d, 7H), 1.34 - 1.22 (m, 10H), 1.20 - 1.06 (m, 4H), 0.93 (d, 6H), 0.85 (br d, 3H).

[0348] Compound 11 [Chem.] S3-2-I4-3-1

[0349] (2S,3R,6R,8R,9R,10R)-3-(4-Benzylpiperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-3-1). Prepared from S3-1-I4-3 and benzaldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 745.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.41 - 7.18 (m, 5H), 5.10 (br s, 1H), 4.35 (d, 1H), 4.03 (br d, 2H), 3.77 - 3.49 (m, 8H), 3.29 - 3.18 (m, 2H), 2.86 (s, 3H), 2.73 - 2.62 (m, 2H), 2.56 - 2.33 (m, 12H), 1.98 (br d, 1H), 1.85 - 1.73 (m, 1H), 1.64 (br d, 1H), 1.54 - 1.44 (m, 2H), 1.38 (d, 5H), 1.33 - 1.21 (m, 10H), 1.19 - 1.05 (m, 4H), 0.95 - 0.81 (m, 6H).

[0350] Compound 12 [Chem.] S3-2-I4-3-2

[0351] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-(4-(3-methoxybenzyl)piperazine-1-carbonyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-3-2). Prepared from S3-1-I4-3 and 3-methoxybenzaldehyde by the method of S3-2-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 775.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.24 (t, 1H), 6.95 - 6.88 (m, 2H), 6.84 (dd, 1H), 5.09 (br s, 1H), 4.36 (d, 1H), 4.10 - 3.96 (m, 2H), 3.79 (s, 3H), 3.74 - 3.46 (m, 8H), 2.85 (s, 3H), 2.77 - 2.61 (m, 2H), 2.56 - 2.30 (m, 12H), 1.97 (br d, 1H), 1.78 (br dd, 2H), 1.63 (br s, 1H), 1.54 - 1.06 (m, 23H), 0.95 - 0.78 (m, 7H).

[0352] Compound 13 [Chem.] S3-2-I4-3-3

[0353] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-(4-phenethylpiperazine-1-carbonyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-3-3). Prepared from S3-1-I4-3 and phenylacetaldehyde by the method of S3-2-I4-1-1 to obtain the title compound as formate. MS (ESI+) m / z: 759.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.29 - 7.15 (m, 5H), 5.11 (br s, 1H), 4.38 - 4.32 (m, 1H), 4.08 - 3.99 (m, 2H), 3.75 - 3.48 (m, 7H), 3.29 - 3.22 (m, 1H), 2.92 - 2.78 (m, 5H), 2.72 - 2.51 (m, 8H), 2.45 - 2.31 (m, 8H), 2.18 - 2.14 (m, 1H), 1.99 (br d, 1H), 1.84 - 1.71 (m, 2H), 1.71 - 1.59 (m, 1H), 1.57 - 1.43 (m, 3H), 1.39 (d, 6H), 1.33 - 1.09 (m, 16H), 0.95 - 0.83 (m, 7H).

[0354] Compound 14 [Chem.] S3-2-I4-3-4

[0355] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(4-isobutylpiperazine-1-carbonyl)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-3-4). Prepared from S3-1-I4-3 and isobutylaldehyde by the method of S3-2-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 711.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 5.18 - 5.03 (m, 1H), 4.35 (d, 1H), 4.07 - 3.98 (m, 2H), 3.74 - 3.52 (m, 6H), 3.29 - 3.21 (m, 1H), 2.87 (s, 3H), 2.76 - 2.61 (m, 2H), 2.51 - 2.29 (m, 12H), 2.13 (d, 2H), 1.99 (br d, 1H), 1.91 - 1.73 (m, 3H), 1.71 - 1.59 (m, 1H), 1.56 - 1.43 (m, 3H), 1.39 (d, 6H), 1.33 - 1.21 (m, 10H), 1.15 (d, 3H), 0.93 (d, 7H), 0.90 - 0.82 (m, 5H).

[0356] Compound 15 [Chem.] S3-4-I4-1-1

[0357] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-(4-(3-methoxybenzoyl)piperazine-1-carbonyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-1-1). To a solution of S3-2-I4-1 (61 mg, 72.19 μmol) in CH 2 Cl 2 (2 mL) were added DMAP (3 mg, 21.66 μmol), DIPEA (47 mg, 360.97 μmol, 62.87 μL), and 3-methoxybenzoyl chloride (37 mg, 216.58 μmol, 29.56 μL) at 20 °C, and the reaction mixture was stirred at the same temperature for 2 h. The reaction was quenched with saturated NaHCO 3 aqueous solution (2 mL), and extracted with CH 2 Cl 2 (2 mL × 3). The combined organic layers were dried (Na 2SO 4 ) It was filtered and concentrated under reduced pressure to obtain crude amide (75 mg, crude) as a yellow oil. It was dissolved in MeOH (8 mL) and heated at 55 °C for 16 hours. The reaction mixture was concentrated. The crude residue was purified by preparative-HPLC to obtain the title compound as a formate salt. MS (ESI+) m / z: 761.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.41 (br d, 1H), 7.40 (t, 1H), 7.09 - 6.99 (m, 3H), 5.19 - 5.05 (m, 1H), 4.48 (d, 1H), 4.00 (br d, 2H), 3.94 - 3.53 (m, 13H), 3.49 - 3.34 (m, 4H), 2.95 - 2.87 (m, 3H), 2.86 - 2.78 (m, 6H), 2.66 - 2.33 (m, 4H), 2.02 (br d, 2H), 1.83 - 1.67 (m, 2H), 1.53 (br d, 1H), 1.44 - 1.12 (m, 20H), 0.86 (br d, 3H).

[0358] Compound 16

Chemical Structure

[0359] (2S,3R,6R,8R,9R,10R)-3-(4-benzoylpiperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-1-2). It was prepared from S3-1-I4-1 and benzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate salt. MS (ESI+) m / z: 731.5 [M + H]+; 1 H NMR (400 MHz, methanol-d4 ) δ = 7.53 - 7.44 (m, 5H), 5.13 - 5.00 (m, 2H), 4.39 (br d, 1H), 4.09 - 3.38 (m, 13H), 2.96 - 2.75 (m, 4H), 2.53 - 2.42 (m, 9H), 2.34 (br t, 1H), 2.04 (br d, 1H), 1.86 - 1.66 (m, 3H), 1.42 - 1.23 (m, 16H), 1.20 - 1.08 (m, 4H), 0.85 (br d, 3H).

[0360] Compound 17

Chem.

[0361] (2S,3R,6R,8R,9R,10R)-3-(4-(3-chlorobenzoyl)piperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-1-3). Prepared from S3-1-I4-1 and 3-chlorobenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 765.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.44 (br s, 1H), 7.55 - 7.44 (m, 3H), 7.43 - 7.36 (m, 1H), 5.11 (br s, 1H), 4.48 (d, 1H), 4.00 (br d, 1H), 3.90 - 3.51 (m, 9H), 3.48 - 3.36 (m, 3H), 2.90 (br s, 3H), 2.81 (s, 6H), 2.55 (br s, 3H), 2.43 (br s, 1H), 2.20 - 2.14 (m, 1H), 2.02 (br d, 1H), 1.90 - 1.72 (s, 2H), 1.52 (q, 1H), 1.42 (s, 3H), 1.38 (br s, 3H), 1.34 - 1.22 (m, 10H), 1.19 (br d, 4H), 0.86 (br d, 3H).

[0362] Compound 18 [Chem.] S3-4-I4-1-4

[0363] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-(3-methylbenzoyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-1-4). Prepared from S3-1-I4-1 and 3-methylbenzoyl chloride by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 745.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.56 (br s, 1H), 7.40 - 7.30 (m, 2H), 7.27 (s, 1H), 7.24 (br d, 1H), 5.07 - 5.20 (m, 1H), 4.47 (d, 1H), 4.05 - 3.34 (m, 15H), 2.89 (br s, 3H), 2.79 (s, 6H), 2.52 (br s, 3H), 2.39 (s, 4H), 2.15 - 2.01 (m, 2H), 1.73 (br d, 2H), 1.56 - 1.46 (m, 1H), 1.44 - 1.34 (m, 6H), 1.34 - 1.21 (m, 10H), 1.18 (br d, 5H), 0.84 (br d, 3H).

[0364] Compound 19 [Chem.] S3-4-I4-1-5

[0365] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-(3-(trifluoromethyl)benzoyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-1-5). Prepared from S3-1-I4-1 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 799.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.54 (br s, 1H), 7.84 - 7.77 (m, 2H), 7.76 - 7.67 (m, 2H), 5.12 - 5.01 (m, 2H), 4.76 - 4.53 (m, 6H), 4.44 (br d, 1H), 4.04 - 3.43 (m, 12H), 3.43 - 3.33 (m, 1H), 3.21 - 3.10 (m, 1H), 2.88 (br s, 3H), 2.66 (s, 6H), 2.50 (br s, 3H), 2.45 - 2.29 (m, 1H), 2.04 (br d, 1H), 1.93 (br d, 1H), 1.82 - 1.63 (m, 2H), 1.48 - 1.34 (m, 7H), 1.33 - 1.23 (m, 9H), 1.22 - 1.07 (m, 5H), 0.90 - 0.80 (m, 3H).

[0366] Compound 20 [Chem.] S3-4-I4-1-6

[0367] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecane-3-carbonyl)-N-phenylpiperazine-1-carboxamide (S3-4-I4-1-6). Prepared from S3-1-I4-1 and phenyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 746.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.36 (br d, 2H), 7.27 (t, 2H), 7.03 (t, 1H), 5.16 - 5.04 (m, 1H), 4.62 - 4.52 (m, 1H), 4.40 (d, 1H), 4.04 - 3.90 (m, 2H), 3.82 - 3.54 (m, 10H), 2.95 - 2.83 (m, 4H), 2.50 (br d, 8H), 2.45 - 2.24 (m, 2H), 2.07 (br d, 1H), 1.91 - 1.66 (m, 3H), 1.56 - 1.23 (m, 17H), 1.23 - 1.08 (m, 5H), 0.86 (br d, 3H).

[0368] Compound 21 [Chemical formula] S3-4-I4-1-7

[0369] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecane-3-carbonyl)-N-(3-methoxyphenyl)piperazine-1-carboxamide (S3-4-I4-1-7). Prepared from S3-1-I4-1 and phenyl 3-methoxyisocyanate by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 776.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.54 (br s, 1H), 7.15 (t, 1H), 7.04 (t, 1H), 6.92 (dd, 1H), 6.60 (dd, 1H), 5.08 (br dd, 1H), 4.41 (d, 1H), 4.06 - 3.89 (m, 2H), 3.86 - 3.47 (m, 14H), 3.02 - 2.84 (m, 4H), 2.66 - 2.47 (m, 9H), 2.40 - 2.25 (m, 1H), 2.06 (br d, 1H), 1.92 - 1.65 (m, 3H), 1.51 - 1.06 (m, 22H), 0.85 (d, 3H).

[0370] Compound 22

Chem.

[0371] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecane-3-carbonyl)-N-isopropylpiperazine-1-carboxamide (S3-4-I4-1-8). Prepared from S3-1-I4-1 and isopropyl isocyanate by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 712.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 5.08 (br dd, 1H), 4.38 (d, 1H), 4.01 (d, 1H), 3.97 - 3.83 (m, 2H), 3.80 - 3.53 (m, 7H), 3.52 - 3.36 (m, 4H), 2.90 (s, 3H), 2.68 (br d, 1H), 2.50 (s, 3H), 2.44 - 2.27 (m, 7H), 2.11 - 2.02 (m, 1H), 1.85 - 1.66 (m, 3H), 1.47 - 1.04 (m, 28H), 0.86 (d, 3H).

[0372] Compound 23

Chem.

[0373] (2S,3R,6R,8R,9R,10R)-3-(4-benzoylpiperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-3-1) Prepared from S3-1-I4-3 and benzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 759.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.57 - 7.37 (m, 5H), 4.37 (br d, 1H), 4.13 - 3.91 (m, 3H), 3.89 - 3.44 (m, 13H), 3.29 - 3.24 (m, 1H), 2.86 (br s, 3H), 2.81 - 2.61 (m, 3H), 2.48 - 2.35 (m, 7H), 1.99 (br d, 1H), 1.86 - 1.71 (m, 2H), 1.70 - 1.48 (m, 2H), 1.45 - 1.08 (m, 23H), 0.95 - 0.84 (m, 5H).

[0374] Compound 24

Chem.

[0375] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-(4-(3-methoxybenzoyl)piperazine-1-carbonyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-3-2). Prepared from S3-1-I4-3 and 3-methoxybenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 789.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.41 (t, 1H), 7.11 - 7.05 (m, 1H), 7.05 - 6.98 (m, 2H), 5.16 - 5.08 (m, 1H), 4.69 - 4.52 (m, 1H), 4.38 (d, 1H), 4.02 (br d, 1H), 3.95 - 3.81 (m, 5H), 3.80 - 3.45 (m, 9H), 3.30 - 3.25 (m, 1H), 2.98 - 2.63 (m, 6H), 2.40 (s, 8H), 2.31 - 2.10 (m, 1H), 1.98 (br s, 1H), 1.80 (br d, 1H), 1.72 - 1.61 (m, 1H), 1.53 (br s, 2H), 1.44 - 1.19 (m, 19H), 1.02 - 0.82 (m, 6H).

[0376] Compound 25 [Chemical formula] S3-4-I4-3-3

[0377] (2S,3R,6R,8R,9R,10R)-3-(4-(3-chlorobenzoyl)piperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-3-3). Prepared from S3-1-I4-3 and 3-chlorobenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 793.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.61 - 7.46 (m, 3H), 7.41 (br d, 1H), 5.11 (br d, 1H), 4.38 (br d, 1H), 4.17 - 4.05 (m, 1H), 4.03 - 3.40 (m, 12H), 3.29 - 3.23 (m, 1H), 2.88 (br s, 3H), 2.78 - 2.64 (m, 3H), 2.40 (s, 8H), 2.00 (br d, 1H), 1.79 (br d, 1H), 1.73 - 1.63 (m, 1H), 1.53 (br s, 3H), 1.45 - 0.98 (m, 23H), 0.96 - 0.78 (m, 6H).

[0378] Compound 26 [Chem.] S3-4-I4-3-4

[0379] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-(4-(3-methylbenzoyl)piperazine-1-carbonyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-3-4). Prepared from S3-1-I4-3 and 3-methylbenzoyl chloride by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 773.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.44 - 7.15 (m, 4H), 5.10 (br s, 1H), 4.35 (d, 1H), 4.19 - 3.93 (m, 2H), 3.91 - 3.40 (m, 11H), 3.25 (br dd, 1H), 2.85 (br s, 3H), 2.73 - 2.53 (m, 2H), 2.51 - 2.37 (m, 5H), 2.33 (s, 6H), 1.98 (br d, 1H), 1.84 - 1.59 (m, 3H), 1.58 - 1.33 (m, 8H), 1.33 - 1.08 (m, 15H), 0.97 - 0.80 (m, 6H).

[0380] Compound 27 [Chem.] S3-4-I4-3-5

[0381] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-3-(4-(3-(trifluoromethyl)benzoyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I4-3-5). Prepared from S3-1-I4-3 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 827.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.87 - 7.80 (m, 2H), 7.78 - 7.68 (m, 2H), 5.12 (br d, 1H), 4.38 (br d, 1H), 4.21 - 4.07 (m, 1H), 4.07 - 3.41 (m, 11H), 3.30 - 3.18 (m, 1H), 2.87 (br s, 3H), 2.77 - 2.65 (m, 2H), 2.63 - 2.26 (m, 8H), 2.01 (br d, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.48 (m, 4H), 1.45 - 1.06 (m, 17H), 1.00 - 0.80 (m, 6H).

[0382] Compound 28 [Chem.] S3-4-I4-3-6

[0383] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecane-3-carbonyl)-N-phenylpiperazine-1-carboxamide (S3-4-I4-3-6). Prepared from S3-1-I4-3 and phenyl isocyanate by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 774.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.66 - 8.48 (m, 0.3H), 7.41 - 7.35 (m, 2H), 7.29 (t, 2H), 7.05 (t, 1H), 5.14 (br s, 1H), 4.41 (d, 1H), 4.18 - 3.95 (m, 2H), 3.83 - 3.53 (m, 10H), 3.42 - 3.35 (m, 1H), 2.90 (s, 4H), 2.81 - 2.60 (m, 1H), 2.59 - 2.40 (m, 8H), 2.10 - 1.94 (m, 1H), 1.93 - 1.76 (m, 2H), 1.76 - 1.63 (m, 1H), 1.59 - 1.49 (m, 2H), 1.45 - 1.27 (m, 16H), 1.24 - 1.12 (m, 4H), 1.01 - 0.83 (m, 6H).

[0384] Compound 29 [Chem.] S3-4-I4-3-7

[0385] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecane-3-carbonyl)-N-(3-methoxyphenyl)piperazine-1-carboxamide (S3-4-I4-3-7). Prepared from S3-1-I4-3 and phenyl 3-methoxyisocyanate by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 804.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 6.70 (t, 1H), 6.59 (t, 1H), 6.46 (dd, 1H), 6.15 (dd, 1H), 4.67 (br s, 1H), 3.90 (d, 1H), 3.68 - 3.52 (m, 2H), 3.38 - 3.03 (m, 14H), 2.84 - 2.76 (m, 1H), 2.43 (s, 3H), 2.35 - 2.18 (m, 2H), 2.05 - 1.86 (m, 8H), 1.56 (br d, 1H), 1.39 - 1.28 (m, 2H), 1.26 - 1.16 (m, 1H), 1.12 - 1.02 (m, 2H), 0.94 (d, 6H), 0.88 - 0.76 (m, 10H), 0.75 - 0.62 (m, 4H), 0.52 - 0.35 (m, 6H).

[0386] Compound 30 [Chem.] S3-4-I4-3-8

[0387] 4-((2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecane-3-carbonyl)-N-isopropylpiperazine-1-carboxamide (S3-4-I4-3-8). Prepared from S3-1-I4-3 and isopropyl isocyanate by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 740.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 5.12 (br s, 1H), 4.36 (d, 1H), 4.13 - 3.98 (m, 2H), 3.89 (td, 1H), 3.77 - 3.54 (m, 7H), 3.47 (br d, 2H), 3.44 - 3.36 (m, 2H), 3.29 - 3.19 (m, 1H), 2.88 (s, 3H), 2.76 - 2.62 (m, 2H), 2.39 - 2.35 (m, 8H), 2.00 (br d, 1H), 1.93 - 1.81 (m, 1H), 1.79 - 1.59 (m, 3H), 1.56 - 1.43 (m, 3H), 1.32 - 1.20 (m, 12H), 1.19 - 1.08 (m, 10H), 0.99 - 0.80 (m, 7H).

[0388] Compound 31 [Chem.] S3-3-I4-1-1

[0389] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-(phenylsulfonyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I4-1-1). Prepared from S3-1-I4-1 and benzenesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 767.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.85 - 7.75 (m, 2H), 7.73 - 7.59 (m, 3H), 7.46 - 7.39 (m, 1H), 5.05 - 4.94 (m, 1H), 4.39 (d, 1H), 3.97 (br d, 1H), 3.89 - 3.41 (m, 8H), 3.14 - 2.90 (m, 5H), 2.87 (s, 3H), 2.50 (br s, 5H), 2.42 (s, 3H), 2.35 - 2.12 (m, 1H), 1.85 (br t, 2H), 1.77 - 1.54 (m, 2H), 1.44 - 1.17 (m, 16H), 1.12 - 0.96 (m, 4H), 0.75 (br d, 3H).

