HK1178906A - Macrocyclic compounds and methods of making and using the same - Google Patents

Description

Macrocyclic compounds and methods of making and using the same

This application is a divisional application entitled "macrocyclic compounds and methods of making and using the same" filed on 25/2/2005 under application number 200580013532.8.

RELATED APPLICATIONS

This application claims priority from U.S. patent application No.60/548,280, filed on day 2, month 27, 2004, and U.S. patent application No.60/575,949, filed on day 6, month 1, 2004, the disclosures of both of which are hereby incorporated by reference in their entirety.

Technical Field

The present application relates to anti-infective, antiproliferative, anti-inflammatory, and peristalsis promoters. More particularly, the invention relates to a family of macrocyclic compounds that are useful as such agents.

Technical Field

Since the discovery of penicillin in the twentieth 20 th century and streptomycin in the fortieth 20 th century, many compounds have been discovered or designed as antibiotic drugs. It is believed at a first time that infectious diseases can be completely controlled and eradicated through the use of such drugs. However, this belief is shaken due to the evolution of cell lines or microorganisms resistant to effective therapeutic agents. Indeed, any developed clinical antibiotic drug eventually encounters problems due to the emergence of resistant bacteria. For example, resistant strains of gram-positive bacteria, such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci, have been developed. These resistant bacteria can lead to serious and even fatal consequences for those infected with these bacteria. Bacteria resistant to macrolide antibiotics have also emerged. Likewise, resistant strains of gram-negative bacteria, e.g., haemophilus influenzae and moraxella catarrhalis, have been found, see, e.g., f.d. lowry, "Antimicrobial Resistance: the Example of staphylococcus aureus, "j.clin.invest., vol.111, No.9, pp.1265-1273 (2003); and Gold, h.s. and molelling, r.c., Jr, "anti-pharmaceutical-Drug Resistance," n.engl.j.med., vol.335, pp.1445-53 (1996).

The problem of drug resistance is not limited to the field of anti-infective drugs, as antiproliferative drugs used in cancer chemotherapy also encounter such problems. Thus, there is a need to find new anti-infective and antiproliferative agents that are effective against both drug resistant bacterial and cancer cell lines.

Despite increasing resistance to antibiotics, ever since 200Year 0No new class of antibiotics has been developed for clinical use after the us market, the brand of oxazolidinone ring-containing antibiotic, linezolid. See, r.c. molelling, jr., "Linezolid: the First azolidineon antimicrobial, ", Annals of Internal Medicine, vol.138, No.2, pp.135-142 (2003). Linezolid is approved for use as an antimicrobial agent active against gram-positive organic microorganisms. However, strains of organic microorganisms resistant to linezolid have been reported. See, Tsiodras et al, Lancet, vol.358, p.207 (2001); gonzales et al, Lancet, vol 357, p.1179 (2001); zurenko et al, Proceedings of The 39^th Annual InterscienceConference On Antibacterial Agents And Chemotherapy(ICCAC)，San Francisco，CA，USA(September 26-29，`1999)。

Another class of antibiotics are macrolide compounds, which are known for their 14-to 16-membered ring characteristics. Macrolide compounds also often contain one or more six-membered saccharide derivative rings linked to a macrolactone ring. The first macrolide compound found was erythromycin, isolated in 1952 in a soil sample from the philippines. Although erythromycin is one of the antibiotics widely used, it has disadvantages of relatively low bioavailability, gastrointestinal side effects, and limited applicable spectrum. Another macrolide compound is azithromycin, which is a nitrogen derivative of erythromycin obtained by introducing a methyl-substituted nitrogen into the macrolide ring in erythromycin. The commercially available azithromycin isThe cards are made. One macrolide compound which has recently been marketed is telithromycin, which is commercially availableThe cards are made. Telithromycin is a semi-synthetic macrolide compound, the molecule of whichThe hydroxyl group in (a) is oxidized to a keto group. See Yong-Ji Wu, high elevations of semi-synthetic Developments from Erythromycin A, Current pharm. design, vol.6, pp 181-.

In the search for new therapeutic agents, researchers have attempted to combine or link portions of different antibiotic molecules to create a new compound with multiple or mixed functions. Additional researchers have attempted to make new macrolide derivatives by attaching more substituents to the macrolide ring or adding sugar rings. However, these methods of making macrolide derivatives have met with limited success.

In view of the above, there is now a need to find a new anti-infective and antiproliferative drug. Further, since many anti-infective and antiproliferative drugs can be used as anti-inflammatory agents and peristalsis promoters, there is also a demand for compounds that can be used as anti-inflammatory agents and peristalsis promoters. The present invention can provide compounds that meet the above-mentioned needs.

Brief description of the invention

The present invention provides compounds that can act as anti-infective and/or anti-proliferative agents, e.g., antibiotics, antimicrobials, and chemotherapeutic agents. The invention also provides compounds that may act as anti-inflammatory agents and/or as motility enhancers (gastrointestinal modulation). The invention also provides pharmaceutically acceptable salts, esters, nitroxides, or prodrugs thereof of these compounds.

The present invention provides compounds having the following structural formulae I and II:

or a stereoisomer, pharmaceutically acceptable salt, ester, oxynitride thereof, or a prodrug thereof. In the formula, the variables T, D, E, F, G, R¹，R²And R³And may be selected from the following chemical groups defined in detail in the present invention.

In addition, the invention also provides a method for synthesizing the compounds. In subsequent combinations, a therapeutically active amount of one or more compounds may be combined with a pharmaceutically acceptable carrier for administration to a mammal, particularly a human, for use as an anti-cancer, antibiotic, antibacterial, antifungal, antiparasitic or antiviral agent, or for the treatment of a proliferative disease, an inflammatory or gastrointestinal motility disorder, or for inhibiting conditions and pathologies caused or modulated by nonsense or missense mutations. Accordingly, the compounds or compositions of the present invention can be administered to a mammal in an effective amount, for example, orally, by injection, or topically.

The foregoing and other aspects and embodiments of the present invention will be more fully understood with reference to the following detailed description and claims.

Detailed Description

The present invention provides a family of compounds useful as antiproliferative agents and/or anti-infective agents. These compounds may be used, but are not limited to, for example, as anticancer agents, antibiotics, antibacterial agents, antifungal agents, antiparasitic agents and/or antiviral agents. Still further, the present invention provides a family of compounds that may be used, but are not limited to, as anti-inflammatory agents, e.g., for the treatment of chronic inflammatory diseases of the airways, and/or as agents that promote gastrointestinal motility, e.g., for the treatment of gastrointestinal motility disorders such as gastroesophageal reflux disease, primary gastroparesis (diabetes and post-operative), irritable bowel syndrome, and constipation. Further, these compounds may be used to treat or prevent disease states caused or modulated by nonsense or missense mutations in a mammal.

The compounds herein may contain asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms may be isolated optically active or in racemic form. It is well known in the art how to separate optically active forms, for example by separation of a racemic mixture or by synthesis from starting optically active starting materials. Many geometric isomers resulting from carbon-carbon double bonds, C ═ N double bonds, and similar structures are also encompassed by the present invention, and such stable isomers are contemplated by the present invention. Cis (Cis) and trans (trans) geometric isomeric forms are contemplated unless a particular stereochemistry or isomeric form is specifically indicated. All methods for preparing the compounds and intermediates of the present invention are part of this invention. Tautomers represented or described by the compounds of the invention are also part of the invention.

1. Definition of

The term "substituted" as used herein means that any one or more of the hydrogen atoms of a particular atom is replaced by a group selected from the group of groups indicated, provided that the normal valency of the particular atom is not exceeded, and that the result of the substitution is a stable compound. When the substituent group is a keto group (C ═ O), then two hydrogen atoms on that atom are replaced. As used herein, a cyclic double bond refers to a bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N, or N ═ N).

The invention also includes all isotopic atoms of each of the upper atoms in these compounds. Isotopes include those atoms that contain the same number of protons but different atomic weights. As a general example, and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When a variable (e.g. R)³) When a compound occurs more than one time in different moieties or formulae, the definition of each occurrence is independent of the definition of another occurrence. Thus, for example, when a group is substituted with one or more R³When substituted with a group, the group may be optionally substituted with one, two, three,four, five, or more R³Is substituted by radicals, and each R³Independently selected from the pair R³Groups in the definition. Also, combinations of these substituents and/or variables are permissible, but such combinations must result in stable compounds.

The dotted lines in the chemical structural formula represent chemical bonds that may or may not be present. For example, a dashed line with a solid bond indicates that there may be a single or double bond.

When a bond on a substituent group is shown to cross a bond connecting two ring atoms, this indicates that the substituent group may be attached at any position on the ring. When an listed substituent group is not explicitly attached to other moieties of a given formula through which atom of the group it is attached, this indicates that the substituent group may be attached through any atom thereof. Different substituents and/or variables can be combined as long as the combination results in a compound that is stable.

When compounds of the invention have nitrogen atoms, these compounds can be oxidized by oxidizing agents (e.g., MCPBA, and/or hydrogen peroxide) to N-oxides to provide other compounds of the invention. Thus, all nitrogen-containing compounds include their N-oxide form derivatives.

The term "anomeric carbon" in the present invention refers to the acetal carbon atom of the glycoside molecule.

The term "glycoside" in the present invention refers to a cyclic acetal.

The term "alkyl" in the present invention includes both branched and straight chain saturated aliphatic hydrocarbons having a specified number of carbon atoms. C_1-6The alkyl group including C₁，C₂，C₃，C₄，C₅And C₆An alkyl group. C_1-8The alkyl group including C₁，C₂，C₃，C₄，C₅，C₆，C₇And C₈An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethylN-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

The term "alkenyl" in the context of the present invention includes straight or branched chain structures in which one or more unsaturated carbon-carbon double bonds may be present in any stable position of the chain, such as ethenyl and propenyl. C_2-6Alkenyl radicals include₂，C₃，C₄，C₅And C and₆an alkenyl group. C_2-8Alkenyl radicals include₂，C₃，C₄，C₅，C₆，C₇And C₈An alkenyl group.

The term "alkynyl" in the context of the present invention includes straight or branched chain structures in which one or more unsaturated carbon-carbon triple bonds may be present in any stable position along the chain, such as ethynyl and propynyl. C_2-6Alkenyl radicals include₂，C₃，C₄，C₅And C₆Alkynyl. C_2-8Alkynyl includes, C₂，C₃，C₄，C₅，C₆，C₇And C₈Alkynyl.

Further, the terms "alkyl", "alkenyl" and "alkynyl" include double groups formed by two points of attachment, and an example of the present invention is when D is selected from these groups. A non-limiting example of such a gemini alkyl group is, for example, -CH₂CH₂-, i.e. a C₂An alkyl group, which is a group in which the terminal carbon atom is covalently bonded to the remainder of the molecule.

As used herein, various carbon-containing molecules are described, including, for example, "alkyl," "alkenyl," "alkynyl," "phenyl," and other like terms, which include monovalent, divalent, or multivalent forms. For example, "C_1-6alkyl-R³"comprises a monovalent C_1-6The alkyl radical being substituted by one R³Radical substitution, "O-C_1-6alkyl-R³"represents a divalent C_1-6Examples of alkyl radicalsE.g. an "alkylene" group, being bound by an oxygen atom and an R³And (4) substituting the group.

The term "cycloalkyl" in the context of the present invention is intended to include saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. C_3-8Cycloalkyl is intended to include C₃，C₄，C₅，C₆，C₇And C₈A cycloalkyl group.

The term "halogen" or "halogen atom" in the present invention means fluorine, chlorine, bromine and iodine. "anion" refers to a small, negatively charged group such as, for example, chloride, bromide, hydroxide, acetate, and sulfate.

"haloalkyl" as used herein includes both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogen atoms (e.g., -C)_VF_WWhere V ═ 1 to 3 and W ═ 1 to (2V + 1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.

The term "alkoxy" in the present invention means that an alkyl group as defined above having the specified number of carbon atoms is attached via an oxygen atom. C_1-6Alkoxy radicals, including C₁，C₂，C₃，C₄，C₅And C₆An alkoxy group. C_1-8Alkoxy radicals, including C₁，C₂，C₃，C₄，C₅，C₆，C₇And C₈An alkoxy group. Examples include, but are not limited to, methylalkoxy, ethylalkoxy, n-propylalkoxy, i-propylalkoxy, n-butylalkoxy, s-butylalkoxy, t-butylalkoxy, n-pentylalkoxy, s-pentylalkoxy, n-hexylalkoxy, n-heptylalkoxy, and n-octylalkoxy.