[0390] Compound 32 [Chem.] S3-3-I4-1-2

[0391] (2S,3R,6R,8R,9R,10R)-3-(4-(Benzylsulfonyl)piperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I4-1-2). Prepared from S3-1-I4-1 and phenylmethanesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 781.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.45 (br dd, 2H), 7.40 - 7.33 (m, 3H), 5.03 (br d, 1H), 4.46 - 4.32 (m, 3H), 3.98 (d, 1H), 3.85 (br d, 1H), 3.73 - 3.49 (m, 7H), 3.24 - 3.02 (m, 4H), 2.87 (s, 3H), 2.75 (m, 1H), 2.50 - 2.20 (m, 10H), 1.98 (br d, 1H), 1.84 - 1.64 (m, 3H), 1.45 - 1.20 (m, 17H), 1.17 - 1.06 (m, 4H), 0.85 (d, 3H).

[0392] Compound 33 [Chem.] S3-3-I4-3-1

[0393] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-(4-(phenylsulfonyl)piperazine-1-carbonyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I4-3-1) Prepared from S3-1-I4-3 and benzenesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 795.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.57 (br s, 0.22H), 7.86 - 7.78 (m, 2H), 7.76 - 7.69 (m, 1H), 7.68 - 7.58 (m, 2H), 5.06 (br s, 1H), 4.37 (d, 1H), 4.11 - 3.92 (m, 2H), 3.87 - 3.68 (m, 4H), 3.66 - 3.48 (m, 3H), 3.29 - 3.23 (m, 1H), 3.04 (br d, 4H), 2.87 (s, 3H), 2.80 - 2.54 (m, 2H), 2.41 (s, 6H), 2.37 - 2.21 (m, 2H), 1.96 - 1.68 (m, 3H), 1.57 (br s, 1H), 1.52 - 1.34 (m, 9H), 1.33 - 1.21 (m, 10H), 1.16 - 1.08 (m, 1H), 1.04 (d, 3H), 0.87 (t, 3H), 0.78 (d, 3H).

[0394] Compound 34 [Chem.] S3-3-I4-3-2

[0395] (2S,3R,6R,8R,9R,10R)-3-(4-(Benzylsulfonyl)piperazine-1-carbonyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I4-3-2). Prepared from S3-1-I4-3 and phenylmethanesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 809.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.55 (br s, 0.24H), 7.51 - 7.43 (m, 2H), 7.42 - 7.34 (m, 3H), 5.07 (br s, 1H), 4.42 (s, 2H), 4.37 (d, 1H), 4.07 - 3.93 (m, 2H), 3.75 - 3.50 (m, 6H), 3.29 - 3.26 (m, 1H), 3.24 - 3.04 (m, 4H), 2.84 (s, 3H), 2.77 (br t, 1H), 2.69 - 2.56 (m, 1H), 2.42 (s, 6H), 2.37 - 2.28 (m, 1H), 1.93 (br d, 1H), 1.86 - 1.66 (m, 2H), 1.62 (br s, 1H), 1.53 - 1.43 (m, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.30 (br d, 4H), 1.28 - 1.22 (m, 6H), 1.14 - 1.09 (d, 4H), 0.93 - 0.81 (m, 6H).

[0396] Compound 35 [Chem.] S3-2-I5-1-1

[0397] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-1). S3-1-I5-1 (36.8 mg, 0.051 mmol) was dissolved in dry THF (0.6 mL) under nitrogen. Phenylsilane (12.5 μL, 1.020 mmol) was added, followed by trifluoroacetic acid (6.8 μL, 0.090 mmol). The reaction mixture was placed in a preheated dry block at 70 °C and stirred for 6 hours. The reaction was cooled and saturated NaHCO3 (1.5 mL) was added to quench, and extracted with EtOAc (1 mL × 3). The combined extracts were dried over Na 2 SO 4 , filtered, and concentrated. The resulting crude substance was dissolved in MeOH (1 mL), heated at 40 °C overnight, and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5 - 50% MeCN - water - 0.1% HCO 2 H) to obtain 8.31 mg of the title compound as the formate salt. MS (ESI+) m / z: 695.33 [M + H]+; 1 H NMR (400 MHz, methanol - d) δ 8.40 (s, 3H), 5.41 (dt, 1H), 4.50 (d, 1H), 4.11 (d, 1H), 3.91 - 3.80 (m, 1H), 3.73 (ddd, 1H), 3.57 - 3.47 (m, 1H), 3.47 - 3.36 (m, 2H), 3.18 (s, 3H), 3.07 (q, 3H), 3.02 (s, 3H), 2.95 - 2.84 (m, 2H), 2.82 (s, 6H), 2.77 - 2.61 (m, 6H), 2.61 - 2.51 (m, 2H), 2.27 (d, 1H), 2.08 - 1.99 (m, 1H), 1.83 (d, 1H), 1.58 - 1.47 (m, 4H), 1.42 - 1.30 (m, 17H), 1.07 (d, 3H).

[0398] Compound 36

Chemical Structure

[0399] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isobutylpiperazin-1-yl)methyl)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-2) According to the method of S3-2-I5-1-1, the title compound was prepared as a formate by replacing isobutylaldehyde. MS (ESI+) m / z: 669.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.57 (s, 1H), 5.44 (br dd, 1H), 4.42 (dd, 1H), 4.26 - 3.99 (m, 1H), 3.98 - 3.74 (m, 1H), 3.65 - 3.38 (m, 3H), 3.31 - 3.19 (m, 2H), 3.15 - 3.00 (m, 2H), 2.96 (s, 2H), 2.94 - 2.74 (m, 2H), 2.71 - 2.42 (m, 8H), 2.42 - 2.24 (m, 9H), 2.21 - 2.11 (m, 3H), 1.92 - 1.65 (m, 4H), 1.59 - 1.48 (m, 2H), 1.46 - 1.18 (m, 17H), 1.10 (br d, 1H), 1.00 - 0.90 (m, 7H).

[0400] Compound 37

Chemical Structure

[0401] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(3-methoxybenzyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-3). According to the method of S3-2-I5-1-1, replacing 3-methoxybenzaldehyde, the title compound was prepared as the formate. MS (ESI+) m / z: 733.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.55 (s, 0.3H), 7.22 (t, 1H), 6.95 - 6.86 (m, 2H), 6.83 (br d, 1H), 5.41 (br dd, 1H), 4.50 - 4.34 (m, 1H), 4.12 - 4.00 (m, 1H), 3.91 - 3.73 (m, 4H), 3.65 - 3.39 (m, 5H), 3.29 - 3.13 (m, 2H), 3.01 (s, 1H), 2.96 - 2.91 (m, 2H), 2.90 - 2.76 (m, 1H), 2.71 - 2.40 (m, 10H), 2.39 - 2.21 (m, 10H), 2.20 - 2.08 (m, 1H), 1.89 - 1.63 (m, 3H), 1.50 (s, 1H), 1.46 - 1.32 (m, 9H), 1.31 - 1.16 (m, 11H), 1.15 - 1.04 (m, 1H), 0.89 (br d, 2H).

[0402] Compound 38

Chem.

[0403] (2S,3S,6R,8R,9R,10R)-3-((4-Benzylpiperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-4) According to the method of S3-2-I5-1-1, the title compound was prepared as a formate by replacing benzaldehyde. MS (ESI+) m / z: 703.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.40 - 7.15 (m, 5H), 4.40 (br d, 1H), 4.15 - 4.01 (m, 1H), 3.91 - 3.78 (m, 1H), 3.65 - 3.46 (m, 4H), 3.28 - 3.14 (m, 2H), 3.10 - 2.75 (m, 6H), 2.70 - 2.09 (m, 21H), 1.93 - 1.62 (m, 3H), 1.55 - 1.47 (m, 1H), 1.44 - 1.16 (m, 19H), 1.11 - 1.00 (m, 2H), 0.96 - 0.82 (m, 2H).

[0404] Compound 39

Chemical Structure

[0405] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(naphthalen-2-ylmethyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-5). According to the method of S3-2-I5-1-1, replacing with 2-naphthaldehyde, the title compound was prepared as the formate. MS (ESI+) m / z: 753.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.63 - 8.48 (m, 1H), 7.85 - 7.75 (m, 4H), 7.51 - 7.43 (m, 3H), 5.52 - 5.31 (m, 1H), 4.39 (d, 1H), 4.11 - 4.03 (m, 1H), 3.91 - 3.77 (m, 1H), 3.72 - 3.45 (m, 5H), 3.29 - 3.12 (m, 2H), 3.10 - 2.97 (m, 1H), 2.94 - 2.75 (m, 4H), 2.72 - 2.51 (m, 6H), 2.45 (br dd, 3H), 2.38 - 2.20 (m, 11H), 2.18 - 2.10 (m, 1H), 1.89 - 1.66 (m, 3H), 1.65 - 1.47 (m, 1H), 1.44 - 1.31 (m, 8H), 1.29 - 1.02 (m, 14H), 0.88 (d, 2H).

[0406] Compound 40 [Chemical formula] S3-2-I5-1-6

[0407] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-phenethylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-6). According to the method of S3-2-I5-1-1, replacing with phenylacetaldehyde, the title compound was prepared as the formate. MS (ESI+) m / z: 717.5 [M + H]+; 11H NMR (400 MHz, methanol-d 4 ) δ = 8.61 - 8.47 (m, 1H), 7.29 - 7.15 (m, 5H), 4.40 (d, 1H), 4.12 - 4.03 (m, 1H), 3.64 - 3.45 (m, 3H), 3.28 - 3.17 (m, 1H), 3.15 - 2.96 (m, 1H), 2.94 (s, 3H), 2.85 - 2.75 (m, 3H), 2.70 - 2.53 (m, 9H), 2.47 (br dd, 3H), 2.38 (s, 3H), 2.36 - 2.29 (m, 8H), 2.25 - 2.06 (m, 1H), 1.94 - 1.59 (m, 3H), 1.54 - 1.33 (m, 8H), 1.31 - 1.03 (m, 15H), 0.90 (d, 3H).

[0408] Compound 41

Chem.

[0409] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(3-methoxybenzyl)piperazin-1-yl)methyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-3-1). According to the method of S3-2-I5-1-1, replacing from S3-1-I5-3 and with 3-methoxybenzaldehyde, the title compound was prepared as the formate. MS (ESI+) m / z: 761.5 [M + H]+; 1 1H NMR (400 MHz, methanol-d 4) δ = 8.68 - 8.48 (m, 0.3H), 7.24 (t, 1H), 6.95 - 6.82 (m, 3H), 4.50 - 4.36 (m, 1H), 4.19 - 4.06 (m, 1H), 4.05 - 3.92 (m, 1H), 3.81 (s, 3H), 3.65 - 3.38 (m, 5H), 3.29 - 3.08 (m, 1H), 3.04 - 2.88 (m, 4H), 2.83 - 2.66 (m, 3H), 2.62 - 2.34 (m, 17H), 2.28 - 2.07 (m, 2H), 1.93 - 1.72 (m, 2H), 1.67 - 1.59 (m, 1H), 1.51 - 1.17 (m, 23H), 1.17 - 1.04 (m, 2H), 0.96 - 0.83 (m, 5H).

[0410] Compound 42 [Chem.] S3-2-I5-3-2

[0411] (2S,3S,6R,8R,9R,10R)-3-((4-Benzylpiperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-3-2). According to the method of S3-2-I5-1-1, starting from S3-1-I5-3 and replacing with benzaldehyde, the title compound was prepared as the formate. MS (ESI+) m / z: 731.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.37 - 7.19 (m, 5H), 4.40 (br d, 1H), 4.08 (br d, 1H), 3.62 - 3.43 (m, 4H), 3.00 - 2.86 (m, 3H), 2.82 - 2.01 (m, 23H), 1.82 - 0.96 (m, 27H), 0.93 - 0.71 (m, 6H).

[0412] Compound 43

Chem.

[0413] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-((4-phenethylpiperazin-1-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-3-3). According to the method of S3-2-I5-1-1, starting from S3-1-I5-3 and replacing with phenylacetaldehyde, the title compound was prepared as a formate. MS (ESI+) m / z: 745.6 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.33 - 7.12 (m, 5H), 4.40 (br d, 1H), 4.08 (br d, 1H), 3.64 - 3.45 (m, 2H), 2.94 (s, 3H), 2.85 - 2.08 (m, 27H), 1.82 - 0.97 (m, 27H), 0.95 - 0.75 (m, 6H).

[0414] Compound 44

Chem.

[0415] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isobutylpiperazin-1-yl)methyl)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-3-4). According to the method of S3-2-I5-1-1, replacing from S3-1-I5-3 and isobutylaldehyde, the title compound was prepared as a formate. MS (ESI+) m / z: 697.6 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 4.82 - 4.61 (m, 1H), 4.40 (br d, 1H), 4.08 (br d, 1H), 3.66 - 3.45 (m, 2H), 3.30 - 3.12 (m, 2H), 3.03 - 2.86 (m, 3H), 2.85 - 2.73 (m, 1H), 2.72 - 2.60 (m, 2H), 2.60 - 2.26 (m, 15H), 2.25 - 1.98 (m, 4H), 1.89 - 1.54 (m, 4H), 1.53 - 1.33 (m, 8H), 1.32 - 1.02 (m, 13H), 0.99 - 0.68 (m, 10H).

[0416] Compound 45

Chem.

[0417] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-1). S3-1-I5-1 (37.4 mg, 0.0521 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) were dissolved in dichloromethane (0.45 mL) and N,N-diisopropylethylamine (0.050 mL, 0.26 mmol). The solution was cooled to 0 °C, methanesulfonyl chloride (0.012 mL, 0.156 mmol) was added, and the reaction mixture was warmed to rt. After 3 h, the reaction was quenched by addition of saturated NaHCO 3 (1 mL), and extracted with EtOAc (1 mL × 3). The combined extracts were dried over Na 2 SO 4 and filtered, then concentrated. The resulting crude material was dissolved in MeOH (1 mL), heated at 40 °C overnight, and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5–50% MeCN–water–0.1% HCO 2 H) to give 14.1 mg of the title compound as the formate salt. MS (ESI+) m / z: 691.30 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.33 (s, 3H), 5.44 (dq, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.90 - 3.80 (m, 1H), 3.72 (ddd, 1H), 3.55 - 3.37 (m, 3H), 3.27 - 3.19 (m, 4H), 3.16 (s, 3H), 3.10 - 3.02 (m, 1H), 3.02 (s, 3H), 2.95 - 2.85 (m, 2H), 2.84 (s, 3H), 2.81 (s, 6H), 2.74 - 2.59 (m, 5H), 2.31 - 2.21 (m, 1H), 2.07 - 1.99 (m, 1H), 1.82 (d, 1H), 1.57 - 1.43 (m, 4H), 1.42 - 1.33 (m, 13H), 1.31 (d, 3H), 1.06 (d, 3H).

[0418] Compound 46 [Chemical formula] S3-3-I5-1-2

[0419] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (S3-3-I5-1-2). Prepared from S3-1-I5-1 and dimethylsulfamoyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 720.24 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.25 (s, 1H), 5.45 (dq, 1H), 4.51 (d, 1H), 4.11 (d, 1H), 3.93 - 3.85 (m, 1H), 3.79 - 3.70 (m, 1H), 3.58 - 3.40 (m, 3H), 3.29 - 3.23 (m, 3H), 3.19 (s, 3H), 3.12 - 2.99 (m, 4H), 2.94 (dd, 1H), 2.89 (s, 3H), 2.87 - 2.81 (m, 9H), 2.68 (q, 1H), 2.64 (s, 6H), 2.63 - 2.56 (m, 2H), 2.37 - 2.20 (m, 1H), 2.10 - 2.02 (m, 1H), 1.84 (d, 1H), 1.61 - 1.47 (m, 4H), 1.44 - 1.26 (m, 15H), 1.08 (d, 3H).

[0420] Compound 47 [Chemical formula] S3-3-I5-1-3

[0421] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-tosylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-3). Prepared from S3-1-I5-1 and p-toluenesulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 767.38 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.36 (s, 3H), 7.63 (d, 2H), 7.41 (d, 2H), 5.38 (dt, 1H), 4.46 (d, 1H), 4.06 (d, 1H), 3.78 (ddd, 1H), 3.74 - 3.66 (m, 1H), 3.51 - 3.35 (m, 3H), 3.03 (s, 3H), 2.99 (d, 5H), 2.96 (s, 3H), 2.88 - 2.82 (m, 2H), 2.80 (s, 6H), 2.71 - 2.62 (m, 2H), 2.62 - 2.52 (m, 3H), 2.42 (d, 3H), 2.25 - 2.14 (m, 1H), 2.04 - 1.97 (m, 1H), 1.78 (d, 1H), 1.55 - 1.41 (m, 5H), 1.37 - 1.24 (m, 16H), 1.00 (d, 3H).

[0422] Compound 48 [Chemical formula] S3-3-I5-1-4

[0423] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-4). Prepared from S3-1-I5-1 and 1-methyl-1H-imidazole-4-sulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as formate. MS (ESI+) m / z: 757.32 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.35 (s, 3H), 7.76 (d, 1H), 7.71 (d, 1H), 5.39 (dt, 1H), 4.47 (d, 1H), 4.07 (d, 1H), 3.85 - 3.78 (m, 1H), 3.77 (s, 3H), 3.71 (ddd, 1H), 3.52 - 3.45 (m, 1H), 3.44 - 3.35 (m, 2H), 3.19 - 3.10 (m, 4H), 3.08 (s, 3H), 3.04 - 2.93 (m, 4H), 2.92 - 2.82 (m, 2H), 2.80 (s, 6H), 2.70 - 2.53 (m, 5H), 2.28 - 2.14 (m, 1H), 2.06 - 1.98 (m, 1H), 1.79 (d, 1H), 1.59 - 1.41 (m, 4H), 1.39 - 1.25 (m, 17H), 1.02 (d, 3H).

[0424] Compound 49 [Chemical formula] S3-3-I5-1-5

[0425] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(phenylsulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-5). Prepared from S3-1-I5-1 and benzenesulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 753.4 [M + H]+; 1 1H NMR (400 MHz, methanol-d 4) δ = 8.56 (br s, 0.16H), 7.86 - 7.74 (m, 2H), 7.73 - 7.66 (m, 1H), 7.66 - 7.59 (m, 2H), 7.47 - 7.38 (m, 1H), 5.39 (br dd, 1H), 4.39 (br d, 1H), 4.14 - 3.95 (m, 1H), 3.88 - 3.69 (m, 1H), 3.66 - 3.39 (m, 2H), 3.28 - 3.10 (m, 1H), 3.09 - 2.94 (m, 6H), 2.91 (s, 2H), 2.87 - 2.41 (m, 8H), 2.34 (br d, 8H), 2.24 - 2.05 (m, 2H), 1.88 - 1.57 (m, 2H), 1.48 (s, 1H), 1.42 - 1.19 (m, 16H), 1.14 (br d, 2H), 1.04 (br d, 1H), 0.94 - 0.72 (m, 2H).

[0426] Compound 50 [Chemical formula] S3-3-I5-1-6

[0427] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-((3-methoxyphenyl)sulfonyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-6). Prepared from S3-1-I5-1 and 3-methoxybenzenesulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 783.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.55 (s, 0.17H), 7.59 - 7.48 (m, 1H), 7.33 (br d, 1H), 7.28 - 7.21 (m, 2H), 5.39 (br dd, 1H), 4.73 - 4.45 (m, 1H), 4.39 (d, 1H), 4.08 - 3.98 (m, 1H), 3.88 (s, 3H), 3.63 - 3.43 (m, 2H), 3.29 - 3.21 (m, 1H), 3.11 - 2.94 (m, 5H), 2.91 (s, 2H), 2.87 - 2.73 (m, 1H), 2.71 - 2.41 (m, 7H), 2.40 - 2.25 (m, 10H), 2.23 - 2.05 (m, 2H), 1.74 (br d, 1H), 1.65 (br s, 1H), 1.45 - 1.00 (m, 21H), 0.85 (d, 3H).

[0428] Compound 51 [Chem.] S3-3-I5-1-7

[0429] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(naphthalene-2-ylsulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-7). Prepared from S3-1-I5-1 and 3-naphthalene-2-sulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 803.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.56 (br s, 1H), 8.39 (br s, 1H), 8.09 (dd, 2H), 8.02 (d, 1H), 7.81 - 7.75 (m, 1H), 7.75 - 7.64 (m, 2H), 5.37 (br dd, 1H), 4.58 (br s, 1H), 4.44 - 4.33 (m, 1H), 4.09 - 4.01 (m, 1H), 3.83 - 3.74 (m, 1H), 3.58 (br dd, 1H), 3.52 - 3.34 (m, 1H), 3.25 - 3.18 (m, 1H), 3.18 - 3.03 (m, 4H), 3.03 - 2.77 (m, 8H), 2.77 - 2.53 (m, 6H), 2.52 - 2.38 (m, 4H), 2.35 (s, 4H), 2.32 - 2.21 (m, 2H), 2.21 - 2.03 (m, 1H), 1.85 - 1.71 (m, 2H), 1.69 - 1.54 (m, 1H), 1.47 (s, 2H), 1.40 - 1.19 (m, 18H), 1.16 - 1.10 (m, 1H), 1.05 - 0.97 (m, 2H), 0.85 - 0.78 (m, 1H).

[0430] Compound 52 [Chem.] S3-3-I5-1-8

[0431] (2S,3S,6R,8R,9R,10R)-3-((4-(Benzylsulfonyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-8). Prepared from S3-1-I5-1 and phenylmethanesulfonyl chloride by the method of S3-3-I5-1-1, and the title compound was obtained as the formate. MS (ESI+) m / z: 767.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.48 - 7.35 (m, 5H), 4.70 - 4.50 (m, 2H), 4.45 - 4.32 (m, 3H), 4.10 -4.06 (m, 2H), 3.88 - 3.77 (m, 1H), 3.69 - 3.45 (m, 3H), 3.31 - 3.11 (m, 7H), 3.03 (s, 2H), 2.95 (s, 3H), 2.82 - 2.56 (m, 4H), 2.55 - 2.30 (m, 14H), 2.29 - 2.10 (m, 2H), 1.93 - 1.65 (m, 3H), 1.65 - 1.48 (m, 2H), 1.47 - 1.20 (m, 19H), 1.10 (br d, 1H), 0.92 (br d, 2H).

[0432] Compound 53 [Chemical formula] S3-3-I5-1-9

[0433] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-9). Prepared from S3-1-I5-1 and 2-propanesulfonyl chloride by the method of S3-3-I5-1-1, and the title compound was obtained as the formate. MS (ESI+) m / z: 719.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 5.56 - 5.38 (m, 1H), 4.77 - 4.58 (m, 3H), 4.41 (br d, 3H), 4.17 - 3.96 (m, 2H), 3.93 - 3.78 (m, 1H), 3.69 - 3.41 (m, 7H), 3.28 - 3.09 (m, 4H), 3.02 (s, 3H), 3.00 - 2.90 (m, 2H), 2.67 - 2.47 (m, 7H), 2.44 - 2.31 (m, 10H), 2.16 (s, 3H), 1.89 - 1.61 (m, 4H), 1.57 - 1.21 (m, 30H), 1.19 - 1.05 (m, 2H), 1.02 - 0.86 (m, 3H).

[0434] Compound 54

Chem.

[0435] (2S,3S,6R,8R,9R,10R)-3-((4-(Benzylsulfonyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-3-1). Prepared from S3-1-I5-3 and phenylmethanesulfonyl chloride by the method of S3-3-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 795.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.48 - 7.33 (m, 4H), 7.32 - 7.16 (m, 1H), 4.95 - 4.82 (m, 1H), 4.47 - 4.29 (m, 3H), 4.18 - 3.86 (m, 2H), 3.66 - 3.54 (m, 1H), 3.53 - 3.40 (m, 1H), 3.39 - 3.31 (m, 1H), 3.18 - 3.06 (m, 4H), 3.01 - 2.81 (m, 4H), 2.76 (br d, 1H), 2.67 - 1.90 (m, 14H), 1.86 - 1.75 (m, 1H), 1.66 (br d, 1H), 1.59 (dt, 1H), 1.53 - 1.15 (m, 19H), 1.14 - 1.01 (m, 1H), 0.93 - 0.79 (m, 4H).

[0436] Compound 55

Chem.

[0437] (2S,3S,6R,8R,9R,10R)-3-((4-acetylpiperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-1). S3-1-I5-1 (36.0 mg, 0.0502 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) were dissolved in dichloromethane (0.45 mL) and N,N-diisopropylethylamine (0.050 mL, 0.26 mmol). The solution was cooled to 0 °C, acetyl chloride (0.0106 mL, 0.150 mmol) was added, and the reaction mixture was warmed to rt. After 2 h, the reaction was placed in the freezer overnight. After stirring for an additional 1 h at rt, the reaction was saturated with NaHCO 3(1 mL) was added for quenching, and extracted with EtOAc (1 mL × 3). The combined extracts were dried over Na 2 SO 4 , filtered, and concentrated. The obtained crude substance was dissolved in MeOH (1 mL), heated at 40 °C overnight, and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5 - 50% MeCN - water - 0.1% HCO 2 H) to obtain 12.9 mg of the title compound as a formate. MS (ESI+) m / z: 655.39 [M + H]+; 1 H NMR (400 MHz, methanol - d) δ 8.35 (s, 3H), 5.43 (dq, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.88 (ddt, 1H), 3.73 (ddd, 1H), 3.65 - 3.36 (m, 7H), 3.18 (d, 3H), 3.07 (t, 1H), 3.02 (d, 3H), 2.98 - 2.85 (m, 2H), 2.82 (d, 6H), 2.68 - 2.53 (m, 4H), 2.53 - 2.44 (m, 1H), 2.26 (d, 1H), 2.09 (s, 3H), 2.07 - 2.01 (m, 1H), 1.83 (d, 1H), 1.59 - 1.43 (m, 4H), 1.42 - 1.37 (m, 5H), 1.37 - 1.33 (m, 9H), 1.33 - 1.27 (m, 3H), 1.07 (d, 3H).

[0438] Compound 56

Chem.

[0439] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-propionylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-2). Prepared from S3-1-I5-1 and propionyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 669.43 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.43 (s, 3H), 5.44 (dt, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.88 (ddd, 1H), 3.73 (ddd, 1H), 3.65 - 3.37 (m, 7H), 3.18 (s, 3H), 3.10 - 2.98 (m, 4H), 2.98 - 2.84 (m, 2H), 2.82 (s, 6H), 2.59 (dt, 3H), 2.53 - 2.45 (m, 1H), 2.40 (q, 2H), 2.27 (d, 1H), 2.03 (ddd, 1H), 1.83 (d, 1H), 1.61 - 1.52 (m, 1H), 1.50 (s, 3H), 1.43 - 1.33 (m, 14H), 1.33 - 1.27 (m, 3H), 1.14 - 1.03 (m, 6H).

[0440] Compound 57 [Chemical formula] S3-4-I5-1-3

[0441] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-pivaloylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-3). Prepared from S3-1-I5-1 and pivaloyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as formate. MS (ESI+) m / z: 697.33 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.37 (s, 3H), 5.42 (dq, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.93 - 3.81 (m, 1H), 3.78 - 3.59 (m, 5H), 3.54 - 3.46 (m, 1H), 3.46 - 3.36 (m, 2H), 3.18 (d, 3H), 3.07 (t, 1H), 3.02 (s, 3H), 2.97 - 2.83 (m, 2H), 2.81 (d, 6H), 2.65 - 2.55 (m, 3H), 2.55 - 2.47 (m, 2H), 2.33 - 2.20 (m, 1H), 2.02 (ddd, 1H), 1.82 (d, 1H), 1.59 - 1.44 (m, 4H), 1.42 - 1.33 (m, 13H), 1.31 (d, 3H), 1.26 (d, 9H), 1.10 - 1.03 (m, 3H).

[0442] Compound 59

Chemical Structure

[0443] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(2,2,2-trifluoroacetyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-5). Prepared from S3-1-I5-1 and trifluoroacetic anhydride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 709.27 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.49 (s, 3H), 5.46 (s, 1H), 4.51 (d, 1H), 4.12 (d, 1H), 3.89 (s, 1H), 3.80 - 3.65 (m, 5H), 3.53 (dd, 1H), 3.49 - 3.34 (m, 2H), 3.19 (s, 3H), 3.04 (s, 4H), 2.93 (dd, 2H), 2.80 (s, 6H), 2.74 - 2.58 (m, 5H), 2.28 (s, 1H), 2.06 - 1.99 (m, 1H), 1.85 (d, 1H), 1.52 (s, 4H), 1.45 - 1.35 (m, 13H), 1.33 (d, 3H), 1.09 (d, 3H).

[0444] Compound 60

Chemical Structure

[0445] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(3-methoxybenzoyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-6). Prepared from S3-1-I5-1 and 3-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to give the title compound as the free base. MS (ESI+) m / z: 747.3 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.57 (br s, 2H), 7.40 (br t, 1H), 7.07 (br d, 1H), 7.02 - 6.95 (m, 2H), 5.47 (br s, 1H), 4.50 (br d, 1H), 4.13 (br d, 1H), 3.91 (br s, 1H), 3.87 - 3.83 (m, 3H), 3.83 - 3.63 (m, 3H), 3.61 - 3.48 (m, 3H), 3.48 - 3.38 (m, 2H), 3.25 - 3.19 (m, 3H), 3.04 (br s, 4H), 3.01 - 2.90 (m, 2H), 2.71 (br s, 7H), 2.68 - 2.45 (m, 5H), 2.43 - 2.21 (m, 1H), 1.99 (br d, 1H), 1.87 (br d, 1H), 1.56 - 1.48 (m, 4H), 1.44 - 1.36 (m, 12H), 1.35 - 1.30 (m, 3H), 1.14 - 1.06 (m, 3H).

[0446] Compound 61

Chemical Structure

[0447] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(4-methoxybenzoyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-7). Prepared from S3-1-I5-1 and 4-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to give the title compound as the formate. MS (ESI+) m / z: 747.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.57 (br s, 2H), 7.40 (br t, 1H), 7.07 (br d, 1H), 7.02 - 6.95 (m, 2H), 5.47 (br s, 1H), 4.50 (br d, 1H), 4.13 (br d, 1H), 3.91 (br s, 1H), 3.87 - 3.83 (m, 3H), 3.83 - 3.63 (m, 3H), 3.61 - 3.48 (m, 3H), 3.48 - 3.38 (m, 2H), 3.25 - 3.19 (m, 3H), 3.04 (br s, 4H), 3.01 - 2.90 (m, 2H), 2.71 (br s, 7H), 2.68 - 2.45 (m, 5H), 2.43 - 2.21 (m, 1H), 1.99 (br d, 1H), 1.87 (br d, 1H), 1.56 - 1.48 (m, 4H), 1.44 - 1.36 (m, 12H), 1.35 - 1.30 (m, 3H), 1.14 - 1.06 (m, 3H).

[0448] Compound 62

Chemical Structure

[0449] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(2-methoxybenzoyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-8). Prepared from S3-1-I5-1 and 2-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 747.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.53 (br s, 1H), 7.46 - 7.39 (m, 1H), 7.21 (br d, 1H), 7.11 - 6.99 (m, 2H), 5.48 - 5.39 (m, 1H), 4.51 - 4.44 (m, 1H), 4.11 (br d, 1H), 3.91 - 3.77 (m, 5H), 3.77 - 3.62 (m, 2H), 3.60 - 3.45 (m, 1H), 3.44 - 3.34 (m, 2H), 3.19 (br s, 4H), 3.12 - 2.50 (m, 15H), 2.48 - 2.37 (m, 1H), 2.36 - 2.15 (m, 1H), 1.96 (br d, 1H), 1.90 - 1.77 (m, 1H), 1.55 - 1.15 (m, 18H), 1.12 - 1.03 (m, 2H).

[0450] Compound 63

Chem.

[0451] (2S,3S,6R,8R,9R,10R)-3-((4-(4-Chlorobenzoyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-9). Prepared from S3-1-I5-1 and 4-chlorobenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 751.2 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.51 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 4.59 - 4.50 (m, 1H), 4.40 (d, 1H), 4.14 - 4.03 (m, 1H), 3.94 - 3.64 (m, 3H), 3.63 - 3.41 (m, 5H), 3.29 - 3.17 (m, 2H), 3.05 - 2.99 (m, 1H), 2.93 (s, 3H), 2.90 - 2.81 (m, 1H), 2.80 - 2.32 (m, 18H), 2.30 - 2.12 (m, 2H), 1.80 - 1.65 (m, 3H), 1.51 (s, 1H), 1.43 - 1.21 (m, 20H), 1.20 - 1.07 (m, 2H), 0.90 (d, 2H).

[0452] Compound 64

Chemical Structure

[0453] (2S,3S,6R,8R,9R,10R)-3-((4-(3-Chlorobenzoyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-10). Prepared from S3-1-I5-1 and 3-chlorobenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 751.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.58 - 8.53 (m, 1H), 7.54 - 7.42 (m, 3H), 7.34 (br d, 1H), 5.52 - 5.40 (m, 1H), 4.41 (d, 1H), 4.15 - 3.98 (m, 1H), 3.95 - 3.65 (m, 2H), 3.63 - 3.34 (m, 4H), 3.29 - 3.14 (m, 2H), 3.11 - 2.99 (m, 1H), 2.99 - 2.83 (m, 3H), 2.76 - 2.59 (m, 3H), 2.59 - 2.30 (m, 12H), 2.28 - 2.09 (m, 1H), 1.95 - 1.63 (m, 3H), 1.51 (s, 1H), 1.44 - 1.14 (m, 17H), 1.13 - 1.08 (m, 1H), 0.91 (br d, 2H).

[0454] Compound 65

Chemical Structure

[0455] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(4-methylbenzoyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-11). Prepared from S3-1-I5-1 and 4-methylbenzoyl chloride by the method of S3-4-I5-1-1 and obtained the title compound as a formate. MS (ESI+) m / z: 731.3 [M + H]+; 1 H NMR (400MHz, methanol-d 4 ) δ = 7.35 - 7.27 (m, 4H), 5.47 (br dd, 0.4H), 4.72 - 4.52 (m, 1H), 4.42 (d, 1H), 4.17 - 4.05 (m, 1H), 3.95 - 3.73 (m, 2H), 3.64 - 3.46 (m, 5H), 3.31 - 3.26 (m, 1H), 3.25 - 3.19 (m, 1H), 2.95 (s, 3H), 2.91 - 2.83 (m, 1H), 2.70 - 2.50 (m, 6H), 2.42 - 2.34 (m, 14H), 2.27 - 2.14 (m, 1H), 1.82 - 1.68 (m, 3H), 1.45 - 1.25 (m, 21H), 1.22 - 1.07 (m, 2H), 0.92 (d, 3H).

[0456] Compound 66

Chemical Structure

[0457] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(3-methylbenzoyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-12). Prepared from S3-1-I5-1 and 3-methylbenzoyl chloride by the method of S3-4-I5-1-1 and obtained the title compound as formate. MS (ESI+) m / z: 731.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.53 (s, 1H), 7.42 - 7.27 (m, 2H), 7.26 - 7.17 (m, 2H), 5.51 - 5.39 (m, 1H), 4.54 - 4.45 (m, 1H), 4.12 (br d, 1H), 3.94 - 3.84 (m, 1H), 3.84 - 3.63 (m, 3H), 3.60 - 3.34 (m, 5H), 3.28 - 3.17 (m, 4H), 3.17 - 2.88 (m, 7H), 2.77 - 2.59 (m, 9H), 2.57 - 2.45 (m, 2H), 2.39 (s, 3H), 2.35 - 2.13 (m, 1H), 2.01 - 1.91 (m, 1H), 1.85 (br d, 1H), 1.56 - 1.44 (m, 4H), 1.44 - 1.25 (m, 16H), 1.09 (br d, 3H).

[0458] Compound 67

Chem.

[0459] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-13). Prepared from S3-1-I5-1 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 785.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.83 - 7.77 (m, 1H), 7.75 - 7.66 (m, 3H), 5.52 - 5.39 (m, 1H), 4.41 (d, 1H), 4.17 - 4.01 (m, 1H), 3.78 (br s, 2H), 3.65 - 3.39 (m, 4H), 3.29 - 3.23 (m, 1H), 3.19 (s, 1H), 3.02 (s, 1H), 2.93 (s, 3H), 2.85 (br d, 1H), 2.70 - 2.43 (m, 6H), 2.43 - 2.25 (m, 10H), 2.19 (br d, 1H), 1.91 - 1.62 (m, 3H), 1.51 (s, 1H), 1.44 - 1.22 (m, 18H), 1.20 - 1.04 (m, 2H), 0.95 - 0.86 (m, 2H).

[0460] Compound 68

Chem.

[0461] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-nicotinoylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-14). Prepared from S3-1-I5-1 and nicotinoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 718.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.69 - 8.51 (m, 3H), 7.90 (br d, 1H), 7.58 - 7.49 (m, 1H), 5.45 (br dd, 0.4H), 4.66 - 4.50 (m, 1H), 4.47 - 4.34 (m, 1H), 4.17 - 4.01 (m, 1H), 3.97 - 3.67 (m, 3H), 3.64 - 3.38 (m, 4H), 3.27 - 3.14 (m, 2H), 3.12 - 3.01 (m, 2H), 2.98 - 2.81 (m, 3H), 2.79 - 2.14 (m, 17H), 1.93 - 1.59 (m, 3H), 1.54 - 1.19 (m, 20H), 1.17 - 1.01 (m, 2H), 0.90 (br d, 1H).

[0462] Compound 69

Chem.

[0463] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-(3-methoxyphenyl)piperazine-1-carboxamide (S3-4-I5-1-15). Prepared from S3-1-I5-1 and 3-methoxyphenyl isocyanate by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 762.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.55 (br s, 1H), 7.18 - 7.11 (m, 1H), 7.04 (s, 1H), 6.91 (br d, 1H), 6.63 - 6.56 (m, 1H), 5.45 (br dd, 1H), 4.67 - 4.50 (m, 1H), 4.41 (br d, 1H), 4.10 (br t, 1H), 3.96 - 3.83 (m, 1H), 3.77 (s, 3H), 3.57 (br s, 3H), 3.52 (br s, 3H), 3.27 - 3.17 (m, 3H), 3.14 - 2.99 (m, 3H), 2.99 - 2.83 (m, 3H), 2.81 - 2.72 (m, 1H), 2.66 (br s, 2H), 2.62 - 2.46 (m, 4H), 2.41 (br s, 4H), 2.38 - 2.19 (m, 6H), 1.96 - 1.65 (m, 3H), 1.51 (br s, 2H), 1.46 - 1.21 (m, 19H), 1.14 - 1.07 (m, 2H), 0.99 - 0.84 (m, 1H).