The term "alkylthio" in the present invention refers to an alkyl group as defined above having a specified number of carbon atomsThe radical is bonded via a sulfur atom. C_1-6Alkylthio radicals including C₁，C₂，C₃，C₄，C₅And C₆An alkylthio group. C_1-8Alkylthio radicals including C₁，C₂，C₃，C₄，C₅，C₆，C₇And C₈An alkylthio group.

The term "carbocycle" or "ring of carbon atoms" in the present invention means, unless otherwise indicated, any stable 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic or tricyclic ring, and may be saturated, unsaturated, or aromatic, noting that a particular number of carbocycles cannot be bicyclic or tricyclic, e.g., a three membered carbocycle can only be monocyclic. Such carbocycles, include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0] bicyclooctyl, [4.3.0] bicyclononyl, [4.4.0] bicyclodecyl, [2.2.2] bicyclooctyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As indicated above, bridged rings are also included in the definition of carbocyclic rings above (e.g., [2.2.2] dioctylalkyl). Bridging occurs when one or more carbon atoms join two carbon ring atoms that are not adjacent. Common bridging is one or two carbon atoms. It is noted that bridging tends to convert a single ring into a tricyclic ring. When a ring is bridged, the substituents thereon are also attached to the bridged ring. Fused (e.g., naphthalene and tetralin) and spiro rings are also included.

The term "heterocycle" in the context of this invention means, unless otherwise indicated, a stable 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic ring (note that a particular number of carbocycles cannot be bicyclic or tricyclic, e.g., only one ternary carbocycle), and may be saturated, unsaturated, or aromatic, and consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic ring in which any of the above defined heteroatoms is located in a second ring (e.g., a phenyl ring), the nitrogen or sulfur heteroatom may be oxidized (e.g., N → O and S (0)_PWhere P is 1 or 2). The nitrogen atom on the ring may be N or NH depending on whether it is attached to a double bond (e.g., a hydrogen atom represents maintaining saturation of the nitrogen atom if desired). The nitrogen atom may be substituted or unsubstituted. (e.g., N, or NR, R being H or other substituent groups, as defined). The heterocyclic ring may be attached to other chains at heteroatoms or carbon atoms to form a stable structure. The heterocyclic ring herein may be substituted at a carbon atom or a heteroatom as long as the product is stable. The nitrogen atoms of the heterocyclic ring may optionally be quaternized. When the total number of S and O atoms on the heterocyclic ring exceeds 1, the heterocyclic ring is not adjacent to other rings. More desirably, the total number of S and O atoms on the heterocycle does not exceed 1. Bridged rings are also included in the heterocyclic ring. Bridging occurs when one or more atoms (e.g., C, O, N, or S) join two non-adjacent carbon or nitrogen rings. Common bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen family. It is noted that bridging always converts a single ring into a tricyclic ring. When a ring is bridged, the ring substituents are also attached to the bridge structure. Spiro and fused rings are also included.

The term "heteroaryl ring" or "heteroaryl" in the context of this invention refers to a stable 5, 6, 7, 8, 9, 10, 11, or 12 membered mono or bi aromatic ring (note that a particular number of carbocyclic rings cannot be aromatic bicyclic rings, e.g., one five-membered ring can only be mono aromatic), and is composed of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, individually selected from among nitrogen, oxygen, and sulfur. In the case of bis-heteroaromatic rings, only one of the two rings need be an aromatic ring (e.g., 2, 3-indoline), although it is possible that both may be (e.g., quinoline). The second ring canEither fused to or bridged to the above-mentioned heterocyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., N → O and S (0)_PWhere P is 1 or 2). It is noted that the total number of S and O atoms on the heterocycle does not exceed 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothiophenyl, benzoxazolylmethyl, benzisothiazole, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro- [2, 3-b ] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolyl, 1H-indazolyl, indolyl, indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isobenzodihydropyranyl, isoindolyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthrinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridimidazolyl, pyridthiazolyl, pyrimidinyl, pyridinyl, pyrimidonyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 2H-quinazolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrazolyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thiadiazo, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, and xanthenyl.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of medical acceptability, compatible with the tissues of human or animal subjects, have no undue toxicity, irritation, allergic response, or other problem or complication, or are subject to reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" in the present invention means a derivative of the compound of the present invention, which is a salt of the compound of the present invention formed by modification with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, organic acid salts of base residues, such as amines; bases or organic salts of acid residues, such as carboxylic acids; and the like. Pharmaceutically acceptable salts include non-toxic salts or quaternary ammonium salts of the compounds of the invention in general, e.g., from non-toxic inorganic or organic acids. For example, such non-toxic salts include, but are not limited to, derivatives from inorganic or organic acids, 2-benzoin acetic acid, 2-hydroxyethyl sulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, dicarbonic acid, carbonic acid, citric acid, ethylene diamine tetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolysarasanoic acid, hexylisophthalic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lauric acid, maleic acid, malic acid, phenylglycolic acid, ethanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, galacturonic acid, propionic acid, salicylic acid, stearic acid, subacic acid, succinic acid, sulfanilic acid, sulfamic acid, sulfonic acid, tannic acid, tartaric acid, and toluenesulfonic acid.

Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a base or acid group by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of a base or acid in water or an organic solvent or a mixed solution of the two; generally, anhydrous media such as esters, ethyl acetate, ethanol, isopropanol, acetonitrile are preferred. A list of suitable solutions can be found in Remington's Pharmaceutical Science 18 th ed. Mack Publishing Company, Easton, PA, USA, p.1445 (1990).

Since prodrugs can enhance many of the pharmaceutically desirable properties (e.g., solubility, bioavailability, processability, etc.), the compounds of the invention can be administered in prodrug form. Thus, the present invention is intended to include prodrugs of the presently claimed compounds, as well as methods of administering such compounds or compositions comprising such compounds. "prodrug" is intended to include all those covalent carriers which are capable of releasing the active substance in an organism when administered to the organism. Prodrugs of the invention are prepared by modifying some of the functional groups of the compounds of the invention by some conventional binding of the parent compound either under manipulation or in vivo. Prodrugs include hydroxides, amines, thiols attached to any functional group of the compounds of the invention which, when administered to a mammal, dissociate into free hydroxides, amines, thiols. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate derivatives of alcohol and amino groups of the compounds of the present invention.

"Stable compound" and "stable structure" refer to a compound that is sufficiently stable to be isolated from a reaction mixture to a useful degree of purity and formulated in a pharmaceutically effective dosage.

The terms "treatment" or "treating" in the present invention refer to the treatment of a disease state in a mammal, particularly a human, and include: (a) preventing the occurrence of a disease state in a mammal, particularly when the mammal has a predisposition to, but has not yet, developed the disease state; (b) inhibiting such a disease state, e.g., arresting its development; and/or (c) alleviating the disease state, e.g., causing regression of the disease state.

The term "mammal" in the present invention refers to both human and non-human patients.

The term "pharmaceutically active amount" as used herein refers to an amount of a compound, or composition, of the invention that is sufficient to elicit a biological response in a recipient, e.g., a drug resistance response, an antibacterial response, an antiviral response, an antiparasitic response, and/or an antiproliferative response. The combination of these compounds is preferably a synergistic combination. Synergism, as described, for example, by Chou and Talalay, adv. enzyme Regul. vol.22, pp.27-55(1984), occurs when the effects are administered in combination more than when each compound in the composition is administered alone in combination. In general, synergy can be clearly demonstrated by compounds at non-optimal concentrations. The potentiating effect may reduce cytotoxicity, increase antiproliferative and/or anti-infective effects, or bring about other benefits, compared to the compound alone.

All percentages or ratios herein are by weight unless otherwise indicated.

Throughout this application, when a composition is described as comprising, including, or consisting of specific ingredients, or a process is described as comprising, including, or consisting of specific steps, that is, a composition of the invention substantially comprises, or consists essentially of, the specified ingredients, as well as a method of the invention substantially comprises, or consists essentially of, the specified steps. Further, it is to be understood that the order of steps or certain specific operations is not necessarily fixed provided that the present invention may be practiced. Also, two or more steps may be performed simultaneously.

Compounds of the invention

In one aspect, the invention provides a compound of the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof,

wherein the content of the first and second substances,

t is a 14-, 15-, or 16-membered macrocyclic lactone compound, linked through a carbon atom on the macrocyclic ring;

R¹and R³Independently selected from the group consisting of: (a) h, (b) C_1-6Alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) -C (O) R⁵，(f)-C(O)OR⁵，(g)-C(O)-NR⁴R⁴R⁴R⁴，(h)-C(S)R⁵，(i)-C(S)OR⁵，(j)-C(O)SR⁵Or (k) -C (S) -NR⁴R⁴R⁴R⁴；R²Is hydrogen OR-OR¹²；

D is selected from the following groups:

(a) a single bond, (b) C_1-6Alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl (e) -C (O) -X-, (f) -C (O) O-X-, (g) -C (O) NR⁴R⁴-X-，(h)-C(＝NR⁴)-X-，(i)-C(＝NR⁴)O-X-，(j)-C(＝NR⁴)N-X-，(K)-SO₂-X-，(l)-C(NR⁴)NR⁴-X-，(m)-C(S)-X-，(n)-C(S)NR⁴-X-，(o)-C(NR⁴)S-X-，or(p)-C(O)S-X-，

Wherein the content of the first and second substances,

(i) d0-2 carbon atoms in groups (b) to (D) may be optionally substituted by one or more groups selected from O, S (O)_PAnd NR⁴Is substituted with a group (b) of (a),

(ii) any of (b) to (d) may be substituted by one or more R⁵The substitution of the group(s),

(iii) when R in (b) to (d)⁵When it is an optional substituent, R³And R⁵May form a 3-to 7-membered ring together with the atoms to which they are attached, and (iv) X is selected fromThe following group (aa) C_1-6Alkyl group, (bb) C_2-6Alkenyl, (cc) C_2-6Alkynyl, wherein any of (aa) - (cc) can be optionally substituted with one or more R⁵Substituted by groups;

f is selected from the following:

(a) a single bond, (b) C_1-6Alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl radicals, in which,

(i) f groups (b) to (d) 0 to 2 carbon atoms may be optionally substituted by a group selected from O, S (O)_PAnd NR⁴Any one of (b) to (d) of (ii) F may be substituted with one or more R⁵(ii) any one of (b) to (d) of (iii) F may be substituted with C_1-6alkyl-R⁵Substituted by groups;

e is selected from the following:

(a) a 3-to 10-membered, saturated/unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(b) 3-to 10-membered, saturated or unsaturated, or aromatic, carbocyclic ring

(c) W- [3-10 membered, saturated or unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur ],

(d) w- [3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ],

(e)-C(O)-，(f)-C(O)O-，(g)-C(O)NR⁴-，(h)-C(＝NR⁴)-，(i)-C(＝NR⁴)O-，(j)-C(＝NR⁴)NR⁴-，(k)-OC(O)-，(l)-OC(O)O-，(m)-OC(O)NR⁴-，(n)-NR⁴C(O)-，(o)-NR⁴C(O)O-，(p)-NR⁴C(O)NR⁴-，(q)-NR⁴C(＝NR⁴)NR⁴-，(r)-S(O)_P-，(s)-NR⁴S(O)₂-，(t)-S(O)₂NR⁴-，(u)-C(N-OR⁴)-，(v)-CH₂-，(w)-C(N-NR⁴R⁴)-，(x)-C(S)NR⁴-，(y)-NR⁴c (S) -, (z) -C (S) O-, or (aa) -OC (S) -,

wherein

i) Any of (a) to (d) may be optionally substituted with one or more R⁵Is substituted by radicals, and

ii) W is selected from the group consisting of:

(aa)-OCO-，(bb)-OC(O)O-，(cc)-OC(O)NR⁴-，(dd)-NR⁴C(O)O-，(ee)-OCNOR⁴-，(ff)-NR⁴-C(O)O-，(gg)-C(S)(NR⁴)-，(hh)-NR⁴-，(ii)-OC(S)O-，(jj)-OC(S)NR⁴-，(kk)-NR⁴C(S)O-，(ll)-OC(S)NOR⁴-，(mm)-C(S)O-，(nn)-，OC(S)-，(oo)-C(O)-，(pp)-C(O)O-，(qq)-C(O)NR⁴-，(rr)-C(＝NR⁴)-，(ss)-C(＝NR⁴)O-，(tt)-C(＝NR⁴)NR⁴-，(uu)-OC(O)-，(vv)-OC(O)O-，(ww)-OC(O)NR⁴-，(xx)-NR⁴C(O)-，(yy)-NR⁴C(O)O-，(zz)-NR⁴C(O)NR⁴-，(aaa)-NR⁴C(＝NR⁴)NR⁴-，(bbb)-S(O)_P-，(ccc)-NR⁴S(O)₂-，(ddd)-S(O)₂NR⁴-，(eee)-C(N-OR⁴)-，(fff)-C(N-NR⁴R⁴)-，(ggg)-C(S)NR⁴-，or(hhh)-NR⁴C(S)-；

g is selected from the following: (a) b ' and (B) B ' -Z-B ', wherein

i) Each B 'and B' is independently selected from (aa) aryl, (bb) heteroaryl, (cc) biaryl, (dd) fused bicyclic or tricyclic ring system, saturated, unsaturated, or aromatic, containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (ee)3-10 membered, saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (ff)3-10 membered, saturated or unsaturated carbocyclic ring, wherein any of (aa) to (ff) may optionally be substituted with one or more R¹¹Substituted by groups; and

ii) Z is selected from the group consisting of (aa) a single bond, (bb) C_1-2Alkyl group, (cc) C₂Alkenyl, (dd) C₂Alkynyl, (ee) -C (O) -, (ff) -C (O) O-, (gg) -C (O) NR⁴-，(hh)-C(＝NR⁴)-，(ii)-C(＝NR⁴)O-，(jj)-C(＝NR⁴)NR⁴-，(kk)-S(O)_p-，(ll)-OC(O)-，(mm)-C(S)-，(nn)-C(S)NR⁴-，(oo)-C(NR⁴)S-，(pp)-C(O)S-，(qq)-O-，(rr)-NR⁴-，(ss)-NR⁴C(O)-，(tt)-OC(NR⁴)-，(uu)-NC(NR⁴)-，(vv)-C(S)O-，(ww)-SC(O)-，or(xx)-OC(S)；

Each occurrence of R⁴Are independently selected from the following:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (g) -C (O) -C_1-6Alkyl, (h) -C (O) -C_2-6Alkenyl, (i) -C (O) -C_2-6Alkynyl, (j) -C (O) -C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (k) -C (O) -3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (l) -C (O) O-C_1-6Alkyl, (m) -C (O) O-C_2-6Alkenyl, (n) -C (O) O-C_2-6Alkynyl, (O) -C (O) O-C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (p) -C (O) O-3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, and (q) -C (O) NR⁶R⁶，

Wherein any of (b) - (p) groups may optionally be substituted with one or more R⁵The substitution is carried out by the following steps,

or, NR⁴R⁴Form a 3-to 7-membered, saturated, unsaturated or aromatic ring, including R⁴Nitrogen atom attached thereto, whereinIs cyclic at R⁴The position other than the nitrogen atom at the linking position may be optionally substituted, and the substituent is selected from the group consisting of O, S (O)_PN, and NR⁸One or more of;

R⁵selected from the following:

(a)R⁷，(b)C_1-8alkyl, (C) C_2-8Alkenyl, (d) C_2-8Alkynyl, (e) a 3-12 membered, saturated or unsaturated, or aromatic carbocyclic ring, and (f) a 3-12 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, or when two R's are present⁵When the groups are attached to the same carbon atom, they may form, together with the attached carbon atom, a spiro-substituted 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur,

wherein any of the above (b) to (f) may optionally be substituted with one or more R⁷Substitution;

each occurrence of R⁶Are independently selected from the following:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (b) to (f) above may be optionally substituted with one or more of the following groups:

(aa) carbonyl, (bb) formyl (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO₂，(ii)-OR⁸，(jj)-S(O)_pR⁸，(kk)-C(O)R⁸，(ll)-C(O)OR⁸，(mm)-OC(O)R⁸，(nn)-C(O)NR⁸R⁸，(oo)-OC(O)NR⁸R⁸，(pp)-C(＝NR⁸)R⁸，(qq)-C(R⁸)(R⁸)OR⁸，(rr)-C(R⁸)₂OC(O)R⁸，(ss)-C(R⁸)(OR⁸)(CH₂)_rNR⁸R⁸，(tt)-NR⁸R⁸，(uu)-NR⁸OR⁸，(vv)-NR⁸C(O)R⁸，(ww)-NR⁸C(O)OR⁸，(xx)-NR⁸C(O)NR⁸R⁸，(yy)-NR⁸S(O)_rR⁸，(zz)-C(OR⁸)(OR⁸)R⁸，(ab)-C(R⁸)₂NR⁸R⁸，(ac)＝NR⁸，(ad)-C(S)NR⁸R⁸，(ae)-NR⁸C(S)R⁸，(af)-OC(S)NR⁸R⁸，(ag)-NR⁸C(S)OR⁸，(ah)-NR⁸C(S)NR⁸R⁸，(ai)-SC(O)R⁸，

(aj)C_1-8Alkyl, (ak) C_2-8Alkenyl, (al) C_2-8Alkynyl, (am) C_1-8Alkoxy (an) C_1-8Mercapto group, (ao) C_1-8Acyl, (ap) -CF₃，(aq)-SCF₃(ar) a 3-10 membered, saturated or unsaturated or aromatic carbocyclic ring, (as) a 3-10 membered, saturated or unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur,

or, NR⁶R⁶Forming a 3-to 10-membered saturated, or unsaturated, or aromatic ring, including the linkage R⁶With the ring being bound to R⁶Any position other than the nitrogen atom at the linking position may be optionally substituted, and the substituent is selected from the group consisting of O, S (O)_PN, and NR⁸；

Or, CR⁶R⁶Forming a carbonyl group;

each occurrence of R⁷Are independently selected from the following:

(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f)I，(g)-CF₃，(h)-CN，(i)-N₃(j)-NO₂，(k)-NR⁶(CR⁶R⁶)_tR⁹，(l)-OR⁹，(m)-S(O)_pC(R⁶R⁶)_tR⁹，(n)-C(O)(CR⁶R⁶)_tR⁹，(o)-OC(O)(CR⁶R⁶)_tR⁹，(p)-SC(O)(CR⁶R⁶)_tR⁹，(q)-C(O)O(CR⁶R⁶)_tR⁹，(r)-NR⁶C(O)(CR⁶R⁶)_tR⁹，(s)-C(O)NR⁶(CR⁶R⁶)_tR⁹，(t)-C(＝NR⁶)(CR⁶R⁶)_tR⁹，(u)-C(＝NNR⁶R⁶)(CR⁶R⁶)_tR⁹，(v)-C(＝NNR⁶C(O)R⁶)(CR⁶R⁶)_tR⁹，(w)-C(＝NOR⁹)(CR⁶R⁶)_tR⁹，(x)-NR⁶C(O)O(CR⁶R⁶)_tR⁹，(y)-OC(O)NR⁶(CR⁶R⁶)_tR⁹，(z)-NR⁶C(O)NR⁶(CR⁶R⁶)_tR⁹，(aa)-NR⁶S(O)_p(CR⁶R⁶)_tR⁹，(bb)-S(O)_pNR⁶(CR⁶R⁶)_tR⁹，(cc)-NR⁶S(O)_pNR⁶(CR⁶R⁶)_tR⁹，(dd)-NR⁶R⁶，(ee)-NR⁶(CR⁶R⁶)，(ff)-OH，(gg)-NR⁶R⁶，(hh)-OCH₃，(ii)-S(O)_pR⁶，(jj)-NC(O)R⁶，

(kk)C_1-6alkyl, (ll) C_2-6Alkenyl, (mm) C_2-6Alkynyl, (nn) a 3-10 membered, saturated, or unsaturated, or aromatic carbocyclic ring, and (oo) a 3-10 membered, saturated, or unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (kk) to (oo) above may optionally be substituted with one or more R⁹Substitution

Or, two R⁷form-O (CH)₂)_UO-；

R⁸Selected from the following:

(a)R⁵，(b)H，(c)C_1-6alkyl, (d) C_2-6Alkenyl, (e) C_2-6Alkynyl, (f) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (g) a 3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (h) -C (O) -C_1-6Alkyl, (i) -C (O) -C_1-6Alkenyl, (j) -C (O) -C_1-6Alkynyl, (k) -C (O) -C_3-10A saturated, unsaturated, or aromatic ring, and (l) -C (O) -3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (c) - (k) above may be optionally substituted with one or more of the following groups:

(aa)H，(bb)F，(cc)Cl，(dd)Br，(ee)I，(ff)CN，(gg)NO₂，(hh)OH，(ii)NH₂，(jj)NH(C_1-6alkyl), (kk) N (C)_1-6Alkyl radical)₂，(ll)C_1-6Alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C_1-6Alkyl, optionally substituted by one or more groups selected from aryl, substituted heteroaryl, F, Cl, Br, CN, NO₂，CF₃，SCF₃And OH substitution;

each occurrence of R⁹Independently selected from the following:

(a)R¹⁰，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic ringA heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen or sulfur,

wherein any of the above (b) to (f) may optionally be substituted with one or more R¹⁰Substituted by groups;

r occurring on any structure¹⁰Independently selected from the following:

(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f)I，(g)-CF₃，(h)-CN，(i)-NO₂，(j)-NR⁶R⁶，(k)-OR⁶，(l)-S(O)_pR⁶，(m)-C(O)R⁶，(n)-C(O)OR⁶，(o)-OC(O)R⁶，(p)NR⁶C(O)R⁶，(q)-C(O)NR⁶R⁶，(r)-C(＝NR⁶)R⁶，(s)-NR⁶C(O)NR⁶R⁶，(t)-NR⁶S(O)_pR⁶，(u)-S(O)_pNR⁶R⁶，(v)-NR⁶S(O)_pNR⁶R⁶，(w)a C_1-6alkyl radical

(x)C_2-6Alkenyl, (y) C_2-6Alkynyl, (z)3-10 membered, saturated or unsaturated, or aromatic ring, and (aa)3-10 membered, saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (w) - (aa) above may be optionally substituted with one or more groups selected from: r⁶，F，Cl，Br，I，CN，NO₂，OR⁶，-NH₂，-NH(C_1-6Alkyl group), -N (C)_1-6Alkyl radical)₂，C_1-6Alkoxy radical, C_1-6Alkylthio, and C_1-6An alkanoyl group;

each occurrence of R¹¹Independently selected from the following:

(a) carbonyl, (b) formate, (c) F, (d) Cl, (e) Br, (F) I, (g) CN, (h) NO₂，(i)OR⁸，(j)-S(O)_pR⁸，(k)-C(O)R⁸，(l)-C(O)OR⁸，(m)-OC(O)R⁸，(n)-C(O)NR⁸R⁸，(o)-OC(O)NR⁸R⁸，(p)-C(＝NR⁸)R⁸，(q)-C(R⁸)(R⁸)OR⁸，(r)-C(R⁸)₂OC(O)R⁸，(s)-C(R⁸)(OR⁸)(CH₂)_rNR⁸R⁸，(t)-NR⁸R⁸，(u)-NR⁸OR⁸，(v)-NR⁸C(O)R⁸，(w)-NR⁸C(O)OR⁸，(x)-NR⁸C(O)NR⁸R⁸，(y)-NR⁸S(O)_rR⁸，(z)-C(OR⁸)(OR⁸)R⁸，(aa)-C(R⁸)₂NR⁸R⁸，(bb)＝NR⁸，(cc)-C(S)NR⁸R⁸，(dd)-NR⁸C(S)R⁸，(ee)-OC(S)NR⁸R⁸，(ff)-NR⁸C(S)OR⁸，(gg)-NR⁸C(S)NR⁸R⁸，

(hh)-SC(O)R⁸，(ii)C_1-8Alkyl group, (jj) C_2-8Alkenyl, (kk) C_2-8Alkynyl, (ll) C_1-8Alkoxy group, (mm) C_1-8Alkylthio, (nn) C_1-8Alkanoyl, (oo) a 3-10 membered, saturated, unsaturated, or aromatic carbocyclic ring, and (pp) a 3-10 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (ii) - (kk) may optionally be substituted with one or more R⁵

Substitution;