[0464] Compound 70 [Chemical Structure] S3-4-I5-1-15

[0465] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-phenylpiperazine-1-carboxamide (S3-4-I5-1-16). Prepared from S3-1-I5-1 and phenyl isocyanate by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 732.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.63 - 8.46 (m, 1H), 7.36 - 7.31 (m, 2H), 7.30 - 7.21 (m, 2H), 7.02 (q, 1H), 5.49 - 5.41 (m, 1H), 4.85 - 4.82 (m, 1H), 4.65 - 4.53 (m, 1H), 4.41 (br dd, 1H), 4.25 - 3.99 (m, 1H), 3.90 (br s, 1H), 3.69 - 3.42 (m, 7H), 3.28 - 3.17 (m, 3H), 3.14 - 3.00 (m, 2H), 3.00 - 2.85 (m, 3H), 2.69 - 2.46 (m, 6H), 2.43 - 2.28 (m, 8H), 2.25 - 2.09 (m, 1H), 1.95 - 1.82 (m, 1H), 1.81 - 1.62 (m, 2H), 1.51 (s, 1H), 1.45 - 1.20 (m, 18H), 1.10 (br d, 1H), 0.92 (br d, 1H).

[0466] Compound 71 [Chemical formula] S3-4-I5-1-16

[0467] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-(naphthalen-2-yl)piperazine-1-carboxamide (S3-4-I5-1-16). Prepared from S3-1-I5-1 and 2-naphthyl isocyanate by the method of S3-4-I5-1-1 to obtain the title compound as formate. MS (ESI+) m / z: 782.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.57 (br s, 1H), 7.86 (d, 1H), 7.76 (dd, J 3H), 7.50 (dd, 1H), 7.46 - 7.40 (m, 1H), 7.39 - 7.33 (m, 1H), 5.53 - 5.41 (m, 1H), 4.48 - 4.37 (m, 1H), 4.17 - 4.03 (m, 1H), 3.93 (br d, 1H), 3.71 - 3.45 (m, 6H), 3.23 (s, 2H), 3.11 - 3.01 (m, 2H), 3.01 - 2.83 (m, 3H), 2.81 - 2.50 (m, 7H), 2.46 - 2.26 (m, 10H), 1.97 - 1.69 (m, 3H), 1.56 - 1.50 (m, 2H), 1.47 - 1.35 (m, 10H), 1.31 - 1.22 (m, 10H), 1.17 - 1.08 (m, 2H), 0.93 (br d, 1H).

[0468] Compound 72

Chem.

[0469] N-Benzyl-4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)piperazine-1-carboxamide (S3-4-I5-1-17). Prepared from S3-1-I5-1 and benzyl isocyanate by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 746.5 [M + H]+; 1 HNMR (400 MHz, methanol-d 4 ) δ = 8.63 - 8.52 (m, 0.3H), 7.34 - 7.22 (m, 5H), 5.46 (br dd, 1H), 4.61 (br s, 1H), 4.47 - 4.31 (m, 3H), 4.22 - 4.03 (m, 1H), 3.98 - 3.84 (m, 1H), 3.67 - 3.46 (m, 5H), 3.46 - 3.38 (m, 2H), 3.29 - 3.18 (m, 3H), 3.12 - 3.00 (m, 3H), 3.00 - 2.84 (m, 3H), 2.82 - 2.59 (m, 3H), 2.57 - 2.39 (m, 7H), 2.39 - 2.11 (m, 6H), 1.97 - 1.63 (m, 3H), 1.53 (s, 2H), 1.46 - 1.21 (m, 20H), 1.11 (br d, 2H), 1.01 - 0.84 (m, 1H).

[0470] Compound 73

Chemical Structure

[0471] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-isopropylpiperazine-1-carboxamide (S3-4-I5-1-18). Prepared from S3-1-I5-1 and isopropyl isocyanate by the method of S3-4-I5-1-1, and the title compound was obtained as the formate. MS (ESI+) m / z: 698.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.57 - 8.52 (m, 0.4H), 5.51 - 5.37 (m, 1H), 4.41 (br d, 1H), 4.13 - 4.05 (m, 1H), 3.93 - 3.83 (m, 2H), 3.63 - 3.45 (m, 3H), 3.44 - 3.33 (m, 5H), 3.29 - 3.13 (m, 3H), 3.02 (s, 2H), 2.94 (s, 2H), 2.86 (br d, 1H), 2.71 - 2.55 (m, 3H), 2.53 - 2.27 (m, 15H), 2.22 - 2.11 (m, 1H), 1.89 - 1.65 (m, 3H), 1.51 (s, 1H), 1.44 - 1.19 (m, 21H), 1.16 - 1.07 (m, 9H), 0.95 - 0.86 (m, 2H).

[0472] Compound 74

Chemical Structure

[0473] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(3-methoxybenzoyl)piperazin-1-yl)methyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-1). Prepared from S3-1-I5-3 and 3-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to give the title compound as the formate. MS (ESI+) m / z: 775.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.39 (t, 1H), 7.05 (dd, 1H), 6.99 - 6.94 (m, 2H), 4.42 (br d, 1H), 4.10 (br d, 1H), 3.84 (s, 3H), 3.76 (br s, 2H), 3.69 - 3.48 (m, 4H), 3.48 - 3.37 (m, 3H), 3.30 - 3.13 (m, 1H), 2.95 - 2.72 (m, 5H), 2.70 - 2.51 (m, 4H), 2.53 - 2.33 (m, 13H), 2.18 (s, 2H), 1.90 - 1.64 (m, 3H), 1.52 - 1.36 (m, 9H), 1.34 - 1.18 (m, 16H), 0.97 - 0.84 (m, 6H).

[0474] Compound 75

Chem.

[0475] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(4-methoxybenzoyl)piperazin-1-yl)methyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-2). Prepared from S3-1-I5-3 and 4-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 775.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.42 - 7.36 (m, 2H), 7.03 - 6.97 (m, 2H), 5.32 (br dd, 1H), 4.63 - 4.44 (m, 2H), 4.17 - 3.92 (m, 3H), 3.86 - 3.82 (m, 4H), 3.78 - 3.50 (m, 7H), 3.49 - 3.35 (m, 4H), 3.26 - 3.11 (m, 2H), 3.08 - 2.88 (m, 6H), 2.81 (br s, 2H), 2.76 (br s, 4H), 2.73 - 2.59 (m, 3H), 2.59 - 2.50 (m, 2H), 2.49 - 2.34 (m, 2H), 2.34 - 2.23 (m, 1H), 2.12 (td, 2H), 2.00 (br d, 1H), 1.83 (br d, 1H), 1.53 - 1.25 (m, 22H), 1.16 - 1.04 (m, 5H), 0.94 - 0.83 (m, 1H).

[0476] Compound 76

Chemical Structure

[0477] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(2-methoxybenzoyl)piperazin-1-yl)methyl)-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-3). Prepared from S3-1-I5-3 and 2-methoxybenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 775.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.47 - 7.39 (m, 1H), 7.25 - 7.15 (m, 1H), 7.13 - 6.96 (m, 2H), 4.46 - 4.37 (m, 1H), 4.08 (d, 1H), 3.89 - 3.66 (m, 5H), 3.64 - 3.46 (m, 2H), 3.25 - 3.16 (m, 3H), 2.97 - 2.90 (m, 3H), 2.86 - 2.70 (m, 2H), 2.67 - 2.35 (m, 12H), 2.32 - 2.09 (m, 5H), 1.84 - 1.72 (m, 1H), 1.68 - 1.54 (m, 1H), 1.51 - 1.19 (m, 22H), 1.10 (br d, 3H), 0.96 - 0.78 (m, 6H).

[0478] Compound 77

Chem.

[0479] (2S,3S,6R,8R,9R,10R)-3-((4-(4-Chlorobenzoyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-4). Prepared from S3-1-I5-3 and 4-chlorobenzoyl chloride by the method of S3-4-I5-1-1 to give the title compound as the formate. MS (ESI+) m / z: 779.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.50 - 7.38 (m, 4H), 4.63 - 4.51 (m, 1H), 4.40 (br d, 1H), 4.14 - 3.99 (m, 1H), 3.78 - 3.65 (m, 2H), 3.63 - 3.45 (m, 3H), 3.45 - 3.35 (m, 2H), 3.27 - 3.04 (m, 1H), 3.02 - 2.85 (m, 4H), 2.85 - 2.63 (m, 3H), 2.60 - 2.35 (m, 13H), 2.34 - 2.05 (m, 4H), 1.85 - 1.68 (m, 2H), 1.66 - 1.56 (m, 1H), 1.49 - 1.41 (m, 5H), 1.41 - 0.97 (m, 20H), 0.93 - 0.82 (m, 6H).

[0480] Compound 78

Chemical Structure

[0481] (2S,3S,6R,8R,9R,10R)-3-((4-(3-Chlorobenzoyl)piperazin-1-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-5). Prepared from S3-1-I5-3 and 3-chlorobenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 779.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.55 - 7.39 (m, 3H), 7.33 (d, 1H), 4.40 (br d, 1H), 4.07 (d, 1H), 3.73 (br d, 2H), 3.61 - 3.47 (m, 3H), 3.40 (br s, 2H), 3.25 - 3.05 (m, 1H), 2.99 - 2.89 (m, 3H), 2.85 - 2.78 (m, 1H), 2.74 - 2.56 (m, 1H), 2.54 - 2.25 (m, 17H), 2.23 - 2.00 (m, 2H), 1.81 - 1.70 (m, 1H), 1.68 - 1.52 (m, 1H), 1.50 - 1.31 (m, 10H), 1.29 - 0.97 (m, 19H), 0.95 - 0.70 (m, 7H).

[0482] Compound 79

Chemical Structure

[0483] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-((4-(4-methylbenzoyl)piperazin-1-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-6). Prepared from S3-1-I5-3 and 4-methylbenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 759.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.34 - 7.27 (m, 4H), 4.42 (br d, 1H), 4.10 (d, 1H), 3.75 (br s, 2H), 3.65 - 3.39 (m, 5H), 3.31 - 3.21 (m, 1H), 2.95 (s, 3H), 2.85 (br d, 1H), 2.76 - 2.52 (m, 4H), 2.49 - 2.32 (m, 16H), 2.28 - 2.12 (m, 2H), 1.90 - 1.56 (m, 3H), 1.52 - 1.36 (m, 9H), 1.34 - 1.22 (m, 14H), 1.22 - 1.16 (m, 1H), 1.13 (br s, 1H), 0.97 - 0.84 (m, 7H).

[0484] Compound 80

Chemical Structure

[0485] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-((4-(3-methylbenzoyl)piperazin-1-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-7). Prepared from S3-1-I5-3 and 3-methylbenzoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 759.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.32 (td, 2H), 7.24 - 7.11 (m, 2H), 4.41 (br d, 1H), 4.08 (br d, 1H), 3.81 - 3.66 (m, 2H), 3.61 - 3.36 (m, 4H), 3.25 - 3.13 (m, 1H), 2.93 (s, 3H), 2.87 - 2.78 (m, 1H), 2.74 - 2.54 (m, 2H), 2.53 - 2.26 (m, 19H), 2.24 - 2.03 (m, 2H), 1.79 - 1.72 (m, 1H), 1.70 - 1.55 (m, 1H), 1.50 - 1.40 (m, 6H), 1.36 (s, 4H), 1.29 - 0.99 (m, 19H), 0.93 - 0.74 (m, 8H).

[0486] Compound 81

Chem.

[0487] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-4-propyl-3-((4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-8). Prepared from S3-1-I5-3 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I5-1-1 to give the title compound as the formate. MS (ESI+) m / z: 813.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.82 - 7.77 (m, 1H), 7.74 - 7.65 (m, 3H), 4.40 (br d, 1H), 4.08 (d, 1H), 3.77 (br s, 2H), 3.68 - 3.45 (m, 3H), 3.41 (br s, 2H), 3.29 - 3.19 (m, 1H), 2.93 (s, 3H), 2.83 (br d, 1H), 2.73 - 2.56 (m, 3H), 2.52 - 2.32 (m, 13H), 2.25 - 2.06 (m, 2H), 1.88 - 1.53 (m, 3H), 1.50 - 1.34 (m, 9H), 1.32 - 1.18 (m, 14H), 0.94 - 0.82 (m, 6H).

[0488] Compound 82

Chemical Structure

[0489] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-3-((4-nicotinoylpiperazin-1-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-3-9). Prepared from S3-1-I5-3 and nicotinoyl chloride by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 746.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.64 (dd, 2H), 8.61 (d, 1H), 7.90 (td, 1H), 7.53 (dd, 1H), 5.02 - 4.89 (m, 1H), 4.41 (br d, 1H), 4.08 (d, 1H), 3.77 (br s, 2H), 3.64 - 3.35 (m, 5H), 3.28 - 3.13 (m, 1H), 2.94 (s, 3H), 2.83 (br d, 1H), 2.78 - 2.58 (m, 3H), 2.54 - 2.32 (m, 13H), 2.29 - 2.09 (m, 3H), 1.92 - 1.69 (m, 2H), 1.68 - 1.55 (m, 1H), 1.50 - 1.35 (m, 9H), 1.33 - 1.03 (m, 16H), 0.95 - 0.82 (m, 6H).

[0490] Compound 83

Chem.

[0491] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,6,8,10,12,12-hexamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-phenylpiperazine-1-carboxamide (S3-4-I5-3-10). Prepared from S3-1-I5-3 and phenyl isocyanate by the method of S3-4-I5-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 760.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.34 (br d, 2H), 7.25 (br t, 2H), 7.05 - 6.98 (m, 1H), 4.41 (br d, 1H), 4.13 - 4.07 (m, 1H), 3.67 - 3.46 (m, 8H), 3.02 - 2.91 (m, 4H), 2.90 - 2.81 (m, 1H), 2.77 - 2.64 (m, 2H), 2.62 - 2.51 (m, 3H), 2.49 - 2.35 (m, 12H), 2.26 - 2.11 (m, 2H), 1.77 (br d, 1H), 1.73 - 1.55 (m, 2H), 1.52 - 1.42 (m, 6H), 1.42 - 1.35 (m, 4H), 1.32 - 1.24 (m, 12H), 1.16 - 1.05 (m, 1H), 0.97 - 0.84 (m, 6H).

[0492] The following example compounds were prepared by replacing the appropriate intermediates from Table 1 according to the method of Scheme 3.

Chemical Structure

[0493] Benzyl 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)piperidine-1-carboxylate (S3-1-I7-3). The oven-dried flask was evacuated and backfilled with nitrogen (twice), then cooled to rt. A solution of S2-1-I7-3 (196 mg, 0.226 mmol, prepared from I7 and propionaldehyde as described in Scheme 1) in ethanol (4 mL) was added to the flask, which was then evacuated and backfilled with nitrogen (twice). 10% Pd / C (50% wet, 40 mg, 0.0187 mmol) was added to the flask, and the reaction mixture was evacuated and backfilled with nitrogen (twice), then evacuated and backfilled with hydrogen (four times). The reaction mixture was stirred under a hydrogen balloon for 1.5 h. The reaction mixture was evacuated and backfilled with nitrogen (four times). Celite® was added, the reaction mixture was stirred for about 10 min, and filtered through Celite®. The wet pad was rinsed with EtOH (5 mL×2), and the combined organic layers were concentrated to give the crude title compound (166.4 mg, 100%), which was used without further purification. MS (ESI+) m / z: 730.26 [M + H]+, formate, 1 H NMR (400 MHz, methanol-d) δ 8.48 (s, 3H), 4.46 (dd, 1H), 4.34 - 4.06 (m, 2H), 3.80 - 3.67 (m, 1H), 3.55 - 3.34 (m, 5H), 3.25 - 3.05 (m, 2H), 3.04 - 2.86 (m, 6H), 2.86 - 2.74 (m, 10H), 2.18 - 1.90 (m, 4H), 1.85 - 1.57 (m, 7H), 1.57 - 1.46 (m, 6H), 1.43 - 1.23 (m, 13H), 1.09 - 0.90 (m, 6H).

[0494] Compound 84 [Chem.] S3-2-I7-3-1

[0495] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-methylpiperidin-4-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-1). Prepared from S3-1-I7-3 and formaldehyde by the method of S3-2-I4-1-2, and the title compound was obtained as the formate. MS (ESI+) m / z: 640.33 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.48 (s, 3H), 4.46 (dd, 1H), 4.34 - 4.06 (m, 2H), 3.80 - 3.67 (m, 1H), 3.55 - 3.34 (m, 5H), 3.25 - 3.05 (m, 2H), 3.04 - 2.86 (m, 6H), 2.86 - 2.74 (m, 10H), 2.18 - 1.90 (m, 4H), 1.85 - 1.57 (m, 7H), 1.57 - 1.46 (m, 6H), 1.43 - 1.23 (m, 13H), 1.09 - 0.90 (m, 6H).

[0496] Compound 85 [Chem.] S3-2-I7-3-2

[0497] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-3-((1-propylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-2). Prepared from S3-1-I7-3 and propionaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as formate. MS (ESI+) m / z: 668.38 [M + H]+; 1 H NMR (400 MHz, methanol-d) δ 8.51 (s, 3H), 4.46 (d, 1H), 4.26 - 3.96 (m, 2H), 3.79 - 3.66 (m, 1H), 3.62 - 3.49 (m, 3H), 3.49 - 3.34 (m, 3H), 3.05 - 2.96 (m, 3H), 2.96 - 2.83 (m, 5H), 2.83 - 2.73 (m, 7H), 2.15 - 1.91 (m, 4H), 1.82 - 1.70 (m, 3H), 1.70 - 1.43 (m, 11H), 1.41 - 1.22 (m, 13H), 1.07 - 0.83 (m, 9H).

[0498] Compound 86

Chemical formula

[0499] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-methylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-1). Prepared from S3-1-I7-2 and formaldehyde by the method of S3-2-I4-1-2, the title compound was obtained as a formate. MS (ESI+) m / z: 209.5 [M + 3H]3+, 313.8 [M + 2H]2+, 626.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ 8.50 (s, 2H), 4.41 (d, 1H), 4.14 (s, 1H), 3.68 (m, 1H), 3.46 - 3.25 (m, 5H), 2.95 - 2.80 (m, 5H), 2.75 (d, 6H), 2.07 - 1.94 (m, 3H), 1.89 (d, 1H), 1.52 (s, 1H), 1.44 (d, 3H), 1.30 (m, 12H), 1.21 (s, 2H), 1.00 - 0.93 (m, 2H).

[0500] Compound 87

Chemical formula

[0501] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-ethylpiperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-2). Prepared from S3-1-I7-2 and acetaldehyde by the method of S3-2-I4-1-2, the title compound was obtained as a formate. MS (ESI+) m / z: 640.35 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.54 (s, 3H), 4.46 (d, 1H), 4.37 - 3.97 (m, 2H), 3.79 - 3.65 (m, 1H), 3.64 - 3.40 (m, 5H), 3.40 - 3.33 (m, 1H), 3.16 - 3.03 (m, 3H), 3.03 - 2.81 (m, 6H), 2.81 - 2.70 (m, 8H), 2.16 - 1.84 (m, 5H), 1.57 - 1.41 (m, 8H), 1.41 - 1.08 (m, 20H), 1.08 - 0.81 (m, 4H).

[0502] Compound 88 [Chemical formula] S3-2-I7-2-3

[0503] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-propylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-3). Prepared from S3-1-I7-2 and propionaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as a formate. MS (ESI+) m / z: 654.30 [M + H]+; 11H NMR (400 MHz, methanol-d) δ 8.51 (s, 2H), 4.46 (d, 1H), 4.36 - 3.90 (m, 2H), 3.78 - 3.65 (m, 1H), 3.62 - 3.39 (m, 5H), 3.39 - 3.33 (m, 1H), 3.07 - 2.82 (m, 8H), 2.82 - 2.67 (m, 8H), 2.14 - 1.87 (m, 4H), 1.82 - 1.60 (m, 5H), 1.60 - 1.41 (m, 8H), 1.41 - 1.24 (m, 14H), 1.24 - 1.07 (m, 3H), 1.07 - 0.81 (m, 6H).

[0504] [Chemical formula] S3-2-I7-2-4-OTBS

[0505] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)methyl)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-2-I7-2-4-OTBS). S3-1-I7-2 (90 mg, 0.13 mmol) was dissolved in dry methylene chloride (2 mL). Acetic acid (0.021 mL, 0.38 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.036 mL, 0.19 mmol) were added. Then, NaBH(OAc) 3 (53 mg, 0.25 mmol) was added to the reaction mixture all at once. The reaction was stirred at rt for 2 h, at which point LC / MS indicated complete conversion. Saturated, NaHCO 3 The reaction was quenched by the addition of aqueous solution (5 mL), and the aqueous layer was extracted with methylene chloride (3 × 10 mL). The combined extracts were MgSO 4It was dried, filtered, and concentrated. The residue was purified by 4 g of silica gel (eluted with 0 - 10% MeOH - dichloromethane + 0.5% of 30% NH 4 OH aqueous solution) to obtain the title compound (60 mg, 55%). MS (ESI+) m / z: 292.2 [M + 3H]3+, 437.8 [M + 2H]2+, 874.6 [M + H]+.

[0506]

Chemical Structure

[0507] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-2-I7-2-4-OBz). S3-2-I7-2-4-OTBS (60 mg, 0.067 mmol) was dissolved in dry THF (2 mL), and TBAF (1 M in THF, 0.20 mL, 0.020 mmol) was added at room temperature. The reaction mixture was stirred at rt for 2 hours and concentrated. The residue was purified by 4 g of silica gel (eluted with 0 - 20% MeOH - dichloromethane + 0.5% of 30% NH 4 OH aqueous solution) to obtain the title compound (46 mg, 88%). MS (ESI+) m / z: 254.2 [M + 3H]3+, 380.8 [M + 2H]2+, 760.5 [M + H]+.

[0508] Compound 89

Chemical Structure

[0509] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-4). Prepared by methanolysis of S3-2-I7-2-4-OTBS according to the method of S3-2-I4-1-2. MS (ESI+) m / z: 219.5 [M + 3H]3+, 328.8 [M + 2H]2+, 656.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4 ) δ 8.53 (s, 2H), 4.45 (d, 1H), 3.84 (t, 2H), 3.71 (ddd, 1H), 3.53 - 3.40 (m, 4H), 3.40 - 3.27 (m, 6H), 3.13 (d, 1H), 3.08 (s, 2H), 2.99 - 2.90 (m, 3H), 2.84 (s, 1H), 2.77 (s, 7H), 2.08 - 1.96 (m, 3H), 1.92 (d, 1H), 1.59 (s, 1H), 1.47 (dd, 5H), 1.39 - 1.27 (m, 12H), 0.97 (s, 2H).

[0510]

Chem.

[0511] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-8-methoxy-3-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecane-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S3-2-I7-2-5-OBz). To an 8 mL vial was added 1,2-dimethoxyethane (2 mL) of S3-2-I7-2-4-OBz pre-cooled to -60 °C. A solution of KHMDS (0.10 mL, 0.10 mmol) was added dropwise. The reaction mixture was stirred at -60 °C for 20 minutes. Then, Me 2 SO 4 (16 μL, 0.17 mmol) was added. The reaction mixture was warmed to -15 °C. LC / MS showed complete conversion. The reaction was quenched by the addition of triethylamine (1 mL), and the resulting mixture was diluted with dichloromethane and saturated NaHCO 3 was added. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over MgSO 4 and filtered and concentrated. The residue was purified by 4 g of silica gel (eluted with 0 - 10% MeOH-dichloromethane + 0.5% of 30% NH 4 OH aqueous solution) to give the title compound (22 mg, 82%). MS (ESI+) m / z: 258.8 [M + 3H]3+, 387.8 [M + 2H]2+, 774.5 [M + H]+.

[0512] Compound 90

Chemical Structure

[0513] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-3-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-5). Prepared by methanolysis of S3-2-I7-2-5-OBz according to the method of S3-2-I4-1-2. MS (ESI+) m / z: 224.2 [M + 3H]3+, 335.8 [M + 2H]2+, 670.5 [M + H]+; 11H NMR (400 MHz, methanol-d 4 ) δ 8.53 (s, 2H), 4.45 (d, 1H), 4.14 (s, 1H), 3.69 (dt, 3H), 3.54 - 3.44 (m, 2H), 3.44 - 3.27 (m, 10H), 3.19 (d, 1H), 3.13 (s, 2H), 2.94 (s, 2H), 2.78 (d, 8H), 2.06 - 1.96 (m, 2H), 1.89 (d, 1H), 1.54 (s, 4H), 1.51 - 1.40 (m, 3H), 1.39 - 1.27 (m, 12H), 1.25 - 1.18 (m, 2H), 0.98 (s, 2H).

[0514] Compound 91 [Chemical formula] S3-2-I7-2-6

[0515] (3R,6R,8R,9R,10R)-3-((1-Benzylpiperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-6). Prepared from S3-1-I7-2 and benzaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as a formate. MS (ESI+) m / z: 702.5 [M + H]+; 1 1H NMR (400 MHz, methanol-d 4) δ = 7.36 (br d, 5H), 4.42 (br s, 1H), 4.34 - 3.85 (m, 3H), 3.82 - 3.54 (m, 4H), 3.37 (br s, 2H), 3.19 - 2.95 (m, 3H), 2.83 (br s, 3H), 2.65 (br d, 7H), 2.39 - 2.07 (m, 3H), 2.04 - 1.69 (m, 5H), 1.60 - 1.21 (m, 22H), 1.07 (br s, 3H), 0.86 (br s, 2H).

[0516] Compound 92

Chem.

[0517] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-3-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-7). Prepared from S3-1-I7-2 and 3-methoxybenzaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as a formate. MS (ESI+) m / z: 732.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (br s, 0.43H), 7.23 (t, 1H), 6.95 - 6.87 (m, 2H), 6.84 (dd, 1H), 4.44 - 4.30 (m, 2H), 4.09 (br d, 1H), 4.01 - 3.95 (m, 1H), 3.90 (br t, 1H), 3.79 (s, 3H), 3.74 - 3.65 (m, 1H), 3.60 - 3.56 (m, 1H), 3.53 (s, 2H), 3.11 - 3.04 (m, 1H), 2.95 (br t, 2H), 2.81 (s, 3H), 2.74 - 2.55 (m, 3H), 2.51 - 2.40 (m, 6H), 2.38 - 2.20 (m, 2H), 2.14 - 2.03 (m, 2H), 2.02 - 1.91 (m, 1H), 1.81 (br d, 2H), 1.76 - 1.65 (m, 2H), 1.53 (s, 3H), 1.46 - 1.20 (m, 20H), 1.14 - 0.95 (m, 5H), 0.84 (br d, 3H).

[0518] Compound 93 [Chemical formula] S3-2-I7-2-8

[0519] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-phenethylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-8). Prepared from S3-1-I7-2 and phenylacetaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as a formate. MS (ESI+) m / z: 716.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (s, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.16 (m, 3H), 4.60 (br s, 1H), 4.42 (br d, 1H), 4.29 (br s, 1H), 4.11 (br s, 1H), 4.04 - 3.88 (m, 2H), 3.77 - 3.59 (m, 2H), 3.39 (br s, 1H), 3.25 - 2.98 (m, 5H), 2.95 - 2.75 (m, 7H), 2.73 - 2.52 (m, 5H), 2.48 - 2.09 (m, 5H), 2.05 - 1.76 (m, 3H), 1.69 (br s, 1H), 1.54 (br s, 4H), 1.47 - 1.18 (m, 20H), 1.15 - 0.97 (m, 4H), 0.95 - 0.76 (m, 3H).

[0520] Compound 94 [Chem.] S3-2-I7-2-9

[0521] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-isobutylpiperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-9). Prepared from S3-1-I7-2 and isobutyl aldehyde by the method of S3-2-I4-1-2 to obtain the title compound as formate. MS (ESI+) m / z: 668.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (br s, 1.33H), 4.56 (br s, 1H), 4.15 - 4.06 (m, 1H), 4.03 - 3.79 (m, 2H), 3.70 (br d, 1H), 3.65 - 3.61 (m, 1H), 3.52 - 3.43 (m, 1H), 3.12 (br d, 3H), 2.97 - 2.89 (m, 2H), 2.81 (br s, 2H), 2.67 (br dd, 3H), 2.52 - 2.20 (m, 12H), 2.07 - 1.61 (m, 8H), 1.53 (s, 3H), 1.50 - 1.21 (m, 22H), 1.06 (br d, 3H), 0.96 (br d, 7H), 0.85 (br d, 3H).

[0522] Compound 95 [Chem.] S3-2-I7-2-10

[0523] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-10). Prepared from S3-1-I7-2 and nicotinaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as the formate. MS (ESI+) m / z: 703.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (s, 0.56H), 8.50 (d, 1H), 8.47 - 8.42 (m, 1H), 7.84 (br d, 1H), 7.42 (dd, 1H), 4.40 (br d, 1H), 4.09 (br d, 1H), 4.03 - 3.79 (m, 2H), 3.76 - 3.54 (m, 4H), 3.35 (br s, 1H), 3.15 - 2.86 (m, 5H), 2.81 (br s, 2H), 2.72 - 2.35 (m, 9H), 2.32 - 2.18 (m, 1H), 2.16 - 1.61 (m, 6H), 1.53 (s, 3H), 1.48 - 1.18 (m, 19H), 1.16 - 0.94 (m, 4H), 0.84 (br d, 2H).

[0524] Compound 96 [Chem.] S3-2-I7-3-1

[0525] (3R,6R,8R,9R,10R)-3-((1-Benzylpiperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-1). Prepared from S3-1-I7-3 and benzaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as a formate. MS (ESI+) m / z: 716.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.53 (br s, 1H), 7.37 (br s, 5H), 4.43 (br d, 1H), 4.24 - 4.09 (m, 1H), 4.02 - 3.93 (m, 1H), 3.91 - 3.81 (m, 1H), 3.73 - 3.55 (m, 5H), 3.48 - 3.35 (m, 2H), 3.07 (br d, 6H), 2.80 (br s, 3H), 2.74 - 2.48 (m, 9H), 2.41 - 2.29 (m, 3H), 2.02 - 1.83 (m, 4H), 1.77 (br d, 3H), 1.56 - 1.20 (m, 26H), 1.04 - 0.70 (m, 7H).

[0526] Compound 97 [Chem.] S3-2-I7-3-2

[0527] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-2). Prepared from S3-1-I7-3 and 3-methoxybenzaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as the formate. MS (ESI+) m / z: 746.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (br s, 0.67H), 7.25 (t, 1H), 6.96 - 6.89 (m, 2H), 6.86 (dd, 1H), 4.45 - 4.35 (m, 1H), 4.18 (br d, 1H), 3.97 (br d, 1H), 3.87 (br t, 1H), 3.80 (s, 3H), 3.72 - 3.50 (m, 4H), 3.36 (br d, 1H), 3.12 - 3.03 (m, 1H), 2.98 (br t, 3H), 2.79 (s, 3H), 2.63 - 2.42 (m, 9H), 2.26 - 2.07 (m, 3H), 2.05 - 1.94 (m, 1H), 1.85 (br t, 2H), 1.78 - 1.59 (m, 3H), 1.51 (s, 3H), 1.49 - 1.38 (m, 4H), 1.37 - 1.20 (m, 18H), 1.05 - 0.88 (m, 5H), 0.83 (br d, 3H).

[0528] Compound 98 [Chem.] S3-2-I7-3-3

[0529] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-phenethylpiperidin-4-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-3). Prepared from S3-1-I7-3 and phenylacetaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as the formate. MS (ESI+) m / z: 730.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.56 (br s, 0.56H), 7.35 - 7.15 (m, 5H), 4.39 (br d, 1H), 4.20 (br d, 1H), 3.97 (br d, 1H), 3.88 (br t, 1H), 3.75 - 3.54 (m, 2H), 3.11 (br s, 3H), 2.99 - 2.75 (m, 7H), 2.72 - 2.37 (m, 11H), 2.24 (br d, 3H), 2.08 - 1.75 (m, 5H), 1.68 (br s, 2H), 1.52 (s, 3H), 1.47 (td, 4H), 1.40 - 1.21 (m, 16H), 1.01 (br dd, 1H), 0.97 - 0.90 (m, 3H), 0.84 (br d, 2H).

[0530] Compound 99 [Chem.] S3-2-I7-3-4

[0531] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((1-isobutylpiperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-4). Prepared from S3-1-I7-3 and isobutylaldehyde by the method of S3-2-I4-1-2 to obtain the title compound as the formate. MS (ESI+) m / z: 682.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (s, 1.28H), 4.42 (br d, 1H), 4.17 (br s, 1H), 3.98 (br d, 1H), 3.89 (br t, 1H), 3.67 (br d, 2H), 3.48 (br s, 2H), 3.27 - 3.17 (m, 1H), 3.08 (br s, 2H), 2.80 (br s, 6H), 2.69 - 2.33 (m, 9H), 2.23 (br s, 1H), 2.09 - 1.77 (m, 5H), 1.68 (br s, 1H), 1.59 - 1.21 (m, 23H), 1.10 - 0.76 (m, 13H).

[0532] Compound 100 [Chemistry] S3-4-I7-2-1

[0533] (3R,6R,8R,9R,10R)-3-((1-benzoylpiperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-2-1). Prepared from S3-1-I7-2 and benzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 716.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 7.50 - 7.34 (m, 5H), 4.75 - 4.64 (m, 1H), 4.38 (br d, 1H), 4.12 (br d, 1H), 4.02 - 3.86 (m, 2H), 3.78 - 3.65 (m, 2H), 3.58 (br dd, 1H), 3.26 - 3.20 (m, 1H), 3.18 - 3.02 (m, 2H), 2.96 - 2.84 (m, 1H), 2.81 (s, 3H), 2.77 - 2.58 (m, 4H), 2.40 (s, 6H), 2.27 (br d, 1H), 2.04 - 1.93 (m, 1H), 1.90 - 1.74 (m, 3H), 1.73 - 1.58 (m, 3H), 1.55 - 1.50 (m, 3H), 1.48 - 1.41 (m, 1H), 1.38 - 1.17 (m, 16H), 1.11 - 0.93 (m, 5H), 0.85 (br d, 3H).

[0534] Compound 101

Chem.

[0535] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-3-((1-(3-methoxybenzoyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-2-2). Prepared from S3-1-I7-2 and 3-methoxybenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 746.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (br s, 0.19H), 7.37 (t, 1H), 7.02 (br d, 1H), 6.98 - 6.89 (m, 2H), 4.62 (br s, 1H), 4.39 (br d, 1H), 4.12 (br d, 1H), 4.01 - 3.89 (m, 2H), 3.83 (s, 3H), 3.71 (br s, 2H), 3.60 (br dd, 1H), 3.19 - 3.03 (m, 2H), 2.95 - 2.74 (m, 5H), 2.73 - 2.57 (m, 3H), 2.47 (br s, 6H), 2.27 (br d, 1H), 2.06 - 1.91 (m, 1H), 1.82 - 1.57 (m, 5H), 1.53 (s, 3H), 1.47 (br s, 1H), 1.42 - 1.20 (m, 16H), 1.13 - 0.98 (m, 4H), 0.93 - 0.78 (m, 3H).

[0536] Compound 102 [Chem.] S3-4-I7-2-3

[0537] (3R,6R,8R,9R,10R)-3-((1-(3-chlorobenzoyl)piperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-2-3). Prepared from S3-1-I7-2 and 3-chlorobenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 750.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.56 (br s, 1H), 7.54 - 7.40 (m, 3H), 7.34 (br d, 1H), 4.60 (br s, 1H), 4.40 (br d, 1H), 4.20 - 4.04 (m, 1H), 4.02 - 3.86 (m, 2H), 3.79 - 3.53 (m, 3H), 3.22 - 3.01 (m, 3H), 2.96 - 2.77 (m, 5H), 2.75 - 2.56 (m, 3H), 2.46 (br s, 6H), 2.35 - 2.22 (m, 1H), 2.00 (br dd, 2H), 1.82 (br d, 2H), 1.74 - 1.60 (m, 3H), 1.59 - 1.43 (m, 1H), 1.42 - 1.15 (m, 17H), 1.15 - 1.05 (m, 3H), 1.03 - 0.96 (m, 1H), 0.86 (br d, 3H).

[0538] Compound 103

Chem.

[0539] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(3-methylbenzoyl)piperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-2-4). Prepared from S3-1-I7-2 and 3-methylbenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 730.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.40 - 7.25 (m, 2H), 7.24 - 7.12 (m, 2H), 4.71 - 4.53 (m, 2H), 4.38 (d, 1H), 4.11 (br d, 1H), 4.01 - 3.88 (m, 2H), 3.81 - 3.64 (m, 2H), 3.58 (td, 1H), 3.25 - 3.21 (m, 1H), 3.17 - 3.03 (m, 2H), 2.81 (s, 4H), 2.75 - 2.57 (m, 4H), 2.45 - 2.18 (m, 10H), 2.06 - 1.93 (m, 1H), 1.83 - 1.74 (m, 2H), 1.70 - 1.42 (m, 7H), 1.37 - 0.95 (m, 22H), 0.86 (br d, 3H).

[0540] Compound 104 [Chem.] S3-4-I7-2-5

[0541] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-2-5). Prepared from S3-1-I7-2 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 784.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.78 (br s, 1H), 7.71 (s, 1H), 7.67 (d, 2H), 4.63 (br s, 1H), 4.37 (br d, 1H), 4.11 (br d, 1H), 4.01 - 3.87 (m, 2H), 3.76 - 3.51 (m, 3H), 3.27 - 3.23 (m, 1H), 3.20 - 3.04 (m, 2H), 3.0 - 2.85 (m, 1H), 2.80 (s, 3H), 2.42 (s, 6H), 2.27 (br d, 1H), 2.05 - 1.91 (m, 1H), 1.89 - 1.74 (m, 2H), 1.73 - 1.57 (m, 2H), 1.55 - 1.42 (m, 4H), 1.40 - 1.13 (m, 18H), 1.10 - 0.94 (m, 4H), 0.92 - 0.75 (m, 3H).