R¹²selected from the following:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl (d) C_2-6Alkynyl (e) -C (O) R⁵，(f)-C(O)OR⁵，(g)-C(O)-NR⁴R⁴R⁴R⁴，(h)-C(S)R⁵，(i)-C(S)OR⁵，(j)-C(O)SR⁵，(k)-C(S)-NR⁴R⁴R⁴R⁴，

(l)C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (m) a 3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (n) - (C)_1-6Alkyl) -C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, or (o) - (C)_1-6Alkyl) -3-to 10-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur,

wherein any of (a) to (d) and (l) to (o) above may optionally be substituted with one or more R⁵Substitution;

p is 0, 1, or 2, occurring at any time;

r is 0, 1, or 2 at any time;

t is 0, 1, or 2 at any time;

u is 0, 1, 2, 3, or 4at any time;

but provided that

i) When T is a 14 or 15 membered macrolide compound, D-E is not

ii) when T is a 14 or 15 membered macrolide compound, F-B' is not

iii) when T is a 14 or 15 membered macrolide compound, B '-Z-B' is not

iv) when T is a 14 or 15 membered macrolide compound, R¹¹Is not provided with

v) when the compound is of formula I, and T is

When D is not a single bond or-CH₂-，

vi) when the compound is of formula I and T is a 14 or 15 membered macrolide compound, -D-E-F-is not-CH₂-，

vii) when the compound is of formula I and T is a 14 or 15 membered macrolide compound, -D-E-F-G-is not a group as in Table A below

In the context of Table A, the following examples,

and

viii) when the compound is of formula II, and T is a 16 membered macrolide compound,

i. -D-E is not a glucoside attached through its anomeric carbon,

ii-D-E-F-G-is not C attached to a 5-10 membered monocyclic or bicyclic carbocyclic or heterocyclic ring, or to a 5-or 6-membered carbocyclic or heterocyclic ring further attached to a 5-or 6-membered carbocyclic or heterocyclic ring_1-4(alkyl group, C)_2-4(alkenyl radical), C_2-4(alkynyl) chains, where all carbocyclic or heterocyclic rings may be optionally substituted with one or more groups selected from, (aa) -OH, (bb) -F, (cc) -Cl, (dd) -I, and (ee) -NO₂And are and

iii. -D-E-F-G-is not a group selected from Table B below

TABLE B

In particular embodiments, the present invention provides compounds of the formula:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T, D, E, F, G, R¹，R²And R³As previously defined.

Other embodiments of the foregoing compounds include compounds having the following formula:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T, D, E, F, G, R¹，R²And R³As previously defined.

Other embodiments of the foregoing compounds also include those having the following formula:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T, D, E, F, G, R¹，R²And R³As previously defined.

Other embodiments of the foregoing compounds of the invention also include those when T is a 14 or 15 membered macrolide compound attached through a macrocyclic carbon atom (i.e., a macrolide compound that is not 16 membered). In other embodiments, T is a 16-membered macrolide compound (i.e., a macrolide compound that is not 14 or 15 membered) attached through a large ring carbon atom.

In other embodiments, when T is a 14-, 15-, or 16-membered macrolide compound,

i) D-E is not

ii) F-B' is not

iii) B '-Z-B' is not

And

iv)R¹¹is not provided with

Other embodiments of the foregoing compounds include those wherein G is B'. Other embodiments of the foregoing compounds include that B' is selected from the following: (a) aryl, (b) heteroaryl, (c) biaryl, and (d) a fused bicyclic or tricyclic unsaturated or aromatic ring system, optionally substituted with one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each of (a) through (d) above may be substituted with one or more R¹¹And (4) substitution.

Other embodiments of the foregoing compounds include those wherein E is

(a) A 3-to 10-membered, saturated, or unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(b) 3-to 10-membered, saturated or unsaturated, or aromatic, carbocyclic ring

(c) W- [3-10 membered, saturated or unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur ],

(d) w- [ 3-to 10-membered, saturated or unsaturated, or aromatic, carbocyclic ]

(e)-C(O)-，(f)-C(O)O-，(g)-C(O)NR⁴-，(h)-C(＝NR⁴)-，(i)-C(＝NR⁴)O-，(j)-C(＝NR⁴)NR⁴-，(k)-OC(O)-，(l)-OC(O)O-，(m)-OC(O)NR⁴-，(n)-NR⁴C(O)-，(o)-NR⁴C(O)O-，(p)-NR⁴C(O)NR⁴-，(q)-NR⁴C(＝NR⁴)NR⁴-，(r)-S(O)_p-，(s)-NR⁴S(O)₂-，(t)-S(O)₂NR⁴-，(u)-C(N-OR⁴)-，(v)-C(N-NR⁴R⁴)-，(w)-C(S)NR⁴-，(x)-NR⁴C(S)-，(y)-C(S)O-，or(z)-OC(S)-，

Wherein

i) Any of (a) to (d) may be optionally substituted with one or more R⁵Is substituted by radicals, and

ii) W is selected from the group consisting of:

(aa)-OCO-，(bb)-OC(O)O-，(cc)-OC(O)NR⁴-，(dd)-NR⁴C(O)O-，(ee)-OCNOR⁴，(ff)-NR⁴-C(O)O-，(gg)-C(S)(NR⁴)-，(hh)-NR⁴，(ii)-OC(S)O-，(jj)-OC(S)NR⁴-，(kk)-NR⁴C(S)O-，(ll)-OC(S)NOR⁴-，(mm)-C(S)O-，(nn)-OC(S)-，(oo)-C(O)-，(pp)-C(O)O-，(qq)-C(O)NR⁴-，(rr)-C(＝NR⁴)-，(ss)-C(＝NR⁴)O-，(tt)-C(＝NR⁴)NR⁴-，(uu)-OC(O)-，(vv)-OC(O)O-，(ww)-OC(O)NR⁴-，(xx)-NR⁴C(O)-，(yy)-NR⁴C(O)O-，(zz)-NR⁴C(O)NR⁴-，(aaa)-NR⁴C(＝NR⁴)NR⁴-，(bbb)-S(O)_p-，(ccc)-NR⁴S(O)₂-，(ddd)-S(O)₂NR⁴-，(eee)-C(N-OR⁴)-，(fff)-C(N-NR⁴R⁴)-，(ggg)-C(S)NR⁴-，or(hhh)-NR⁴C(S)-.

other embodiments of the foregoing compounds include those

D is selected from the following groups:

(a)C_1-6alkyl, (b) C_2-6Alkenyl, (C) C_2-6Alkynyl radicals, in which,

(i) d any one of groups (a) to (c) having 0 to 2 carbon atoms optionally substituted by one or more groups selected from O, S (O)_PAnd NR⁴Is substituted with a group (b) of (a),

(ii) any of (a) to c) of D may be substituted by one or more R⁵Is substituted by radicals, and

f is selected from the following groups:

(a) single bond (b) C_1-6Alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl radicals, in which,

(i) of F(b) 0-2 carbon atoms of any one of groups (a) to (d) may be optionally substituted by a group selected from O, S (O)_PAnd NR⁴Is substituted with a group (b) of (a),

(ii) any of (b) to (d) of F may be substituted by one or more R⁵The substitution of the group(s),

(iii) any of (b) to (d) of F may be substituted by C_1-6alkyl-R⁵Substituted by groups;

other embodiments of the foregoing compounds include those wherein E is selected from the group consisting of:

(a) a 3-to 10-membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(b)3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ring,

(c) w- [3-10 membered, saturated, or unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur ],

(d) w- [3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ],

(e)-C(O)-，(f)-C(O)O-，(g)-C(O)NR⁴-，(h)-C(＝NR⁴)-，(i)-C(＝NR⁴)O-，(j)-C(＝NR⁴)NR⁴-，(k)-OC(O)-，(l)-OC(O)O-，(m)-OC(O)NR⁴-，(n)-NR⁴C(O)-，(o)-NR⁴C(O)O-，(p)-NR⁴C(O)NR⁴-，(q)-NR⁴C(＝NR⁴)NR⁴-，(r)-S(O)_p-，(s)-NR⁴S(O)₂-，(t)-S(O)₂NR⁴-，(u)-C(N-OR⁴)-，(v)-CH₂-，(w)-C(N-NR⁴R⁴)-，(x)-C(S)NR⁴，(Y)-NR⁴C(S)-，(Z)-C(S)O-，or(aa)-OC(S)-，

wherein

i) Any of (a) to (d) may be optionally substituted with one or more R⁵Is substituted by radicals, and

ii) W is selected from the group consisting of:

(aa)-OCO-，(bb)-OC(O)O-，(cc)-OC(O)NR⁴-，(dd)-NR⁴C(O)O-，(ee)-OCNOR⁴-，(ff)-NR⁴-C(O)O-，(gg)-C(S)(NR⁴)-，(hh)-NR⁴，(ii)-OC(S)O-，(jj)-OC(S)NR⁴-，(kk)-NR⁴C(S)O-，(ll)-OC(S)NOR⁴-，(mm)-C(S)O-，(nn)-OC(S)，(oo)-C(O)-，(pp)-C(O)O-，(qq)-C(O)NR⁴-，(rr)-C(＝NR⁴)-，(ss)-C(＝NR⁴)O-，(tt)-C(＝NR⁴)NR⁴-，(uu)-OC(O)-，(vv)-OC(O)O-，(ww)-OC(O)NR⁴-，(xx)-NR⁴C(O)-，(yy)-NR⁴C(O)O-，(zz)-NR⁴C(O)NR⁴-，(aaa)-NR⁴C(＝NR⁴)NR⁴-，(bbb)-S(O)_p-，(ccc)-NR⁴S(O)₂-，(ddd)-S(O)₂NR⁴-，(eee)-C(N-OR⁴)-，(fff)-C(N-NR⁴R⁴)-，(ggg)-C(S)NR⁴-，or(hhh)-NR⁴C(S)-.

other embodiments of the foregoing compounds include, E is selected from the group consisting of:

(a) a 3-to 10-membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(b)3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ring,

wherein (a) and (b) may be optionally substituted with one or more R⁵And (4) substituting the group.

Other embodiments of the foregoing compounds include, E is selected from the group consisting of:

(a)-C(O)-，(b)-C(O)O-，(c)-C(O)NR⁴-，(d)-C(＝NR⁴)-，(e)-C(＝NR⁴)O-，(f)-C(＝NR⁴)NR⁴-，(g)-OC(O)-，(h)-OC(O)O-，(i)-OC(O)NR⁴-，(j)-NR⁴C(O)-，(k)-NR⁴C(O)O-，(l)-NR⁴C(O)NR⁴-，(m)-NR⁴C(＝NR⁴)NR⁴-，(n)-S(O)_p-，(o)-NR⁴S(O)₂-，(p)-S(O)₂NR⁴-，(q)-C(N-OR⁴)-，(r)-CH₂-，(s)-C(N-NR⁴R⁴)-，(t)，-C(S)NR⁴，(u)-NR⁴C(S)-，(v)-C(S)O，and(w)-OC(S)-.

other embodiments of the foregoing compounds include that T is:

or an N-oxide, pharmaceutically acceptable salt, ester, or prodrug thereof,

wherein:

m is selected from the following groups:

(a)-C((O)-，(b)-CH(-OR¹¹⁴)-，(c)-NR¹¹⁴-CH₂-，(d)-CH₂-NR¹¹⁴-，(e)-CH(NR¹¹⁴R¹¹⁴)-，(f)-C(＝NNR¹¹⁴R¹¹⁴)-，(g)-NR¹¹⁴-C(O)-，(h)-C(O)NR¹¹⁴-，(i)-C(＝NR¹¹⁴)-，and(j)-CR¹¹⁵R¹¹⁵-，(k)-C(＝NOR¹²⁷)-；

R¹⁰⁰selected from hydrogen or C_1-6An alkyl group;

R¹⁰¹selected from the following groups:

(a)H，(b)Cl，(c)F，(d)Br，(e)I，(f)-NR¹¹⁴R¹¹⁴，(g)-NR¹¹⁴C(O)R¹¹⁴，(h)-OR¹¹⁴，(i)-OC(O)R¹¹⁴，(j)-OC(O)OR¹¹⁴，(k)-OC(O)NR¹¹⁴R¹¹⁴，(l)-O-C_1-6alkyl, (m) -OC (O) -C_1-6Alkyl, (n) -OC (O) O-C_1-6Alkyl, (o) -OC (O) NR¹¹⁴C_1-6Alkyl, (p) C_1-6Alkyl, (q) C_1-6Alkenyl, (r) C_1-6Alkynyl radical

Wherein any of (l) to (R) may optionally be substituted with one or more R¹¹⁵Substitution;

R¹⁰²is a hydrogen atom, and is,

R¹⁰³selected from the following groups:

(a)H，(b)-OR¹¹⁴，(c)-O-C_1-6alkyl-R¹¹⁵，(d)-OC((O)R¹¹⁴，(e)-OC(O)-C_1-6alkyl-R¹¹⁵，(f)-OC(O)OR¹¹⁴，(g)-OC(O)O-C_1-6alkyl-R¹¹⁵，(h)-OC(O)NR¹¹⁴R¹¹⁴，(i)-OC(O)NR¹¹⁴-C_1-6alkyl-R¹¹⁵And (j)

Or, R¹⁰²And R¹⁰³Together form a carbonyl group;

or, R¹⁰¹And R¹⁰³Are all single bond with the carbon to which they are attached, such that at R¹⁰⁰And R¹⁰²A double bond is formed between the two;

or, R¹⁰¹And R¹⁰³Taken together from the epoxy group.