[0542] Compound 105 [Chemical formula] S3-4-I7-2-6

[0543] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-phenylpiperidine-1-carboxamide (S3-4-I7-2-6). Prepared from S3-1-I7-2 and phenyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 731.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.56 (s, 0.31H), 7.36 - 7.31 (m, 2H), 7.29 - 7.21 (m, 2H), 7.01 (t, 1H), 4.39 (d, 1H), 4.26 - 4.07 (m, 3H), 4.03 - 3.89 (m, 2H), 3.79 - 3.53 (m, 3H), 3.20 - 3.09 (m, 1H), 2.97 - 2.85 (m, 3H), 2.82 (s, 3H), 2.75 - 2.57 (m, 3H), 2.45 (s, 6H), 2.40 - 2.34 (m, 1H), 2.28 (br d, 1H), 2.06 - 1.95 (m, 1H), 1.91 - 1.74 (m, 4H), 1.69 (br s, 1H), 1.60 - 1.43 (m, 6H), 1.41 - 1.20 (m, 18H), 1.13 - 0.96 (m, 5H), 0.85 (br d, 3H).

[0544] Compound 106

Chem.

[0545] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide (S3-4-I7-2-7). Prepared from S3-1-I7-2 and phenyl 3-methoxyisocyanate by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 761.5 [M + H]+; 1 H NMR (399 MHz, methanol-d 4) δ = 7.15 (t, 1H), 7.04 (t, 1H), 6.91 (td, 1H), 6.59 (dd, 1H), 4.45 - 4.36 (m, 1H), 4.26 - 4.06 (m, 3H), 4.04 - 3.86 (m, 2H), 3.78 (s, 3H), 3.74 - 3.68 (m, 1H), 3.65 - 3.55 (m, 1H), 3.40 - 3.34 (m, 1H), 3.22 - 3.10 (m, 1H), 2.96 - 2.80 (m, 6H), 2.77 - 2.60 (m, 3H), 2.57 - 2.43 (m, 5H), 2.41 - 2.35 (m, 1H), 2.29 (br d, 1H), 2.07 - 1.96 (m, 1H), 1.93 - 1.73 (m, 3H), 1.72 - 1.60 (m, 1H), 1.58 - 1.44 (m, 5H), 1.41 - 1.16 (m, 17H), 1.11 - 0.98 (m, 4H), 0.86 (br d, 3H).

[0546] Compound 107

Chem.

[0547] N-Benzyl-4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)piperidine-1-carboxamide (S3-4-I7-2-8). Prepared from S3-1-I7-2 and benzyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 745.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.34 - 7.27 (m, 4H), 7.26 - 7.18 (m, 1H), 4.40 (s, 1H), 4.37 (s, 2H), 4.19 - 3.89 (m, 6H), 3.79 - 3.67 (m, 1H), 3.59 (br dd, 1H), 3.31 - 3.23 (m, 1H), 3.13 (td, 1H), 2.90 - 2.76 (m, 6H), 2.75 - 2.59 (m, 5H), 2.38 (s, 7H), 2.30 (br d, 1H), 2.00 (br dd, 1H), 1.90 - 1.62 (m, 5H), 1.56 (s, 4H), 1.51 - 1.41 (m, 3H), 1.36 (s, 3H), 1.32 - 1.22 (m, 13H), 1.20 - 1.13 (m, 2H), 1.08 (br t, 4H), 1.03 - 0.96 (m, 1H), 0.87 (d, 3H).

[0548] Compound 108 [Chemical formula] S3-4-I7-2-9

[0549] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-isopropylpiperidine-1-carboxamide (S3-4-I7-2-9). Prepared from S3-1-I7-2 and isopropyl isocyanate by the method of S3-4-I4-1-1, and the title compound was obtained as the formate. MS (ESI+) m / z: 697.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 4.38 (d, 1H), 4.11 (br dd, 1H), 4.07 - 3.83 (m, 5H), 3.76 - 3.65 (m, 1H), 3.58 (br dd, 1H), 3.30 - 3.24 (m, 1H), 3.09 (br d, 1H), 2.81 (s, 3H), 2.78 - 2.55 (m, 7H), 2.38 (s, 6H), 2.28 (br d, 1H), 1.98 (br dd, 1H), 1.71 (br d, 4H), 1.58 - 1.51 (m, 3H), 1.50 - 1.38 (m, 2H), 1.34 (s, 3H), 1.31 - 1.20 (m, 11H), 1.19 - 1.10 (m, 8H), 1.09 - 1.03 (m, 4H), 1.02 - 0.97 (m, 1H), 0.85 (d, 3H).

[0550] Compound 109 [Chem.] S3-4-I7-3-1

[0551] (3R,6R,8R,9R,10R)-3-((1-benzoylpiperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-3-1). Prepared from S3-1-I7-3 and benzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 730.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.54 (s, 1.31H), 7.58 - 7.29 (m, 5H), 4.65 (br s, 1H), 4.45 (br d, 1H), 4.08 (br s, 2H), 3.85 - 3.64 (m, 3H), 3.62 - 3.38 (m, 2H), 3.34 (br s, 1H), 3.30 - 3.26 (m, 1H), 3.13 (br s, 2H), 3.01 - 2.81 (m, 4H), 2.76 (s, 6H), 2.10 - 1.95 (m, 3H), 1.93 - 1.13 (m, 27H), 0.98 (br s, 6H).

[0552] Compound 110 [Chem.] S3-4-I7-3-2

[0553] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((1-(3-methoxybenzoyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-3-2). Prepared from S3-1-I7-3 and 3-methoxybenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 760.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.55 (br s, 0.22H), 7.37 (t, 1H), 7.06 - 7.00 (m, 1H), 6.98 - 6.90 (m, 2H), 4.62 (br s, 1H), 4.38 (br d, 1H), 4.20 (br d, 1H), 4.02 - 3.94 (m, 1H), 3.89 (br t, 1H), 3.83 (s, 3H), 3.78 - 3.53 (m, 3H), 3.10 (br s, 2H), 2.79 (s, 5H), 2.65 - 2.49 (m, 3H), 2.43 (br s, 6H), 2.24 (br d, 1H), 2.09 - 1.73 (m, 4H), 1.73 - 1.55 (m, 3H), 1.54 - 1.41 (m, 6H), 1.38 - 1.06 (m, 16H), 1.06 - 0.97 (m, 1H), 0.94 (br t, 3H), 0.84 (br d, 3H).

[0554] Compound 111

Chem.

[0555] (3R,6R,8R,9R,10R)-3-((1-(3-chlorobenzoyl)piperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-3-3). Prepared from S3-1-I7-3 and 3-chlorobenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 764.4 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.54 (br s, 1.32H), 7.54 - 7.40 (m, 3H), 7.34 (br d, 1H), 4.63 (br s, 1H), 4.45 (br d, 1H), 4.07 (br s, 2H), 3.80 - 3.50 (m, 3H), 3.47 - 3.38 (m, 1H), 3.34 (br s, 1H), 3.30 - 3.26 (m, 1H), 3.15 (br s, 2H), 3.02 - 2.81 (m, 5H), 2.76 (s, 6H), 2.00 (br d, 2H), 1.85 (br s, 2H), 1.69 (br s, 2H), 1.61 - 1.12 (m, 23H), 0.98 (br s, 5H).

[0556] Compound 112 [Chem.] S3-4-I7-3-4

[0557] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(3-methylbenzoyl)piperidin-4-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-3-4). Prepared from S3-1-I7-3 and 3-methylbenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 744.4 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.54 (br s, 1.18H), 7.38 - 7.27 (m, 2H), 7.25 - 7.13 (m, 2H), 4.71 - 4.56 (m, 1H), 4.45 (br d, 1H), 4.08 (br s, 2H), 3.85 - 3.49 (m, 3H), 3.47 - 3.39 (m, 1H), 3.49 - 3.38 (m, 1H), 3.34 (br s, 1H), 3.29 - 3.25 (m, 1H), 3.20 - 3.00 (m, 1H), 2.88 (br d, 4H), 2.81 - 2.67 (m, 6H), 2.39 (s, 3H), 2.00 (br d, 2H), 1.92 - 1.11 (m, 25H), 0.98 (br s, 6H).

[0558] Compound 113 [Chem.] S3-4-I7-3-5

[0559] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-3-((1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I7-3-5). Prepared from S3-1-I7-3 and 3-trifluoromethylbenzoyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 798.5 [M + H]+; 1 H NMR (400MHz, methanol-d 4) δ = 8.54 (br s, 1.09H), 7.84 - 7.76 (m, 1H), 7.71 (s, 1H), 7.68 (d, 2H), 4.65 (br s, 1H), 4.44 (br d, 1H), 4.29 - 3.84 (m, 2H), 3.80 - 3.52 (m, 3H), 3.47 - 3.37 (m, 1H), 3.29 - 3.08 (m, 3H), 3.00 - 2.79 (m, 4H), 2.74 (s, 6H), 2.66 - 2.41 (m, 1H), 2.13 (br s, 1H), 2.07 - 1.95 (m, 2H), 1.94 - 1.13 (m, 27H), 1.09 - 0.61 (m, 6H).

[0560] Compound 114 [Chem.] S3-4-I7-3-6

[0561] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-phenylpiperidine-1-carboxamide (S3-4-I7-3-6). Prepared from S3-1-I7-3 and phenyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 745.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 8.56 (s, 0.4H), 7.36 - 7.32 (m, 2H), 7.26 (t, 2H), 7.02 (t, 1H), 4.42 (br d, 1H), 4.31 - 4.11 (m, 3H), 4.07 - 3.82 (m, 2H), 3.76 - 3.57 (m, 2H), 3.50 - 3.34 (m, 2H), 3.20 - 3.06 (m, 1H), 3.04 - 2.84 (m, 4H), 2.81 (s, 3H), 2.67 - 2.43 (m, 10H), 2.25 (br d, 1H), 2.03 (br s, 1H), 1.94 - 1.83 (m, 2H), 1.79 (br d, 2H), 1.70 (br s, 1H), 1.59 - 1.39 (m, 9H), 1.39 - 1.26 (m, 15H), 1.25 - 1.11 (m, 3H), 1.09 - 0.90 (m, 5H), 0.85 (br d, 3H).

[0562] Compound 115

Chem.

[0563] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide (S3-4-I7-3-7). Prepared from S3-1-I7-3 and phenyl 3-methoxyisocyanate by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 775.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.14 (t, 1H), 7.03 (s, 1H), 6.91 (br d, 1H), 6.58 (dd, 1H), 4.38 (d, 1H), 4.29 - 4.09 (m, 3H), 3.98 (d, 1H), 3.90 (br t, 1H), 3.77 (s, 3H), 3.74 - 3.64 (m, 1H), 3.62 - 3.53 (m, 1H), 3.29 - 3.24 (m, 1H), 3.20 - 3.15 (m, 1H), 3.20 - 3.05 (m, 2H), 2.97 - 2.84 (m, 3H), 2.77 - 2.65 (m, 1H), 2.64 - 2.48 (m, 3H), 2.38 (s, 6H), 2.25 (br d, 1H), 2.10 - 1.97 (m, 1H), 1.88 (br d, 1H), 1.78 (br d, 2H), 1.69 (br s, 1H), 1.59 - 1.39 (m, 8H), 1.38 - 1.09 (m, 18H), 1.02 (br dd, 1H), 0.97 - 0.89 (m, 3H), 0.84 (d, 3H).

[0564] Compound 116 [Chem.] S3-4-I7-3-8

[0565] N-Benzyl-4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)piperidine-1-carboxamide (S3-4-I7-3-8). Prepared from S3-1-I7-3 and benzyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 759.5 [M + H]+; 11H NMR (400 MHz, methanol-d 4 ) δ = 7.32 - 7.18 (m, 5H), 4.41 - 4.32 (m, 3H), 4.20 (br d, 1H), 4.11 - 4.00 (m, 2H), 4.00 - 3.94 (m, 1H), 3.93 - 3.84 (m, 1H), 3.68 (br dd, 1H), 3.58 (br dd, 1H), 3.29 - 3.21 (m, 1H), 3.20 - 3.05 (m, 1H), 2.85 - 2.76 (m, 5H), 2.75 - 2.47 (m, 5H), 2.38 (s, 6H), 2.31 - 2.18 (m, 1H), 2.07 - 1.97 (m, 1H), 1.86 - 1.61 (m, 5H), 1.56 - 1.39 (m, 8H), 1.36 - 1.08 (m, 17H), 1.05 - 0.91 (m, 4H), 0.88 - 0.82 (m, 3H).

[0566] Compound 117

Chem.

[0567] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-isopropylpiperidine-1-carboxamide (S3-4-I7-3-9). Prepared from S3-1-I7-3 and isopropyl isocyanate by the method of S3-4-I4-1-1 to obtain the title compound as the formate. MS (ESI+) m / z: 711.5 [M + H]+; 1 1H NMR (400MHz, methanol-d 4) δ = 4.37 (d, 1H), 4.19 (br d, 1H), 4.09 - 3.94 (m, 3H), 3.92 - 3.83 (m, 2H), 3.74 - 3.64 (m, 1H), 3.58 (br dd, 1H), 3.29 - 3.24 (m, 1H), 3.17 - 3.04 (m, 1H), 2.84 - 2.67 (m, 6H), 2.65 - 2.46 (m, 3H), 2.39 (s, 6H), 2.24 (br d, 1H), 2.08 - 1.95 (m, 1H), 1.87 - 1.61 (m, 4H), 1.52 (s, 3H), 1.50 - 1.37 (m, 4H), 1.34 (s, 3H), 1.32 - 1.20 (m, 11H), 1.14 (d, 7H), 1.09 - 0.97 (m, 2H), 0.94 (t, 3H), 0.84 (d, 3H).

[0568] Compound 118

Chem.

[0569] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I7-2-1). Prepared from S3-1-I7-2 and benzenesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 752.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.78 (br d, 2H), 7.72 - 7.65 (m, 1H), 7.65 - 7.57 (m, 2H), 4.63 - 4.53 (m, 0.4H), 4.45 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.13 - 4.01 (m, 1H), 3.96 (br d, 1H), 3.92 - 3.82 (m, 1H), 3.79 - 3.72 (m, 2H), 3.71 - 3.53 (m, 2H), 3.10 - 2.96 (m, 2H), 2.95 - 2.83 (m, 1H), 2.83 - 2.76 (m, 2H), 2.73 - 2.57 (m, 3H), 2.54 - 2.43 (m, 5H), 2.40 - 2.17 (m, 4H), 2.41 - 2.17 (m, 5H), 1.69 - 1.58 (m, 1H), 1.51 (s, 3H), 1.43 - 1.15 (m, 19H), 1.13 - 0.93 (m, 4H), 0.90 - 0.76 (m, 3H).

[0570] Compound 119

Chem.

[0571] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-3-((1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I7-2-3). Prepared from S3-1-I7-2 and 3-methoxybenzenesulfonyl chloride by the method of S3-4-I4-1-1 to give the title compound as the formate. MS (ESI+) m / z: 782.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.58 - 7.49 (m, 1H), 7.35 (d, 1H), 7.29 - 7.21 (m, 2H), 4.38 (d, 1H), 4.13 - 4.02 (m, 1H), 3.98 (d, 1H), 3.94 - 3.84 (m, 4H), 3.83 - 3.64 (m, 3H), 3.64 - 3.54 (m, 1H), 3.28 (br dd, 1H), 3.14 - 3.00 (m, 1H), 2.81 (s, 3H), 2.76 - 2.51 (m, 4H), 2.43 - 2.18 (m, 9H), 1.96 (br dd, 1H), 1.91 - 1.84 (m, 1H), 1.83 - 1.74 (m, 2H), 1.71 - 1.62 (m, 1H), 1.53 (s, 3H), 1.47 - 1.16 (m, 19H), 1.11 - 1.03 (m, 3H), 1.01 - 0.95 (m, 1H), 0.85 (d, 3H).

[0572] Compound 120 [Chemical formula] S3-3-I7-2-3

[0573] (3R,6R,8R,9R,10R)-3-((1-(Benzylsulfonyl)piperidin-4-yl)methyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I7-2-3). Prepared from S3-1-I7-2 and phenylmethanesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 766.5 [M + H]+; methanol-d 4) δ = 7.48 - 7.36 (m, 5H), 4.39 (d, 1H), 4.34 (s, 2H), 4.16 - 4.05 (m, 1H), 3.99 (d, 1H), 3.91 (t, 1H), 3.76 - 3.52 (m, 4H), 3.30 - 3.25 (m, 1H), 3.13 - 3.04 (m, 1H), 2.82 (s, 3H), 2.77 - 2.53 (m, 6H), 2.39 (s, 6H), 2.28 (br d, 1H), 1.98 (br dd, 1H), 1.85 - 1.63 (m, 4H), 1.55 (s, 3H), 1.49 - 1.22 (m, 17H), 1.16 (dt, 2H), 1.07 (t, 3H), 1.04 - 0.98 (m, 1H), 0.86 (d, 3H).

[0574] Compound 121 [Chem.] S3-3-I7-2-4

[0575] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I7-2-4). Prepared from S3-1-I7-2 and isopropylsulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 718.5 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 4.38 (d, 1H), 4.19 - 4.06 (m, 1H), 4.02 - 3.86 (m, 2H), 3.84 - 3.64 (m, 3H), 3.62 - 3.53 (m, 1H), 3.30 - 3.20 (m, 2H), 3.11 (br t, 1H), 2.92 (br t, 2H), 2.81 (s, 3H), 2.75 - 2.60 (m, 4H), 2.47 - 2.34 (m, 6H), 2.28 (br d, 1H), 2.07 - 1.93 (m, 1H), 1.92 - 1.83 (m, 1H), 1.78 (br d, 2H), 1.69 (br s, 1H), 1.54 (s, 3H), 1.50 - 1.41 (m, 2H), 1.40 - 1.14 (m, 22H), 1.07 (br t, 3H), 1.03 - 0.94 (m, 1H), 0.85 (br d, 3H).

[0576] Compound 122 [Chem.] S3-3-I7-3-1

[0577] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I7-3-1). Prepared from S3-1-I7-3 and benzenesulfonyl chloride by the method of S3-4-I4-1-1 to obtain the title compound as a formate. MS (ESI+) m / z: 766.4 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ = 7.83 - 7.76 (m, 2H), 7.73 - 7.66 (m, 1H), 7.66 - 7.59 (m, 2H), 4.39 (d, 1H), 4.12 (br s, 1H), 3.97 (d, 1H), 3.90 - 3.72 (m, 3H), 3.70 - 3.53 (m, 2H), 3.30 (br d, 1H), 3.05 (br s, 1H), 2.79 (s, 3H), 2.64 - 2.52 (m, 2H), 2.50 - 2.39 (m, 7H), 2.38 - 2.25 (m, 2H), 2.21 (br d, 1H), 2.08 - 1.94 (m, 1H), 1.89 (br d, 1H), 1.84 - 1.72 (m, 2H), 1.66 (br s, 1H), 1.54 - 1.38 (m, 6H), 1.34 (s, 3H), 1.31 - 1.15 (m, 13H), 1.01 (br dd, 1H), 0.93 (t, 3H), 0.83 (d, 3H).

[0578] Compound 123 [Chem.] S3-2-I8-1-1

[0579] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-((4-methylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-1). Prepared from S3-2-I8-1 and formaldehyde by the method of S3-2-I4-1-2 to give 7.33 mg of the title compound as the formate. (ESI+) m / z: 205.04 [M + 3H]3+, 307.01 [M + 2H]2+, 613.01[M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.53 (s, 2H), 4.58 (d, 1H), 4.45 (d, 1H), 4.34 (t, 1H), 4.26 (d, 1H), 3.90 (d, 1H), 3.77 - 3.67 (m, 1H), 3.54 - 3.33 (m, 3H), 3.19 (s, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.76 (s, 9H), 2.73 - 2.54 (m, 7H), 2.45 (s, 3H), 2.18 (s, 1H), 2.04 - 1.95 (m, 1H), 1.57 (s, 3H), 1.53 - 1.43 (m, 1H), 1.39 (d, 6H), 1.33 (dd, 6H), 1.04 (d, 3H).

[0580] Compound 124 [Chem.] S3-2-I8-1-2

[0581] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-ethylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-2). Prepared from S3-2-I8-1 and acetaldehyde by the method of S3-2-I4-1-2 to give 6.82 mg of the title compound as the formate. (ESI+) m / z: 209.72 [M + 3H]3+, 313.98 [M + 2H]2+, 627.02 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.53 (s, 2H), 4.58 (d, 1H), 4.46 (d, 1H), 4.34 (t, 1H), 4.25 (d, 1H), 3.83 (s, 1H), 3.77 - 3.68 (m, 1H), 3.54 - 3.36 (m, 2H), 3.14 (s, 1H), 3.02 (s, 3H), 2.92 - 2.78 (m, 6H), 2.76 (s, 8H), 2.74 - 2.64 (m, 5H), 2.60 (dd, 2H), 2.17 (s, 1H), 2.06 - 1.97 (m, 1H), 1.70 (s, 2H), 1.55 (s, 3H), 1.54 - 1.44 (m, 1H), 1.39 (d, 6H), 1.33 (dd, 6H), 1.20 (t, 3H), 1.03 (d, 3H).

[0582] Compound 125 [Chem.] S3-2-I8-1-3

[0583] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isopropylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-3). Prepared from S3-2-I8-1 and acetone by the method of S3-2-I4-1-2 to give 11.7 mg of the title compound as the formate. (ESI+) m / z: 214.41 [M + 3H]3+, 321.01 [M + 2H]2+, 641.09 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.59 (s, 2H), 4.64 (d, 1H), 4.51 (d, 1H), 4.39 (t, 1H), 4.29 (d, 1H), 3.85 (s, 1H), 3.82 - 3.73 (m, 1H), 3.58 - 3.43 (m, 2H), 3.27 - 3.12 (m, 2H), 3.05 (s, 7H), 2.82 (s, 14H), 2.66 (dd, 2H), 2.20 (s, 1H), 2.11 - 2.00 (m, 1H), 1.75 (s, 2H), 1.59 (s, 3H), 1.58 - 1.48 (m, 1H), 1.44 (s, 6H), 1.38 (dd, 6H), 1.30 (d, 6H), 1.08 (d, 3H).

[0584] Compound 126 [Chemical formula] S3-2-I8-2-1

[0585] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((4-methylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-1). Prepared from S3-2-I8-2 and formaldehyde by the method of S3-2-I4-1-2 to obtain 7.63 mg of the title compound as the formate. (ESI+) m / z: 209.74 [M + 3H]3+, 314.01 [M + 2H]2+, 627.11 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.49 (s, 2H), 4.69 (s, 1H), 4.46 (d, 1H), 4.29 (s, 1H), 4.15 (d, 1H), 3.79 - 3.66 (m, 1H), 3.54 (s, 2H), 3.49 - 3.33 (m, 2H), 3.25 - 3.00 (m, 3H), 2.95 (s, 6H), 2.81 (s, 8H), 2.61 (s, 7H), 2.10 - 1.97 (m, 2H), 1.88 (s, 1H), 1.61 - 1.47 (s, 4H), 1.41 - 1.29 (m, 12H), 1.24 (t, 3H), 0.99 (d, 3H).

[0586] Compound 127 [Chemical formula] S3-2-I8-2-2

[0587] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((4-ethylpiperazin-1-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-2). Prepared from S3-2-I8-2 and acetaldehyde by the method of S3-2-I4-1-2 to obtain 6.83 mg of the title compound as the formate. (ESI+) m / z: 214.41 [M + 3H]3+, 321.03 [M + 2H]2+, 641.14 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.52 (s, 2H), 4.54 (s, 1H), 4.46 (d, 1H), 4.19 (s, 1H), 4.09 (d, 1H), 3.78 - 3.65 (m, 1H), 3.59 (s, 1H), 3.44 (dd, 2H), 3.35 (dd, 1H), 2.90 (s, 8H), 2.83 (d, 3H), 2.78 (s, 9H), 2.60 (s, 4H), 2.00 (ddd, 2H), 1.91 (s, 1H), 1.53 (d, 3H), 1.48 (dd, 1H), 1.36 (s, 4H), 1.32 (d, 9H), 1.23 (t, 4H), 1.19 - 1.13 (m, 2H), 0.94 (d, 3H).

[0588] Compound 128 [Chem.] S3-2-I8-2-3

[0589] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isopropylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-3). Prepared from S3-2-I8-2 and acetone by the method of S3-2-I4-1-2 to give 6.11 mg of the title compound as the formate. (ESI+) m / z: 219.05 [M + 3H]3+, 328.02 [M + 2H]2+, 655.08 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.52 (s, 2H), 4.53 (s, 1H), 4.46 (d, 1H), 4.18 (s, 1H), 4.08 (d, 1H), 3.76 - 3.66 (m, 1H), 3.61 (s, 1H), 3.44 (dd, 1H), 3.35 (dd, 1H), 3.25 (d, 1H), 3.07 (s, 4H), 2.89 (s, 6H), 2.78 (s, 7H), 2.71 - 2.52 (m, 4H), 2.01 (dd, 2H), 1.88 (s, 1H), 1.52 (s, 3H), 1.51 - 1.44 (m, 1H), 1.36 (s, 3H), 1.34 - 1.22 (m, 15H), 1.18 (d, 3H), 0.93 (d, 3H).

[0590] Scheme 4.

Chem.

[0591]

Chem.

[0592]

Chem.

[0593] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-(((1r,3S)-3-((tert-Butoxycarbonyl)(methyl)amino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate (S4-1-I8-1). S1-5-I8-1 (212 mg, 0.273 mmol) was dissolved in 1,2-dimethoxyethane (2.72 mL), and the reaction mixture was cooled to -78 °C in a dry ice / acetone bath. Potassium bis(trimethylsilyl)amide (1.0 M solution in THF; 0.818 mL, 0.818 mmol) was added. After 5 minutes, dimethyl sulfate (0.128 mL, 1.36 mmol) was added. The dry ice was removed from the acetone bath, and the reaction mixture was slowly warmed to -10 °C over 50 minutes. Triethylamine (0.378 mL, 2.27 mmol) was added, and the reaction was warmed to room temperature over 30 minutes. The reaction was quenched by the addition of NH 4 Cl (saturated, aqueous solution) and diluted with EtOAc. The EtOAc layer was washed with water (2 times) and brine (1 time), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by elution with 12 g of silica gel (0 - 12% MeOH-dichloromethane - 0.5% NH 4 OH gradient) to give 120 mg of the title compound. MS (ESI+) m / z: 401.77 [M + 2H]2+, 802.19 [M + H]+; 1 H NMR (400 MHz, chloroform-d) δ 8.08 - 7.97 (m, 2H), 7.59 - 7.49 (m, 1H), 7.43 (t, 2H), 5.03 (dd, 1H), 4.60 (d, 2H), 4.04 - 3.86 (m, 3H), 3.58 (dd, 1H), 3.51 - 3.36 (m, 1H), 2.82 (d, 7H), 2.50 - 2.39 (m, 1H), 2.25 (s, 7H), 2.21 (s, 3H), 2.05 - 1.96 (s, 1H), 1.95 - 1.79 (m, 4H), 1.80 - 1.57 (m, 3H), 1.43 (s, 9H), 1.38 (s, 4H), 1.31 (s, 3H), 1.27 (d, 4H), 1.22 (s, 3H), 1.04 (d, 3H), 0.94 (dd, 1H), 0.83 (d, 4H).

[0594] Compound 129 [Chemistry] S4-2-I8-1-1

[0595] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((1r,3S)-3-(dimethylamino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-1). A solution of S4-1-I8-1 (120 mg, 0.149 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.25 mL) was stirred at room temperature for 2 hours and concentrated. The residue was suspended in ethyl acetate and washed with saturated NaHCO 3 aqueous solution (twice), the washing solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting secondary amine (25 mg, 0.0356 mmol) was dissolved in dichloromethane (1 mL), and Na(OAc) 3 BH (15 mg, 0.0712 mmol) was added, followed by formaldehyde (37 wt% aqueous solution, 0.0238 mL, 0.356 mmol). After 15 minutes, the reaction mixture was quenched with saturated NaHCO 3 aqueous solution and extracted with dichloromethane (thrice). The combined extracts were concentrated under reduced pressure. The residue was dissolved in methanol (1.5 mL), and the reaction mixture was heated at an external temperature of 45 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by HPLC (Atlantis T3 column, 2 - 40% MeCN - water - 0.1% HCO 2 H) to obtain the title compound as the formate salt (15.8 mg, 0.0236 mmol, 61%). MS (ESI+) m / z: 204.79 [M + 3H]3+, 306.59 [M + 2H]2+, 612.21 [M + H]+; 1 H NMR (400 MHz, methanol - d 4) δ 8.55 (s, 2H), 4.69 (s, 1H), 4.42 (d, 1H), 4.36 - 4.01 (m, 2H), 3.68 (ddd, 2H), 3.36 (dd, 1H), 3.24 - 2.69 (m, 9H), 2.60 (s, 7H), 2.40 - 2.14 (m, 10H), 1.94 (dd, 4H), 1.88 - 1.69 (m, 1H), 1.52 (s, 3H), 1.47 - 1.25 (m, 13H), 1.03 (s, 3H).

[0596] Compound 130 [Chem.] S4-2-I8-1-2

[0597] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((1r,3S)-3-(isobutyl(methyl)amino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-2). According to the method of S4-2-I8-1-1, 11.09 mg of the title compound was prepared as a formate by replacing isobutyl aldehyde. MS (ESI+) m / z: 218.78 [M + 3H]3+, 327.61 [M + 2H]2+, 654.31 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.54 (s, 2.5H), 4.66 (s, 1H), 4.44 (d, 1H), 4.33 - 4.12 (m, 2H), 3.72 (ddd, 1H), 3.66 (s, 0.5H), 3.53 (s, 1H), 3.47 - 3.34 (m, 2H), 3.34 - 3.26 (m, 1H), 3.04 (s, 5H), 2.84 (s, 3H), 2.76 (s, 6H), 2.58 - 2.30 (m, 8H), 2.29 - 1.94 (m, 6H), 1.87 - 1.57 (m, 3H), 1.56 - 1.44 (m, 4H), 1.40 (d, 6H), 1.33 (dd, 6H), 1.05 (d, 3H), 1.01 (d, 6H).

[0598] Compound 131 [Chem.] S4-2-I8-1-3

[0599] (3R,6R,8R,9R,10R)-3-(((1r,3S)-3-((Cyclopropylmethyl)(methyl)amino)cyclobutyl)methyl)-9-(((2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-3). According to the method of S4-2-I8-1-1, replacing with cyclopropanecarboxaldehyde, 16.73 mg of the title compound was prepared as the formate. MS (ESI+) m / z: 218.12 [M + 3H]3+, 326.61 [M + 2H]2+, 652.27 [M + H]+; 1 H NMR (400 MHz, methanol-d 4) δ 8.55 (s, 2.6H), 4.65 (s, 1H), 4.44 (d, 1H), 4.32 - 4.13 (m, 2H), 3.78 - 3.67 (m, 2H), 3.60 (s, 0.4H), 3.48 - 3.34 (m, 2H), 3.35 - 3.25 (m, 1H), 3.04 (s, 4H), 2.90 - 2.77 (m, 4H), 2.76 (s, 7H), 2.69 (s, 3H), 2.59 - 2.34 (m, 3H), 2.27 - 1.95 (m, 5H), 1.87 - 1.58 (m, 3H), 1.56 - 1.44 (m, 4H), 1.39 (d, 6H), 1.33 (dd, 6H), 1.15 - 0.96 (m, 4H), 0.76 - 0.68 (m, 2H), 0.42 - 0.28 (m, 2H).

[0600] Compound 132 [Chem.] S4-2-I11-1-1

[0601] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((1r,3S)-3-(isopropyl(methyl)amino)cyclobutyl)methyl)-8-methoxy-3,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I11-1-1). According to the method of S4-2-I8-1-1, 5.5 mg of the title compound was prepared as a formate by replacing intermediate I11 and acetone. MS (ESI+) m / z: 218.82 [M + 3H]3+, 327.69 [M + 2H]2+, 654.32[M + H]+; 11H NMR (400 MHz, methanol-d) ...

Claims

1. A pharmaceutical composition for treating a genetic disease, comprising as an active ingredient a compound of formula I: 【Chemistry 1】 [During the ceremony, R ２ａ and R ２ｂ One of them is R ２ａ and R ２ｂ wherein C is selected from the group consisting of １－１０ Alkyl, C １－１０ Alkoxy and C ２－１０ 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 ４ａ and R ４ｂ Each of the groups independently represents H and optionally substituted C １－１０ selected from the group consisting of alkyl; R ５ is H, a hydroxyl protecting group, and 【Chemistry 2】 selected from the group consisting of: R ６ａ is an optionally substituted C １－１０ is alkyl; R ６ｂ is H, C １－１０ Alkyl, C １－１０ hydroxyalkyl, aryl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; 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, optionally substituted C １－１０ Alkyl, C(=O)C １－６ Alkyl, C １－６ Alkylene-OH,C １－６ Alkylene -O-C １－６ Alkyl, C １－６ Alkylene-cycloalkyl, C(=O)C １－６ selected from the group consisting of alkylene-cycloalkyl, C(=O)cycloalkyl, C(=O)heterocycloalkyl, C(=O)aryl, C(=O)heteroaryl and C(=O)NH-aryl; R １０ａ and R １０ｂ one of which is H and optionally substituted C １－１０ alkyl; R １０ａ and R １０ｂ The other is -L ａ -L ｂ -L ｃ -L ｄ where: L ａ is C ２－６ Alkenylene or C １－６ alkylene, where C １－６ One methylene unit of alkylene is oxo 【Chemistry 3】 may be substituted with; L ｂ is absent or is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; L ｃ does not exist or C １－６ Alkylene, C １－６ Alkylene-N(C １－６ alkyl), NH, N-C １－６ Alkyl, N-C １－６ Cycloalkyl, -NH-C １－６ Alkylene, -N(C １－６ Alkyl)-C １－６ Alkylene, -NH-C １－６ Alkylene-heteroarylene, -N-C １－６ Alkylene-cycloalkyl, N-C １－６ Alkylene-heterocycloalkyl, N-C １－６ Alkylene-aryl, N-C １－６ Alkylene-heteroaryl, C(=O), C(=O)O-, OC(O)-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C １－６ Alkylene, C(=O)N(C １－６ Alkyl)-C １－６ Alkylene, N(C １－６ alkyl)-C(=O)-C １－６ Alkylene, SO ２ , S.O. ２ N.H., S.O. ２ N-C １－６ Alkyl, SO ２ N-(C １－６ Alkyl)-(C １－６ alkylene), OC(=O)-NH, OC(=O)-N-alkyl, SO ２ , S.O. ２ C １－６ Alkylene, SO ２ N.H., S.O. ２ N(C １－６ alkyl), SO ２ NH-(C １－６ alkylene), SO ２ N(C １－６ Alkyl)-(C １－６ alkylene), SO ２ N(C １－６ alkylene-aryl), SO ２ N(C １－６ alkylene-heteroaryl), 【Chemistry 4】 and L ｄ is H, C １－６ Alkyl, OH, alkoxy, NH ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , C １－６ Alkyl, C １－６ haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted benzyl; and R １１ａ and R １１ｂ each independently represents —H and optionally substituted C １－１０ selected from the group consisting of alkyl; Where: 【Chemistry 5】 indicates the point of attachment. or a pharma- ceutically acceptable salt thereof.

2. The compound of formula I is represented by formula IH 【Chemistry 6】 2. The pharmaceutical composition of claim 1, wherein the compound is:

3. (a)R １０ｂ , R １１ａ and R １１ｂ are each independently H or methyl; or (b) R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; or (c) -L a -L b -L c -L d wherein L a is C 2-6 alkenylene; L b and L c are absent and L d is H; optionally L a is -CH 2 ═CH 2 -, L b and L c are absent and L d is H; or (d) L a is a C 1-6 alkylene selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 —, where one methylene unit of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 — may optionally be replaced by oxo (C═O); optionally L a is CH 2 or oxo (C═O); L b is absent; L c is CO, C(═O)NH—C 1-6 alkylene, —NH—C 1-6 alkylene or N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or N(C 1-6 alkyl) 2 ; The pharmaceutical composition of claim 2.