R¹⁰⁴Taken from the following groups:

(a)H，(b)R¹¹⁴，(c)-C(O)R¹¹⁴(d)-C(O)OR¹¹⁴(e)-C(O)NR¹¹⁴R¹¹⁴，(f)-C_1-6alkyl-K-R¹¹⁴，(g)-C_2-6alkenyl-K-R¹¹⁴And (h) -C_2-6alkynyl-K-R¹¹⁴；

Or, R¹⁰³And R¹⁰⁴To which they are connectedTogether form:

k is selected from the following groups:

(a)-C(O)-，(b)-C(O)O-，(c)-C(O)NR¹¹⁴-，(d)-C(＝NR¹¹⁴)-，(e)-C(＝NR¹¹⁴)O-，(f)-C(＝NR¹¹⁴)NR¹¹⁴-，(g)-OC(O)-，(h)-OC(O)O-，(i)-OC(O)NR¹¹⁴-，(j)-NR¹¹⁴C(O)-，(k)-NR¹¹⁴C(O)O-，(l)-NR¹¹⁴C(O)NR¹¹⁴-，(m)-NR¹¹⁴C(＝NR¹¹⁴)NR¹¹⁴-, and (o) -S (O)_p-；

R¹⁰⁵Selected from the following groups:

(a)R¹¹⁴，(b)-OR¹¹⁴，(c)-NR¹¹⁴R¹¹⁴，(d)-O-C_1-6alkyl-R¹¹⁵，(e)-C(O)-R¹¹⁴，(f)-C(O)-C_1-6alkyl-R¹¹⁵，(g)-OC(O)-R¹¹⁴，(h)-OC(O)-C_1-6alkyl-R¹¹⁵，(i)-OC(O)O-R¹¹⁴，(j)-OC(O)O-C_1-6alkyl-R¹¹⁵，(k)-OC(O)NR¹¹⁴R¹¹⁴，(l)-OC(O)NR¹¹⁴-C_1-6alkyl-R¹¹⁵，(m)-C(O)-C_2-6alkenyl-R¹¹⁵And (n) -C (O) -C_2-6alkynyl-R¹¹⁵；

Or, R¹⁰⁴And R¹⁰⁵Taken together with the atoms to which they are attached form:

wherein Q is CH or N, and R¹²⁶is-OR¹¹⁴，-NR¹¹⁴Or R is¹¹⁴；

Or R¹⁰⁴And R¹⁰⁵Taken together with the atoms to which they are attached form:

wherein

i)R¹⁰¹As defined above;

ii) or R¹⁰¹And R¹⁰⁹Together form a carbonyl group which,

iii) or R¹⁰¹And R¹⁰⁹Together form-O (CR)¹¹⁶R¹¹⁶)_UO-；

Or R¹⁰⁴And R¹⁰⁵Taken together with the atoms to which they are attached form:

i)R¹³⁰is-OH, ═ C (O), or R¹¹⁴，

ii)R¹³¹is-OH, ═ C (O) or R¹¹⁴，

iii) or, R¹³⁰And R¹³¹Together with the carbon atoms to which they are commonly attached form a 3-7 membered, saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring, optionally substituted with one or more R¹¹⁴Substituted by groups;

R¹⁰⁶selected from the following groups:

(a)-OR¹¹⁴，(b)-C_1-6alkoxy-R¹¹⁵，(c)-C(O)R¹¹⁴，(d)-OC(O)R¹¹⁴，(e)-OC(O)OR¹¹⁴，(f)-OC(O)NR¹¹⁴R¹¹⁴and (g) -NR¹¹⁴R¹¹⁴，

Or, R¹⁰⁵And R¹⁰⁶The atoms to which they are commonly attached, are joined by a group selected from the group consisting of:

(a)-OC(R¹¹⁵)₂O-，(b)-OC(O)O-，(c)-OC(O)NR¹¹⁴-，(d)-NR¹¹⁴C(O)O-，(e)-OC(O)NOR¹¹⁴-，(f)-NOR¹¹⁴-C(O)O-，(g)-OC(O)NNR¹¹⁴R¹¹⁴-，(h)-NNR¹¹⁴R¹¹⁴-C(O)O-，(i)-OC(O)C(R¹¹⁵)₂-，(j)-C(R¹¹⁵)₂C(O)O-，(k)-OC(S)O-，(l)-OC((S)NR¹¹⁴-，(m)-NR¹¹⁴C(S)O-，(n)-OC(S)NOR¹¹⁴-，(o)-NOR¹¹⁴-C(S)O-，(p)-OC(S)NNR¹¹⁴R¹¹⁴-，(q)-NNR¹¹⁴R¹¹⁴-C(S)O-，(r)-OC(S)C(R¹¹⁵)₂-，and(s)-C(R¹¹⁵)₂C(S)O-；

or, M, R¹⁰⁵And R¹⁰⁶Together with the atoms to which they are attached form:

wherein J is selected from O, S and NR¹¹⁴；

Or, M and R¹⁰⁴Together with the atoms to which they are attached form the following structure:

R¹⁰⁷selected from the following groups:

(a)H，(b)-C_1-4alkyl, (C) -C_2-4Alkenyl, and may be further substituted by C_1-12Alkyl or one orMore halogen atoms substituted, (d) -C_2-4Alkynyl and may be further substituted by C_1-12Alkyl or one or more halogen atoms, (e) aryl or heteroaryl, and may be further substituted by C_1-12Alkyl or one or more halogen atoms, (f) -C (O) H, (g) -COOH, (H) -CN (i) -COOR¹¹⁴，(j)-C(O)N R¹¹⁴R¹¹⁴，(k)-C(O)R¹¹⁴And (l) -C (O) SR¹¹⁴The above (b) may be further substituted with one or more of the following groups:

(aa)-OR¹¹⁴(bb) halogen, (cc) -SR¹¹⁴，(dd)C_1-12Alkyl which may be further substituted by halogen atoms and hydroxy groups, (ee) -OR¹¹⁴，(ff)-SR¹¹⁴，(gg)-N R¹¹⁴R¹¹⁴，(hh)-CN，(ii)-NO₂，(jj)-NC R¹¹⁴，(kk)-COO R¹¹⁴，(ll)-N₃，(mm)＝N-O-R¹¹⁴，(nn)＝N R¹¹⁴，(oo)＝NNR¹¹⁴R¹¹⁴，(pp)＝N-NH-C(O)R¹¹⁴And (qq) ═ N-NH-c (o) N R¹¹⁴R¹¹⁴；

Or, R¹⁰⁶And R¹⁰⁷Together with the atoms to which they are attached form an epoxy group, carbonyl group, alkene, or substituted alkene, or a C_3-7Carbocyclic ring, carbonate or carbamate, the nitrogen of said carbamate being further substituted by C_1-6Alkyl substitution;

R¹⁰⁸selected from the following groups:

(a)C_1-6alkyl, (b) C_2-6Alkenyl, and (C) C_2-6Alkynyl, any of said (a) to (c) optionally substituted with one or more R¹¹⁴Substitution;

R¹¹¹selected from H and-C (O) R¹¹⁴；

R¹¹²Selected from H, OH and-OR¹¹⁴；

R¹¹³Selected from the following groups:

(a)H，(b)R¹¹⁴，(c)-C_1-6alkyl-K-R¹¹⁴，(d)-C_2-6alkenyl-K-R¹¹⁴，(e)-C_2-6alkynyl-K-R¹¹⁴，

Wherein any of (c) - (e) may optionally be substituted with one or more R¹¹⁵Substitution;

each occurrence of R¹¹⁴Independently selected from the group consisting of:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (g) -C (O) -C_1-6Alkyl, (h) -C (O) -C_2-6Alkenyl, (i) -C (O) -C_2-6Alkynyl, (j) -C (O) -C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (k) -C (O) -3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (l) -C (O) O-C_1-6Alkyl, (m) -C (O) O-C_2-6Alkenyl, (n) -C (O) O-C_2-6Alkynyl, (O) -C (O) O-C_6-10A saturated, unsaturated, or aromatic carbocyclic ring, (p) -C (O) O-3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, and (q) -C (O) NR¹¹⁶R¹¹⁶，

Wherein any of (b) - (p) may optionally be substituted with one or more R¹¹⁵(ii) any of (b) - (p) wherein any non-terminal carbon may optionally be replaced by oxygen, S (O)_Por-NR¹¹⁶Substitution;

or, NR¹¹⁴R¹¹⁴Forming a 3-7 membered, saturated or unsaturated, or aromatic carbocyclic ring, including¹¹⁴To a nitrogen atom, and optionally substituted by one or more oxygen atoms, S (O)_PNitrogen or-NR¹¹⁸Substitution;

R¹¹⁵selected from:

(a)R¹¹⁷，(b)C_1-8alkyl, (C) C_2-8Alkenyl, (d) C_2-8Alkynyl, (e) C_3-12A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, wherein any of (b) - (p) groups may optionally be substituted with one or more R¹¹⁷Substitution;

each occurrence of R¹¹⁶Independently selected from the group consisting of:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (b) - (p) wherein any of the non-terminal carbons may optionally be replaced by oxygen, S (O)_Por-NR¹¹⁶(ii) wherein any one of (b) - (p) groups may be optionally substituted with one or more of the following groups:

(aa) carbonyl, (bb) formate, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) N₃，(ii)NO₂，(jj)OR¹¹⁸，(kk)-S(O)_pR¹¹⁸，(ll)-C(O)R¹¹⁸，(mm)-C(O)OR¹¹⁸，(nn)-OC(O)R¹¹⁸，(oo)-C(O)NR¹¹⁸R¹¹⁸，(pp)-OC(O)NR¹¹⁸R¹¹⁸，(qq)-C(＝NR¹¹⁸)R¹¹⁸，(rr)-C(R¹¹⁸)(R¹¹⁸)OR¹¹⁸，(ss)-C(R¹¹⁸)₂OC(O)R¹¹⁸，(tt)-C(R¹¹⁸)(OR¹¹⁸)(CH₂)_rNR¹¹⁸R¹¹⁸，(uu)-NR¹¹⁸R¹¹⁸；(vv)-NR¹¹⁸OR¹¹⁸，(ww)-NR¹¹⁸C(O)R¹¹⁸，(xx)-NR¹¹⁸C(O)OR¹¹⁸，(yy)-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸，(zz)-NR¹¹⁸S(O)_rR¹¹⁸，(ab)-C(OR¹¹⁸)(OR¹¹⁸)R¹¹⁸，(ac)-C(R¹¹⁸)₂NR¹¹⁸R¹¹⁸，(ad)＝NR¹¹⁸，(ae)-C(S)NR¹¹⁸R¹¹⁸，(af)-NR¹¹⁸C(S)R¹¹⁸，(ag)-OC(S)NR¹¹⁸R¹¹⁸，(ah)-NR¹¹⁸C(S)OR¹¹⁸，(ai-NR¹¹⁸C(S)NR¹¹⁸R¹¹⁸，(aj)-SC(O)R¹¹⁸，(ak)C_1-8Alkoxy group (al) C_2-8Alkenyl, (am) C_2-8Alkynyl, (an) C_1-8alkoxy，(ao)C_1-8Mercapto group, (ap) C_1-8The acyl group,

(aq)C_3-10a saturated, unsaturated, or aromatic carbocyclic ring, and (ar) a 3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

or, NR¹¹⁶R¹¹⁶Form a 3-to 10-membered saturated, unsaturated, or aromatic ring, including the linkage to R¹¹⁶Optionally with one or more oxygen atoms, S (O)_PNitrogen and-NR¹¹⁸Substitution;

or, CR¹¹⁶R¹¹⁶Forming a carbonyl group;

each occurrence of R¹¹⁷Independently selected from the group consisting of:

(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f) I，(g)(CR¹¹⁶R¹¹⁶)_rCF₃，(h)(CR¹¹⁶R¹¹⁶)_rCN，(i)(CR¹¹⁶R¹¹⁶)_rNO2，(j)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(k)(CR¹¹⁶R¹¹⁶)_rOR¹¹⁹，(l)(CR¹¹⁶R¹¹⁶)_rS(O)_p(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(m)(CR¹¹⁶R¹¹⁶)_rC(O)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(n)(CR¹¹⁶R¹¹⁶)_rOC(O)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(o)(CR¹¹⁶R¹¹⁶)_rSC(O)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(p)(CR¹¹⁶R¹¹⁶)_rC(O)O(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(q)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶C(O)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(r)(CR¹¹⁶R¹¹⁶)_rC(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(s)(CR¹¹⁶R¹¹⁶)_rC(＝NR¹¹⁶)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(t)(CR¹¹⁶R¹¹⁶)_rC(＝NNR¹¹⁶R¹¹⁶)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(u)(CR¹¹⁶R¹¹⁶)_rC(＝NNR¹¹⁶C(O)R¹¹⁶)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(v)(CR¹¹⁶R¹¹⁶)_rC(＝NOR¹¹⁹)(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(w)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶C(O)O(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(x)(CR¹¹⁶R¹¹⁶)_rOC(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(y)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶C(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(z)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶S(O)_p(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(aa)(CR¹¹⁶R¹¹⁶)_rS(O)_pNR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(bb)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶S(O)_pNR¹¹⁶(CR¹¹⁶R¹¹⁶)_tR¹¹⁹，(cc)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶R¹¹⁶，(dd)C_1-6alkyl, (ee) C_2-6Alkenyl, (ff) C_2-6An alkynyl group,

(gg)(CR¹¹⁶R¹¹⁶)_r-a 3-10 membered saturated, unsaturated, or aromatic carbocyclic ring, and (hh) (CR)¹¹⁶R¹¹⁶)_r-a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (dd) to (hh) may optionally be substituted with one or more R¹¹⁹Substituted by groups;

or two R¹¹⁷The radical forming-O (CH)₂)_UO-；

Each occurrence of R¹¹⁸Independently selected from the group consisting of:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (g) -C (O) -C_1-6Alkyl, (h) -C (O) -C_1-6Alkenyl, (g) -C (O) -C_1-6Alkynyl, (i) -C (O) -C_3-10Saturated, unsaturated, or aromatic carbocyclic rings, (j) -C (O) -C_3-10A saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (b) to (j) may be optionally substituted with: (aa) H, (bb) F, (cc) C1, (dd) Br, (ee) I, (ff) CN, (gg) NO₂，(hh)OH，(ii)NH₂，(jj)NH(C_1-6Alkyl), (kk) N (C)_1-6Alkyl radical)₂，(ll)C_1-6Alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C_1-6Alkyl, aryl optionally substituted by one or more aryl, arylAryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO₂And OH substitution;

each occurrence of R¹¹⁹Independently selected from the group consisting of:

(a)R¹²⁰，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (b) - (f) groups may optionally be substituted with one or more R¹¹⁹Substitution;

each occurrence of R¹²⁰Independently selected from the group consisting of:

(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f)I，(g)(CR¹¹⁶R¹¹⁶)_rCF₃，(h)(CR¹¹⁶R¹¹⁶)_rCN，(i)(CR¹¹⁶R¹¹⁶)_rNO₂，(j)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶R¹¹⁶，(k)(CR¹¹⁶R¹¹⁶)_rOR¹¹⁴，(l)(CR¹¹⁶R¹¹⁶)_rS(O)_pR¹¹⁶，(m)(CR¹¹⁶R¹¹⁶)_rC(O)R¹¹⁶，(n)(CR¹¹⁶R¹¹⁶)_rC(O)OR¹¹⁶，(o)(CR¹¹⁶R¹¹⁶)_rOC(O)R¹¹⁶，(p)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶C(O)R¹¹⁶，(q)(CR¹¹⁶R¹¹⁶)_rC(O)NR¹¹⁶R¹¹⁶，(r)(CR¹¹⁶R¹¹⁶)_rC(＝NR¹¹⁶)R¹¹⁶，(s)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶C(O)NR¹¹⁶R¹¹⁶，(t)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶S(O)_pR¹¹⁶，(u)(CR¹¹⁶R¹¹⁶)_rS(O)_pNR¹¹⁶R¹¹⁶(v)(CR¹¹⁶R¹¹⁶)_rNR¹¹⁶S(O)_pNR¹¹⁶R¹¹⁶，

(w)C_1-6alkyl, (x) C_2-6Alkenyl, (y) C_2-6Alkynyl, (z) (CR)¹¹⁶R¹¹⁶)_r-a 3-to 10-membered saturated, unsaturated or aromatic carbocyclic ring, and (aa) (CR)¹¹⁶R¹¹⁶)_r-a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (w) to (aa) may be substituted by one or more groups selected from R¹¹⁶、F、Cl、Br、I、CN、NO₂、-OR¹¹⁶、-NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂、C_1-6Alkoxy radical, C_1-6Mercapto group and C_1-6An acyl group;

each occurrence of R¹²¹Independently selected from the group consisting of:

(a)H，(b)-OR¹¹⁸，(c)-O-C_1-6alkyl-OC (O) R¹¹⁸，(d)-O-C_1-6alkyl-OC (O) OR¹¹⁸，(e)-O-C_1-6alkyl-OC (O) NR¹¹⁸R¹¹⁸，(f)-O-C_1-6alkyl-C (O) NR¹¹⁸R¹¹⁸，(g)-O-C_1-6alkyl-NR¹¹⁸C(O)R¹¹⁸，(h)-O-C_1-6alkyl-NR¹¹⁸C(O)OR¹¹⁸，(i)-O-C_1-6alkyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸，(j)-O-C_1-6alkyl-NR¹¹⁸C(＝N(H)NR¹¹⁸R¹¹⁸，(k)-O-C_1-6alkyl-S (O)_pR¹¹⁸，(l)-O-C_2-6alkenyl-OC (O) R¹¹⁸，(m)-O-C_2-6alkenyl-OC (O) OR¹¹⁸，(n)-O-C_2-6alkenyl-OC (O) NR¹¹⁸R¹¹⁸，(o)-O-C_2-6alkenyl-C (O) NR¹¹⁸R¹¹⁸，(p)-O-C_2-6alkenyl-NR¹¹⁸C(O)R¹¹⁸，(q)-O-C_2-6alkenyl-NR¹¹⁸C(O)OR¹¹⁸，(r)-O-C_2-6alkenyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸，(s)-O-C_2-6alkenyl-NR¹¹⁸C(＝N(H)NR¹¹⁸R¹¹⁸，(t)-O-C_2-6alkenyl-S (O)_pR¹¹⁸，(u)-O-C_2-6alkynyl-OC (O) R¹¹⁸，(v)-O-C_2-6alkynyl-OC (O) OR¹¹⁸，(w)-O-C_2-6alkynyl-OC (O) NR¹¹⁸R¹¹⁸，(x)-O-C_2-6alkynyl-C (O) NR¹¹⁸R¹¹⁸，(y)-O-C_2-6alkynyl-NR¹¹⁸C(O)R¹¹⁸，(z)-O-C_2-6alkynyl-NR¹¹⁸C(O)OR¹¹⁸，(aa)-O-C_2-6alkynyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸，(bb)-O-C_2-6alkynyl-NR¹¹⁸C(＝N(N)NR¹¹⁸R¹¹⁸，(cc)-O-C_2-6alkynyl-S (O)_pR¹¹⁸(ii) a And (dd) -NR¹¹⁸R¹¹⁸；

Or two R¹²¹The radicals forming ═ O, ═ NOR¹¹⁸And ═ NNR¹¹⁸R¹¹⁸；

R¹²²Is R¹¹⁵；

R¹²³Selected from the following groups: (a) r¹¹⁶，(b)F，(c)Cl，(d)Br，(e)I，(f)CN，(g)NO₂And (h) OR¹¹⁴，

Or R¹²²And R¹²³form-O (CH)₂)_UO-；

Each occurrence of R¹²⁴Independently selected from the group consisting of: (a) h, (b) F, (c) Cl, (d) Br, (e) I, (F) CN, (g) OR¹¹⁴，(h)NO₂(i)-N R¹¹⁴R¹¹⁴，(j)C_1-6Alkyl, (k) C_1-6Acyl group, and (l) C_1-6An alkoxy group;

R¹²⁵selected from the following groups: (a) c_1-6Alkyl, (b) C_2-6Alkenyl, (C) C_2-6Alkynyl, (d) C_1-6Acyl group, (e) C_1-6Alkoxy, (f) C_1-6Mercapto group, (g) C_5-10A saturated, unsaturated, or aromatic carbocyclic ring, (h) a 5-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (i) -O-C_1-6Alkyl-5-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (j) -NR¹¹⁴-C_1-6Alkyl-5-10 membered saturated, unsaturated, OR aromatic heterocycle containing one OR more heteroatoms selected from nitrogen, oxygen, OR sulfur, (k)10 membered saturated, unsaturated, OR aromatic bicyclic ring containing optionally one OR more heteroatoms selected from nitrogen, oxygen, OR sulfur, (l)13 membered saturated, unsaturated, OR aromatic tricyclic ring containing one OR more optionally heteroatoms selected from nitrogen, oxygen, OR sulfur, (m) -OR¹¹⁴，(n)-N R¹¹⁴R¹¹⁴，(o)-S(O)_PR¹¹⁴And (p) -R¹²⁴，

Wherein any of (a) - (l) groups may optionally be substituted with one or more R¹¹⁵Substitution;

or, R¹²⁵And R¹²⁴Form a 5-to 7-membered, saturated or unsaturated, carbocyclic ring with the carbon atoms to which they are attached, and optionally substituted by one or more R¹¹⁵Substituted by groups; or a 5-7 membered, saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, optionally substituted with one or more R¹¹⁵Substituted by groups;

each occurrence of R¹²⁶Independently selected from the group consisting of:

(a) h, (b) an electron-removing group, (C) an aryl group, (d) a substituted aryl group, (e) a heteroaryl group, (f) a substituted heteroaryl group, (g) C_1-6Alkyl, optionally substituted by one or more R¹¹⁵Substitution;

or, any of R¹²⁶And any of R¹²³Together with the atom to which they are attached form a 5-to 7-membered saturated orUnsaturated carbocyclic ring, and optionally substituted by one or more R¹¹⁵Substitution; or form a 5-to 7-membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, and optionally substituted with one or more R¹¹⁵Substitution;

R¹⁰⁹is H or F;

R¹²⁷is R¹¹⁴Mono-or disaccharides (including amino sugars or halo sugars),

-(CH₂)_n-(O-CH₂CH₂-)_m-O(CH₂)_pCH₃or-(CH₂)_n-(O-CH₂CH₂-)_m-OH

R¹²⁸is R¹¹⁴

R¹²⁹Is R¹¹⁴

R¹¹⁰Is R¹¹⁴

Or, R¹⁰⁹And R¹¹⁰Together with the carbon atoms to which they are attached form the following structure:

or, R¹²⁸And R¹²⁹Together with the carbon to which they are attached form a 3-6 membered, saturated, unsaturated, aromatic carbocyclic or heterocyclic ring, and may optionally be substituted with one or more R¹¹⁴Substitution;

each occurrence of m is 0, 1, 2, 3, 4, or 5;

each occurrence of n is 1, 2, or 3;

other embodiments of the foregoing compounds include those wherein T is a macrolide compound selected from the group consisting of:

or an N-oxide, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein M, R¹⁰⁰，R¹⁰¹，R¹⁰⁴，R¹⁰⁵，R¹⁰⁶，R¹⁰⁷，R¹⁰⁸，R¹⁰⁹，R¹¹⁰And R¹²⁰As defined above.