4. L ａ CH ２ or oxo; L ｂ is an optionally substituted cycloalkyl or heterocycloalkyl selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, any of which may be optionally substituted; L ｃ does not exist or C １－６ Alkylene, C １－６ Alkylene-N(C １－６ alkyl), NH, N-C １－６ Alkyl, N-C １－６ Cycloalkyl, -NH-C １－６ Alkylene, -N(C １－６ Alkyl)-C １－６ Alkylene, -N-C １－６ Alkylene-cycloalkyl, N-C １－６ Alkylene-heterocycloalkyl, N-C １－６ Alkylene-aryl, N-C １－６ Alkylene-heteroaryl, C(=O), C(=O)O-, OC(O)-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C １－６ Alkylene, C(=O)N(C １－６ Alkyl)-C １－６ Alkylene, SO ２ , S.O. ２ N.H., S.O. ２ N-C １－６ Alkyl, OC(=O)-NH, OC(=O)-N-alkyl, N(C １－６ alkyl)-C(=O)-C １－６ Alkylene, SO ２ , S.O. ２ C １－６ Alkylene, SO ２ N.H., S.O. ２ N(C １－６ alkyl), SO ２ NH-(C １－６ alkylene), SO ２ N(C １－６ Alkyl)-(C １－６ alkylene), SO ２ N(C １－６ alkylene-aryl), SO ２ N(C １－６ alkylene-heteroaryl), 【Chemistry 7】 and ； and L ｄ H, -OH, C １－６ Alkyl, C １－６ haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; (a) L a is CH 2 or C(═O); L b is azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, or morpholinyl; L c is absent or is C 1-6 alkylene, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene or C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, —OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or (b) L a is CH 2 or oxo; L b is piperidinyl, piperazinyl, pyrrolidinyl, or morpholinyl; L c is C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene or C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, methyl, ethyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, hydroxy, methoxy, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 【Chemistry 8】 is; (c) L a L b 【Chemistry 9】 wherein L c is absent and L d is H; L a L b 【Chemistry 10】 and L c is absent and L d is H; or L a L b 【Chemistry 11】 and L c is absent and L d is H; or (d) L a L b is 【Chemistry 12】 and L c is absent or is CH 2 , CH 2 CH 2 , CHCH 3 , CH 2 CHCH 3 or C(CH 3 ) 2 ; and L d is H, —OH, —OMe, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 【Chemistry 13】 is; or (e) L a L b is 【Chemistry 14】 and L c is oxo; and L d is H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, phenyl, trifluoromethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 【Chemistry 15】 is; or (f) L a L b is 【Chemistry 16】 and L c is SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N—C 1-6 alkyl or SO 2 N—(C 1-6 alkyl)(C 1-6 alkylene); and L d is H, methyl, ethyl, propyl, isopropyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 【Chemistry 17】 is; or (g) L a L b 【Chemistry 18】 and L c is absent or is C 1-6 alkylene, C(═O), C(═O)O, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene or C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, hydroxyl, C 1-6 alkyl, alkoxy, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or (h) L a is CH 2 or oxo; L b is cyclobutyl; L c is absent or is -NH-C 1-6 alkylene or N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, methyl, ethyl, isopropyl, cyclopropyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; 【Chemistry 19】 is; or (i) L a L b is 【Chemistry 20】 and L c is NHCH 2 —, N(Me)CH 2 —, N(Et)CH 2 —, N(iPr)CH 2 —, or N(isobutyl)CH 2 —; and L d is H or cyclopropyl; The pharmaceutical composition of claim 1. (i) The compound of formula I has formula A: 【Chemistry 21】 [During the ceremony, X is H ２ or O; Y is N, CH, C-(C １－６ alkyl) or O; R ９ａ is H, optionally substituted C １－６ Alkyl, C １－６ Alkylene-OH,C １－６ Alkylene -O-C １－６ Alkyl, C(=O)C １－６ Alkyl, C １－６ selected from the group consisting of alkylene-cycloalkyl and C(═O)cycloalkyl; L ｃ does not exist or C １－４ Alkylene, C １－４ Alkylene-N(C １－４ alkyl), NH, N-C １－４ Alkyl, N-C １－４ Cycloalkyl, -NH-C １－４ Alkylene, -N(C １－４ Alkyl)-C １－４ Alkylene, -N-C １－４ Alkylene-cycloalkyl, N-C １－４ Alkylene-heterocycloalkyl, N-C １－４ Alkylene-aryl, N-C １－４ Alkylene-heteroaryl, C(=O), C(=O)O-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C １－４ Alkylene, C(=O)N(C １－４ Alkyl)-C １－４ AlkyleneSO ２ , S.O. ２ N.H., S.O. ２ N-C １－４ Alkyl, SO ２ N-(C １－４ Alkyl)-(C １－４ alkylene), OC(=O)-NH, OC(=O)-N-C １－４ Alkyl, SO ２ , S.O. ２ C １－４ Alkylene, SO ２ N.H., S.O. ２ N(C １－４ alkyl), SO ２ NH-(C １－４ Alkylene, SO ２ N(C １－４ Alkyl)-(C １－４ alkylene), SO ２ N(C １－４ alkylene-aryl), SO ２ N(C １－４ alkylene-heteroaryl), 【Chemical 22】 and L ｄ H, C １－６ Alkyl, OH, alkoxy, NH ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , C １－６ haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted benzyl; and R １１ａ is H or C １－６ It is alkyl. or a pharma- ceutically acceptable salt thereof; (a) R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or is C 1-4 alkylene, NH, N(C 1-4 alkyl), N(C 1-4 alkyl)-C 1-4 alkylene, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH-C 1-4 alkylene, OC(═O)—NH, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl) or 【Chemistry 23】 and ； and L d is H, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, hydroxy, methoxy, cyclopropyl, cyclobutyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; 【Chemistry 24】 is; or (b) X is H2 or O; Y is N or CH; and R 11a is H or methyl; or (ii) the compound of formula I has formula A1: 【Chemistry 25】 [During the ceremony, X is H2 or O; R 9a is H or C 1-4 alkyl; R 11a is H or C 1-4 alkyl; L c is absent or is C 1-3 alkylene, C(═O), C(═O)NH, C(═O)NH—C 1-3 alkylene or SO 2 C 1-3 alkylene; and L d is NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, where cycloalkyl, aryl and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy. or a pharma- ceutically acceptable salt thereof; (a) R 9a is H, Me, Et, Pr, butyl or isopropyl; R 11a is H or Me; Lc is CH2, CH2CH2, C(=O)NH, C(=O), C(=O)NHCH2 or SO2CH2; and L d is N(CH 3 ) 2 , NHCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, phenyl, naphthalenyl, imidazolyl, pyrimidinyl or pyridinyl, wherein phenyl, imidazolyl, pyrimidinyl and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe or CF 3 ; or (iii) the compound of formula I is of formula A2: 【Chemistry 26】 [During the ceremony, R 9a is H or C 1-4 alkyl; L c is C 1-3 alkylene, C(═O), C(═O)NH, C(═O)NH—C 1-3 alkylene, SO 2 or SO 2 C 1-3 alkylene; and L d is OH, NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy. or a pharma- ceutically acceptable salt thereof; R 9a is H, Me, Et, Pr, butyl or isopropyl; Lc is CH2, CH2CH2, C(=O), C(=O)NH, C(=O)NHCH2, SO2 or SO2CH2; and L d is OH, N(CH 3 ) 2 , NHCH(CH 3 ) 2 , phenyl or pyridinyl, where phenyl and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe or CF 3 ; or (iv) the compound of formula I is of formula B: 【Chemical 27】 [During the ceremony, X is H2 or O; R 9a is selected from the group consisting of H, optionally substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O-C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cycloalkyl, C(═O)cycloalkyl and C(═O)NH-aryl; L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N-C 1-4 alkyl, N-C 1-4 cycloalkyl, -NH-C 1-4 alkylene, -N(C 1-4 alkyl)-C 1-4 alkylene, -N-C 1-4 alkylene-cycloalkyl, N-C 1-4 alkylene-heterocycloalkyl, N-C 1-4 alkylene-aryl, N-C 1-4 alkylene-heteroaryl, C(═O), C(═O)O-C(═O)NH, C(═O)N-alkyl, C(═O)NH-C 1-4 alkylene, C(═O)N(C 1-4 alkyl)-C 1-4 alkyleneSO 2 , SO 2 NH, SO 2 N-C 1-4 alkyl, SO 2 N—(C 1-4 alkyl)-(C 1-4 alkylene), OC(═O)—NH, OC(═O)—N—C 1-4 alkyl, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), SO 2 NH—(C 1-4 alkylene, SO 2 N(C 1-4 alkyl)-(C 1-4 alkylene), SO 2 N(C 1-4 alkylene-aryl), SO 2 N(C 1-4 alkylene-heteroaryl), 【Chemistry 28】 and L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted benzyl; and R 11a is H or C 1-6 alkyl. or a pharma- ceutically acceptable salt thereof; (a) R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or is C 1-4 alkylene, NH, N—C 1-4 alkyl or —N(C 1-4 alkyl)-C 1-4 alkylene; and L d is H, C 1-6 alkyl or C 1-4 cycloalkyl; or (b) X is H2 or O; R 9a is —H or methyl; and R 11a is H or methyl; The pharmaceutical composition of claim 1.

6. L ａ CH ２ CH ２ or CH ２ CH ２ CH ２ where L ａ one methylene unit of optionally replaced by oxo; (a) L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 or CH 2 COCH 2 ; L b is absent or is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; L c is absent or is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -NH-C 1-6 alkylene-heteroarylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl, N-C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, OC(O)—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkyleneSO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N-C 1-6 alkyl, OC(═O)-NH, OC(═O)-N-alkyl, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH-(C 1-6 alkylene, SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl), 【Chemical 29】 and ； and L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or (b) L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 or CH 2 COCH 2 ; L b is C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl; L c is absent; and L d is H, OH, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl; or (c) L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 or CH 2 COCH 2 ; L b is absent; L c is absent; and L d is pyrrolidinyl, oxazolyl; 【Chemistry 30】 and Where: 【Chemistry 31】 indicates the point of attachment; or (d) L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 or CH 2 COCH 2 ; L b is absent; L c is N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -NH-C 1-6 alkylene-heteroarylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl or N-C 1-6 alkylene-heteroaryl; and L d is H, OH, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; L a L b is CH 2 CH 2 CH 2 ; and L c L d is NH 2 , NH-Me, NH-Et, NH-isopropyl, NH-cyclopropyl, NH-cyclobutyl, NH-cyclopentyl, N(Me) 2 , N(Et) 2 , N(Me)(Et), N(Me)-cyclopropyl, N(Me)-cyclobutyl, N(Me)-cyclopentyl, N(Me)CH 2 -imidazolyl, N(Me)(iPr), N(Me)(tBu), NH-cyclopropyl, NH-oxazolyl, NH-pyrimidinyl, NH-pyridyl, NHCH 2 -cyclopropyl, NHCH 2 -oxazolyl, NHCH 2 -pyrimidinyl, NHCH 2 -pyridyl, NHCH 2 -quinazolinyl, NHCH 2 -quinolinyl or NHCH 2-oxadiazolene-phenyl; or (e) L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is OH or alkoxy; or (f) L a is CH 2 CH 2 CH 2 ; L b is absent; L c is N(Me), N(Et), N(Me)(CH 2 ) or NH; and L d is H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, or imidazolyl; or (g) L a is CH 2 CH 2 CH 2 ; L b is absent; L c is CO, C(═O)O—, OC(═O)—NH, C(═O)NH or C(═O)NHCH 2 ; and L d is H, C 1-6 alkyl or optionally substituted aryl or heteroaryl; or (h) L a L b is CH 2 CH 2 CH 2 ; and L c L d is O—C(═O)NH—phenyl, or 【Chemistry 32】 is; or (i) L a is CH 2 CH 2 CH 2 ; L b is an optionally substituted cycloalkyl or heterocycloalkyl; L c is absent; and L d is H, OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or (j) L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is pyrrolidinyl, piperidinyl, piperazinyl; 【Chemical 33】 or (k) L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is H, methyl, trifluoromethyl, phenyl, pyridyl, pyrimidinyl, OH, 【Chemical 34】 where: 【Chemistry 35】 indicates the point of attachment; or (l) L a is COCH 2 CH 2 ; L b is absent; L c is absent; and L d is phenyl, pyridyl, pyrimidinyl, OH, 【Chemical 36】 where: 【Chemical 37】 indicates the point of attachment; or (m) L a is COCH 2 CH 2 ; L b is absent; L c is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N-C 1-6 alkyl, N-C 1-6 cycloalkyl, -NH-C 1-6 alkylene, -N(C 1-6 alkyl)-C 1-6 alkylene, -N-C 1-6 alkylene-cycloalkyl, N-C 1-6 alkylene-heterocycloalkyl, N-C 1-6 alkylene-aryl, N-C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH-C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkyleneSO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N—C 1-6 alkyl, OC(═O)—NH, OC(═O)—N-alkyl, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH—(C 1-6 alkylene, SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl), 【Chemical 38】 and and L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; L a is COCH 2 CH 2 ; L b is absent; L c is NH or NHCH 2 ; and L d is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; L a is COCH 2 CH 2 ; L b is absent; L c is NH or NHCH 2 ; and L d is optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted oxazolyl or optionally substituted cyclobutyl; The pharmaceutical composition of claim 4.

7. The compound of formula I, 【Chemical 39】 [During the ceremony, Z is H ２ or O; R ９ａ is H, optionally substituted C １－６ Alkyl, C １－６ Alkylene-OH,C １－６ Alkylene -O-C １－６ Alkyl, C(=O)C １－６ Alkyl, C １－６ selected from the group consisting of alkylene-cycloalkyl, C(=O)cycloalkyl, and C(=O)NH-aryl; L ｃ does not exist or C １－４ Alkylene, C １－４ Alkylene-N(C １－４ alkyl), NH, N-C １－４ Alkyl, N-C １－４ Cycloalkyl, -NH-C １－４ Alkylene, -NH-C １－６ Alkylene-heteroarylene, -N(C １－４ Alkyl)-C １－４ Alkylene, -N-C １－４ Alkylene-cycloalkyl, N-C １－４ Alkylene-heterocycloalkyl, N-C １－４ Alkylene-aryl, N-C １－４ Alkylene-heteroaryl, C(=O), C(=O)O-C(=O)NH, C(=O)N-alkyl, C(=O)NH-C １－４ Alkylene, C(=O)N(C １－４ Alkyl)-C １－４ AlkyleneSO ２ , S.O. ２ N.H., S.O. ２ N-C １－４ Alkyl, SO ２ N-(C １－４ Alkyl)-(C １－４ alkylene), OC(=O)-NH, OC(=O)-N-C １－４ Alkyl, SO ２ , S.O. ２ C １－４ Alkylene, SO ２ N.H., S.O. ２ N(C １－４ alkyl), SO ２ NH-(C １－４ Alkylene, SO ２ N(C １－４ Alkyl)-(C １－４ alkylene), SO ２ N(C １－４ alkylene-aryl), SO ２ N(C １－４ alkylene-heteroaryl), 【Chemistry 40】 and L ｄ H, C １－６ Alkyl, OH, alkoxy, NH ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , C １－６ Alkyl, C １－６ haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted benzyl; and R １１ａ is H or C １－６ It is alkyl. or a pharma- ceutically acceptable salt thereof; (a) R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N(C 1-4 alkyl), N(C 1-4 cycloalkyl), -NH-C 1-4 alkylene, -N(C 1-4 alkyl)-C 1-4 alkylene, C(=O), C(=O)O-, C(=O)NH, C(=O)N-alkyl, C(=O)NH-C 1-4 alkylene, C(=O)N(C 1-4 alkyl)-C 1-4 alkylene or OC(=O)-NH; L d is H, C 1-6 alkyl, OH, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-12 aryl or optionally substituted 5-10 membered heteroaryl; or (b) Z is H2 or O; R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, acetyl, C(=O)-NH-phenyl, C(=O)-ethyl, C(=O)-cyclopropyl, CH 2 -cyclobutyl or CH 2 CH 2 OH; and R 11a is H or methyl; The pharmaceutical composition of claim 1. (a) the compound of formula I has formula C1: 【Chemistry 41】 [During the ceremony, R ９ａ H, C １－６ Alkyl, C １－６ Alkylene-OH,C １－６ Alkylene -O-C １－６ Alkyl, C(=O)C １－６ Alkyl, C １－６ selected from the group consisting of alkylene-cycloalkyl, C(=O)cycloalkyl, and C(=O)NH-aryl; L ｃ NH, NH-C １－４ Alkylene, NH-C １－４ alkylene-(5-10 membered heteroarylene), C(=O)O-, C(=O)NH or OC(=O)-NH; and L ｄ C ３－６ cycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein cycloalkyl, aryl, and heteroaryl are each independently and optionally selected from halo, C １－４ Alkyl, C １－４ Haloalkyl or C １－４ is substituted with alkoxy. or a pharma- ceutically acceptable salt thereof; R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)-NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is NH, NH—CH 2 , NH—CH 2 —(5- to 6-membered heteroarylene), C(═O)O—, C(═O)NH, or OC(═O)—NH; and L d is C 3-6 cycloalkyl, phenyl or 5-10 membered heteroaryl; or (b) the compound of formula I is of formula C2: 【Chemistry 42】 [During the ceremony, R 9a is selected from the group consisting of H, substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O-C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cycloalkyl, C(═O)cycloalkyl and C(═O)NH-aryl; L c is absent or is NH or NH—C 1-4 alkylene; and L d is OH, C 3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy. or a pharma- ceutically acceptable salt thereof; R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)-NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe or CH 2 CH 2 OH; L c is absent or is NH or NH—CH 2 ; and L d is OH, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl or 6- to 10-membered nitrogen-containing heteroaryl; The pharmaceutical composition of claim 1.

9. The compound of formula I is 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】 【Table 26】 【Table 27】 【Table 28】 【Table 29】 【Table 30】 【Table 31】 【Table 32】 【Table 33】 【Table 34】 【Table 35】 【Table 36】 【Table 37】 【Table 38】 【Table 39】 【Table 40】 【Table 41】 【Table 42】 【Table 43】 【Table 44】 【Table 45】 or a pharma- ceutically acceptable salt thereof, or 【Table 46】 【Table 47】 【Table 48】 【Table 49】 【Table 50】 【Table 51】 【Table 52】 【Table 53】 【Table 54】 【Table 55】 【Table 56】 【Table 57】 【Table 58】 【Table 59】 【Table 60】 【Table 61】 【Table 62】 【Table 63】 【Table 64】 【Table 65】 【Table 66】 【Table 67】 【Table 68】 【Table 69】 【Table 70】 【Table 71】 【Table 72】 【Table 73】 【Table 74】 【Table 75】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

10. A compound selected from the following, or a pharma- ceutically acceptable salt thereof: 【Table 76】 【Table 77】 【Table 78】 【Table 79】 【Table 80】 【Table 81】 【Table 82】 【Table 83】 【Table 84】 【Table 85】 【Table 86】 【Table 87】 【Table 88】 【Table 89】 【Table 90】 【Table 91】 【Table 92】 【Table 93】 【Table 94】 【Table 95】 【Table 96】 【Table 97】 【Table 98】 【Table 99】 【Table 100】 【Table 101】 【Table 102】 【Table 103】 【Table 104】 【Table 105】

11. 11. A pharmaceutical composition comprising a compound of claim 10 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

12. The pharmaceutical composition of any one of claims 1 to 9, wherein the genetic disease is associated with a premature termination codon mutation.

13. The pharmaceutical composition of any of claims 1 to 9, wherein a compound of formula I or a pharma- ceutically acceptable salt thereof is administered to a subject alone or in any combination with an agent selected from the group consisting of aminoglycosides, potentiators, correctives, amplifiers and any combination thereof.

14. Genetic diseases include cystic fibrosis (CF), muscular dystrophies (Duchenne (DMD), Becker (BMD), congenital), spinal muscular atrophy (SMA), ataxia telangiectasia, mucopolysaccharidosis type 1 (MPS1) (Hurler syndrome), hemophilia (A and B), Usher syndrome (retinitis pigmentosa, X-linked retinitis pigmentosa), Tay-Sachs, factor VII deficiency, familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, mucopolysaccharidoses, nephrogenic cystinosis, polycystic kidney disease, Rett syndrome, cystinosis, epidermolysis bullosa severe, Dravet syndrome, X-linked nephrogenic diabetes insipidus (XNDI), cancer, beta-thalassemia, obesity, epidermolysis bullosa (EB) and familial adenomatous polyposis (FAP). ); optionally the genetic disease is selected from the group consisting of cystic fibrosis (CF), muscular dystrophies (Duchenne (DMD), Becker (BMD), congenital), spinal muscular atrophy (SMA), hemophilia (A and B), Usher syndrome (retinitis pigmentosa, X-linked retinitis pigmentosa), mucopolysaccharidoses, nephrogenic cystinosis, Rett syndrome, cancer, beta-thalassemia, obesity, epidermolysis bullosa (EB) and familial adenomatous polyposis (FAP); further optionally the genetic disease is selected from the group consisting of cystic fibrosis, epidermolysis bullosa, epidermolysis bullosa severe, dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa, junctional epidermolysis bullosa and familial adenomatous polyposis; preferably the genetic disease is (i) Cystic fibrosis; (ii) recessive dystrophic epidermolysis bullosa; (iii) Junctional epidermolysis bullosa; or (iv) familial adenomatous polyposis, The pharmaceutical composition according to any one of claims 1 to 9.

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