Other embodiments of the foregoing compounds include those wherein T is a macrolide compound selected from the group consisting of:

and

or an N-oxide, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein M, R¹⁰⁰，R¹⁰¹，R¹⁰²，R¹⁰⁴，R¹⁰⁹，R¹¹⁴，R¹²⁶And R¹²⁷As defined above.

Other embodiments of the foregoing compounds include those wherein T is a macrolide compound selected from the group consisting of:

or an N-oxide, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein M, R¹，R²，R¹⁰⁴，R¹¹⁴，R¹⁰⁹And R¹²⁷As defined above.

Other embodiments of the foregoing compounds include those wherein T is a macrolide compound selected from the group consisting of T1 to T33:

in another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically active amount of one or more of the foregoing compounds and a pharmaceutically acceptable carrier. In another aspect, the invention also provides a method of treating a bacterial infection, and a fungal infection, a parasitic disease, a proliferative disease, an infection by a viral bacterium, an inflammation, or a gastrointestinal motility disorder in a mammal by administering an effective amount of a compound of the invention or a pharmaceutically acceptable compound of the invention. In embodiments of this aspect, the compounds of the invention may be administered orally, by injection, or topically. In another aspect, the invention also provides a medical device, for example, a medical stent, comprising or coated with one or more of the aforementioned compounds of the invention.

3. Synthesis of Compounds of the invention

The invention also provides methods of making the compounds of the invention. The following schemes illustratively describe chemical processes that can be used to prepare the compounds of the present invention.

The compounds numbered 1, 2, 3, etc. used in the third section entitled "synthesis of compounds of the invention" are used only in this section and are not to be confused with any similarly numbered compound numbered in section 6 entitled "6. example".

Scheme 1 shows the synthesis of triazole compounds of types 5 and 6. Erythromycin can be N-demethylated, and secondary amine 1 can be obtained as described in the prior art (U.S. patent No.3,725, 385; Flynn et al (1954) J.AM. CHEM.SOC.76: 3121; Ku et al (1997) BIOORG.MED.CHEM.LETT.7: 1203; Stenmark et al (2000) J.ORG.CHEM.65: 3875). Alkylation of 1 with electrophile No.2 can result in alkyne No.3 containing an alkyl chain of suitable length, typically between one and four carbon atoms, between the nitrogen atom and the alkynyl group. Cycloaddition of the azide, number 4, and the alkyne, number 3, yields two isomers of triazole. The reaction may be thermally catalyzed or accelerated by the addition of various catalysts (for example, but not limited to, copper (I) iodide, see Tornoe, C.W.et al (2002) J.ORG.CHEM.67: 3057). The major isomer (due to steric arrangement) is the "trans" isomer 5, a1, 4 disubstituted triazole. A minor component is the "cis" isomer 6, a1, 5 disubstituted triazole.

Scheme 1

It is understood that other macrolides, such as, but not limited to, azithromycin and clarithromycin, may be demethylated and used as starting materials in scheme one. Target compounds derived from such macrolide precursors are also within the scope of the present invention.

Scheme 2 shows the synthesis of a reproducible tetrazole derivative of the invention. Alkylation of amine 1 (or other macrolide amine) with a class 7 electrophile containing a cyano group can yield a class 8 macrolide nitrile intermediate. The nitrile of number 8 undergoes cycloaddition reaction with the azide of number 4 to give two tetrazole isomers; disubstituted tetrazoles of class 9 (expected major product), and 1, 5 isomers of class 10.

Scheme 2

Scheme 3 shows the synthesis of isoxazole derivatives of the invention. Treatment of an alkyne of class 3 with a nitrile oxide of class 11 affords the cycloaddition isomers 12 and 13. Due to steric structural considerations, the major isomer product is also the 12 "trans" derivative.

Scheme 3

Other similar methods can yield derivatives of classes 5, 6, 9, 10, 12, and 13, as indicated in scheme 4. Treatment of the alkynol group 14 with the azide group 4 affords the alcohol intermediate group 15 (with a small amount of triazole isomer). Acylation of 15 sulfonic acid gives 16, 16 as alkylating agent for macrolide amine compound No.1 to give the target product 5 (and isomer 6 thereof). (it will be appreciated that other sulphonic acid derivatives or halides may be synthesised via intermediate alcohol 15 and these may serve as electrophiles for alkylation of macrolide compounds like 1 to give compounds of the invention). Hydroxyalkyl nitriles of the type 17 (where n is not equal to 1) can undergo cycloaddition with azide 4 to give tetrazole intermediate 18 (with a small amount of tetrazole isomer). Acylation of 18 sulfonic acid gives 19, 19 which can be alkylated with a class 1 amine to give derivative 9 (and its isomer 10). In a similar manner, acetylene 14 can be converted to isoxazole 20 (and its isomers). An electrophile derived from 20 can alkylate amine 1 to give the desired product 12 (and its isomer 13)

Scheme 4

Other starting materials for the synthesis of the compounds of the invention are readily synthesized. For example, des-methyl macrolide amines 22 and 23 can be prepared from azithromycin and clarithromycin, respectively, using the same procedure used to synthesize 1 from erythromycin. Ketolide derivatives of the compounds of the present invention (C-3 ketone compounds synthesized from macrolide compounds) can be prepared by the procedure of scheme 5. Alkylation of the amine derivative of clarithromycin 23 with tosylate 24 gives the alkyne 25. Hydrolysis of C-3 cladinose provides C-3 hydroxy intermediate 26, selective acetylation of 26 by the hydroxy group of the amino sugar provides 27.27 which is oxidized to provide C-3 ketone derivative 28, deacetylation of 28 provides alkyne 29. Alkyne 29 can produce the triazole and isoxazole compounds of the present invention, which possess the structure of the clarithromycin C-3 one derivatives, by the chemical methods described in schemes 1 and 3 above. It will be appreciated that alkylation of 23 with electrophile 27, which product is then exposed to azide in the process of schemes 5 and 2, will yield a tetrazole having a clarithromycin C-3 ketone structure. Additionally, C-3 keto azithromycin and erythromycin intermediates may be prepared by 1 and 22 using the procedures of scheme 5, and may further serve as starting materials for the synthesis of compounds of the present invention.

Scheme 5

Acetylene, numbered class 2 compounds, used to synthesize alkyl chains of variable length on the present compounds, can be prepared using commercially available haloalkyl groups such as propargyl bromide, or can be synthesized by hydroxyalkyl acetylene using methods commonly used in the art. Scheme 6 shows how to synthesize the compounds of class 14 from hydroxyalkyl acetylene using simple methods known in the art.

Scheme 6

The azide intermediates of class 4, used in the preparation of the compounds of the present invention, can be synthesized using the methods of schemes 7 and 8. Phenols, anilines, and thiophenols of group number 30 can be etherified with α, ω -haloethanol (e.g., but not limited to 2-bromoethanol) to form halides of group number 31. Replacement of the halogen atom by the sodium azide salt gives the azide numbered 4 a. Similarly, direct alkylation of the intermediate numbered 30 with α, ω -haloethanol may give an ethanol numbered 32, which may be converted to the halide 31 or to a sulfonate derivative such as 33, which may be further substituted with azide to give the azide of 4 a. The aryl propanol group of number 34, and the pyridine propanol group of number 35, like 36 and 37, can be converted to azides of 4b and 4c by sulfonation. It is well known that substituted (straight or branched) pyridine derivatives, and chains of only a certain length of the aryl and azide groups, can be prepared by chemical methods commonly used in the art. The scope of protection of the present invention relates to all such isomers and homologues.

Scheme 7

Scheme 8

The azide oxide of class 11, used in the preparation of the compounds of the present invention, can be synthesized by the method in scheme 9. Various lengths of chains between the aryl and alkanol groups, the aryl alkanol (or pyridyl alkanol) of group number 32 can be oxidized to the aldehyde 38. The aldehyde can then be converted to the oxime 39 by using chloramine T (or other reagents used in organic amine base synthesis such as N-bromosuccinimide, N-chlorosuccinimide, T-butyl hypochlorite, lead tetraacetate, etc.). The reaction to form the nitroxide can be carried out in the presence of a suitable alkyne to directly obtain the unstable intermediate 11, resulting in a mixed product of trans and cis isoxazoles.

Scheme 9

4. Characterization of the compounds of the invention:

once a compound designed, selected and/or optimized by the methods described above has been prepared, it can be tested for biological activity by methods well known to those skilled in the art. For example, the compounds molecules can be evaluated for their predicted activity, binding activity and/or binding specificity by conventional means, including but not limited to those described below.

Further, high throughput screening can be used to accelerate such analysis. As a result, it speeds up the detection and assessment of properties of the molecules described herein, such as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral properties. At the same time, it can also assess how the compound interacts with ribosomes or ribosomal subunits and/or why it is as effective as a regulatory gene (e.g., repressor) in protein synthesis in the prior art. Conventional procedures for high throughput screening are described, for example, in Devrin (1998)High Throuhput ScreeningMarcel Dekker; and U.S. Pat. No.5,763,263. High throughput assessment may be adapted to one or more different assessment techniques, including, but not limited to, the following:

(1) surface binding studies. Many binding studies are available to screen for binding activity of new molecules. One method involves Surface Plasmon Resonance (SPR), which allows the assessment of the binding properties of the molecule to be investigated to the ribosome or ribosomal subunit or fragments thereof.

The SPR method is a method of measuring the interaction between two or more macromolecules in real time by quantum mechanical surface plasmon generation. An apparatus (biacore Biosensor RTM from Pharmacia Biosensor, Piscatawy, n.j) provides a polychromatic light concentration at the interface between the gold film (assuming a disposable Biosensor "chip") and the buffer that can be adjusted by the user. Attached to the gold film was a 100 nm thick "hydrogel" consisting of dextran carboxylates, which can provide a covalently cured matrix for the assay. When the spot light reacts with the free electron cloud of the gold film, the plasmon resonance is enhanced. The reflected light related to the resonance portion is consumed. By separating the colored light components by wavelength (through the prism), determining the frequency of the portion that is consumed, the BIAcore establishes an optical interface that can report the occurrence of surface plasmon resonances in a timely manner. When designed as described above, the plasmon resonance (and the vanishing spectrum) is very sensitive to the amount of evanescent zone (corresponding to the thickness of the hydrogel). Once one component of an interaction pair is immobilized on the hydrogel, the other component of the pair passes through a buffer, and the interaction between the two components can be measured in real time, based on the accumulation of the amount of evanescent fields, and their corresponding effect on plasmon resonance by measurement of depletion spectra. This system allows for rapid and sensitive real-time measurement of molecular interactions without the need to label each component.

(2) The fluorescence is polarized photometrically. Fluorescence Polarization (FP) is a convenient measurement method that can be readily applied to protein-protein, protein-ligand, or RNA-ligand interactions to obtain an IC for an association reaction between two molecules_50SAnd KDs. In this method, one of the molecules under investigation is bound to a fluorophore. Typically the smaller molecules in the system (in the present invention, the compounds under investigation). The mixed sample, comprising the ligand-probe binding body and the ribosome or ribosomal subunit or fragment thereof, is excited by vertically polarized light. The light is absorbed by the detector fluorophore and re-emitted after a short period of time. The polarization photometry of the emitted light is measured. The degree of polarization of the emitted light depends on several factors, but most importantly on the viscosity of the solution and the fluorophore surface molecular weight. Under appropriate control, the degree of polarization of the emitted light can vary depending only on the change in the surface molecular weight of the fluorophore, and thus only on whether the probe-ligand pair is free or bound to a receptor in solution. FP-based binding assessment has a number of important advantages, including determination of IC under truly homogeneous equilibrium point conditions_50SAnd KDs, speed up analysis and make automation pleasant, and enable measurement in turbid suspensions and colored solutions.

(3) And (3) protein synthesis. It is predicted that the compounds of the invention may also act as modulators of certain activities of ribosomes or ribosomal subunits (e.g., inhibitors of protein synthesis), in addition to the properties determined by the aforementioned chemical evaluation.

Further, the compounds of the present invention can be administered to whole organisms, tissues, organs, organelles, cells, a cellular or subcellular extract, or purified ribosomes by measuring, for example, its Inhibition Constant (IC)₅₀) The pharmacological and inhibitory properties of the protein synthesis were observed for its inhibition.³H leucine or³⁵Binding of S-methionine, or similar assays, can be used to observe protein synthesis activity. Changes in the rate or amount of protein synthesis in the cell in the presence of the compounds of the invention suggest that the compound molecule is a modulator of protein synthesis. A decrease in the rate or amount of protein synthesis indicates that the molecule is an inhibitor of protein synthesis.

In addition, the antiproliferative or anti-infective properties of the present compounds can be assessed at the cellular level. For example, when the target organism is a microorganism, the activity of the compound of the invention can be assessed by culturing the microorganism in a medium with or without the compound of the invention. Inhibition of growth may indicate that the compound molecule may act as an inhibitor of protein synthesis. More specifically, the resistance of the compounds of the present invention to pathogens can be demonstrated by the inhibition of the growth of human pathogen strains by the compounds. To this end, a panel of strains of different bacteria is collected, including a number of different classes of pathogens, some of which contain the drug resistance. The use of such an organism allows the determination of the relationship between structure and activity not only in relation to the spectrum but also in relation to the avoidance of resistance. The experiments can be carried out under conventional microtitre conditions, as described in the National Committee for Clinical Laboratory Standard (NCCLS) guidelines (NCCLS. M7-A5-Methods for Dilution analysis compatibility Tests for bacterial third hand Grow Aerobically; applied Standard-Fifth edition. NCCLS Document M100-S12/M7(ISBN 1-56238-394-9)).

5. Formulation and administration

The compounds of the present invention are useful for inhibiting or treating diseases in humans or other animals, including mammals and non-mammals, including, for example, bacterial infections, fungal infections, viral infections, parasitic diseases and cancers. It is expected that, once established, the active molecules of the invention can be used with all suitable carriers of the prior art. The dose of active molecule, the mode of administration and the appropriate carrier used will depend on the patient or the organism of interest. Whether for animal or human formulations, generally comprise a compound of the invention and a pharmaceutically acceptable carrier.

The carrier should be "acceptable" in terms of compatibility with the other ingredients of the formulation and non-toxic to the patient. Pharmaceutically acceptable carriers, in this sense, are intended to include any and all solvents, dispersion vehicles, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other similar components, compatible with pharmacological administration. Methods of using such media or agents as pharmaceutically active ingredients are well known. Unless any medium or agent within the ordinary scope is incompatible with the active compound (as defined or contemplated herein). Additional active compounds (of the prior art) may also be incorporated into the composition. The formulations may be prepared in dosage unit form by methods well known in pharmacy/microbiology. In general, some formulations are prepared by mixing the present compounds into a liquid carrier or a divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

The pharmaceutically acceptable compositions of the invention are compatible with their route of administration. The administration route is, for example, oral, injection such as intravenous injection, subcutaneous injection, inhalation administration, transdermal (topical), transmucosal and rectal administration. Solutions or suspensions for injection, subcutaneous injection or subcutaneous administration may include the following: sterile diluents such as water for injection, saline, solidified oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium sulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. The Ph can be adjusted with acid or base, for example, hydrochloric acid or sodium hydroxide.

Solutions useful for oral or injectable administration can be prepared by methods well known in the art of pharmacy and are described, for example, in Remington's pharmaceutical science, (Gennaro A., ed.), Mack Pub., (1990) formulations for injectable administration can include glycocholate for oral administration, or methoxysalicylate for rectal administration, or citric acid for vaginal administration. The injection formulation may be prepared in a single dose formulation, in a disposable syringe or in vials made of glass or plastic for multiple doses. Suppositories for rectal administration of the drug may be prepared by mixing the drug with non-irritating excipients such as cocoa butter, other glycerides, or other excipients which are solid at room temperature and liquid at body temperature. Formulations may also include, for example, polyethylene glycol, vegetable oils, and hydrogenated naphthalenes. Formulations for direct administration may include glycerin and other high tonicity components. Other injection vehicles useful for these drugs include microparticles of ethylene-vinyl acetate copolymer, or oily solutions for nasal drops, or gels for intranasal administration. Retention enemas may also be added for rectal administration.

Formulations of the invention suitable for oral administration may be in the form of: discrete units such as capsules, gel capsules, sachets, tablets, troches or lozenges, each serving containing a predetermined amount of a drug; a powdered or granular composition; solutions or aqueous or non-aqueous suspensions; or an oil-in-water type emulsion or a water-in-oil type emulsion. The medicament may also be administered in the form of a bolus, electuary or syrup. Tablets the medicament and other acceptable ingredients may be prepared in pressed or die-cast form. Compressed tablets may be prepared by compression in a suitable machine by compressing in a free-flowing form such as a powder or granules, optionally with a binder, lubricant, inert diluent, surface active or dispersing agent. The cast pieces can be cast by wet mixing the powdered medicament with a suitable carrier and inert diluent in a suitable machine.

Oral compositions typically include a non-irritating diluent or an edible carrier. For the purpose of oral treatment, the active compounds may be used in combination with excipients. Oral compositions are prepared by incorporating the compound in a mouth wash using a flowable carrier and applying to the mouth and gargling and expectorating. Pharmaceutically acceptable coagulant and/or adjuvant materials may be included in the composition ingredients. Tablets, pills, capsules, troches may contain any of the following ingredients, or compounds of the same nature: a solidifying agent such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; a disintegrating agent such as alginic acid, sodium starch glycolate, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

Pharmaceutical compositions suitable for injection typically comprise a sterile aqueous solution (water-soluble) or dispersion and a sterile powder for ready-to-use sterile solution or dispersion. For intravenous administration, suitable carriers include saline, bacteriostatic water, Cremophor ELTM (BASF Parsippany, NJ), saline Phosphate Buffered Saline (PBS). It should be stable under the conditions of preparation and storage and be resistant to, for example, bacterial and fungal infection. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols, polyols (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and stable mixtures of the above. Suitable fluids may be maintained, for example, by coating lecithin, by using a suitable particle shape in the presence of a dispersant, and by using a surfactant. Under any conditions, isotonic agents, for example, sugars, polyglycols such as xylitol, sorbitol, sodium chloride may be included in the composition. Various agents that act to delay absorption, such as aluminum monostearate and gelatin, are incorporated into the injectable composition to prolong absorption.

Sterile injectable solutions can be prepared by dissolving the active compound and one or more of the above ingredients in the required amount in a suitable solvent, followed by filtered sterilization, if necessary. In the case of scholars, the preparation takes place by injecting the active compound into a sterile container containing a base dispersion medium and the other required ingredients enumerated above. For sterile powders for sterile injectable solutions, the preparation process involves vacuum drying and freeze-drying to obtain a powder comprising the active ingredient and any additional ingredients desired from a previously filter-sterilized solution.

Formulations suitable for intra-articular administration may be prepared in sterile liquids, and the drug may be in microcrystalline form, for example, in the form of a liquid microcrystalline suspension. Liposomes or bionitrated polymers are useful for intra-articular and intraocular administration.

Formulations suitable for topical administration, including ophthalmic treatments, may be formulated to include liquids or semi-liquids, such as liniments, lotions, gels, applications, oil-in-water or water-in-oil emulsions, such as creams, ointments or slurries; or solutions or suspensions such as drops. Topical formulations for application to the skin surface may be prepared by dispersing the drug in a dermatologically acceptable carrier, such as a lotion, cream, ointment or grease. Particularly useful are those that form a layer of film or drug on the skin surface that can be applied topically and not migrate. For topical administration to internal tissues, the formulation may be dispersed in a fluid that adheres to the tissue or other substance that enhances absorption from the surface of the tissue. Alternatively, a solution capable of covering the tissue, such as a formulation containing a gum, may be used.

For inhalation therapy, the inhalation powder (self-propelled or spray formulation) is located in a spray cartridge, and a nebulizer or spray bottle may be used. Such formulations may be formulated as powder or self-propelled powder dispensing formulations suitable for administration to the lungs from a spray device. In self-propelled solutions and spray formulations, such an effect can be achieved by selecting a valve containing the desired spray properties (e.g., a spray of a predetermined dose can be made) or making the active ingredient into particles of a certain size as a suspended powder. For administration by inhalation, the compounds may also be delivered in the form of an aerosol spray presentation from a pressurised container or dispenser containing a suitable propellant, for example a gas such as carbon dioxide, or a nebulizer.

Systemic administration may be by transmucosal or transdermal routes. For transmucosal or transdermal administration, suitable penetrants appropriate to the particular barrier to be permeated are included in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transdermal administration can be achieved by the use of nasal sprays and suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or gels in a manner known in the art.

The active compounds may be formulated with carriers that protect the compound from rapid metabolism, such as controlled release formulations, including infusion and microencapsulated delivery systems. Polymers that are bio-digestible and acceptable, such as ethylene-vinyl acetate copolymers, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, may be used. The person skilled in the art is aware of methods for preparing these formulations. Liposomal suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods well known to those skilled in the art, see, for example, U.S. Pat. No.4,522,811.

Oral or injectable administration may be made as convenient and fixed dose units. Dosage unit form, meaning discrete units suitable as unit doses for administration to a subject; each dosage unit contains a predetermined amount of the active compound, together with a pharmaceutically acceptable carrier as required to produce the desired therapeutic effect. The particular dosage of the compounds of the invention in the unit form depends on and depends upon the individual nature of the active compound and the particular therapeutic effect desired, and is also subject to some inherent limitations in the art of compositions for which the active compound is to be treated in an individual. Further, the administration may be by periodic injection, or may be more continuous from an external bag (e.g., an infusion bag) through intravenous muscle or peritoneal membranes.

When it is desired that the composition adhere to the tissue surface, the composition may include a composition of the agent dispersed in the fibrinogen-thrombin or other adhesive. In this way, the compound may be painted, sprayed, or otherwise applied to the desired tissue surface. Alternatively, the medicament may be administered orally or by injection to a human or other mammal, e.g., a therapeutically effective amount of the present compound, e.g., such as to provide to the target tissue a suitable concentration sufficient to elicit the desired effect in the target tissue.

When the active compounds are used as a step in transplantation surgery, they can be applied to living tissues and organs before they are removed from the donor. The present compounds may be provided to a donor. Alternatively, the organ or living tissue may be preserved in a solution containing the compound once removed from the donor. In any event, the active compound can be administered directly to the desired tissue, by injection, or can be administered systemically, whether orally or by injection, using any of the methods and formulations described in the prior art. Any commercially available preservation solution may be used when the medicament comprises a solution for preserving a tissue or organ. For example, solutions useful in the prior art include Collin solution, Wisconsin solution, Belzer solution, Eurocollins solution and Ringer's lactate solution.

The compounds of the present invention may be administered directly to the site of a particular tissue by incorporating the compound into a medical device located on the tissue. An example of a medical device is a stent that contains or is coated with one or more compounds of the present invention.

For example, the active compound may be used at a site of vascular damage. The scaffold may be prepared by any method known in the art of pharmacy. See, e.g., Fattori, R.andPiva, T., "Drug Eluting Steps in Vascular interaction", Lancet, 2003361, 247-; "A New Era in the Treatment of coronary Disease? "European Heart Journal, 2003, 24, 209-; and toutoutoutouza, k.et al, "Sirolimus-exercise Stent: a Review of Experimental and Clinical files, "Z. Kardiol., 2002, 91(3), 49-57. The stent may be made of stainless steel metal or other biocompatible metal, or may be made of a biocompatible polymer. The active compound is associated with the surface of the scaffold and is released from the surface of the polymeric material or is encapsulated and released by a carrier covering the surface of the scaffold. The scaffold may be used for single or multiple administration, the compound being administered to the tissue adjacent to the scaffold.

Active compounds designed according to the methods of the present invention can be administered to a subject to treat a disease (prophylactic or therapeutic). In conjunction with such treatment, pharmacogenetic factors (studying the response of an individual gene to an individual to an external compound) need to be considered. The relationship between the different doses and the blood concentration of the pharmaceutically active drug is such that metabolic differences in treatment can lead to severe toxicity or treatment failure. Thus, a physician or pharmacist can apply the knowledge gained from pharmacogenetic studies to decide whether to select a dose of medication or to use a diet containing the medication.

In therapeutic applications for treating or inhibiting bacterial infections in mammals, the compounds of the present invention or pharmaceutical compositions containing them may be administered orally, by injection and/or topically at dosages that achieve and maintain a concentration, either at blood or tissue level, that is an effective antibacterial amount of the active ingredient in the animal during the course of treatment. In general, an effective dose of the active ingredient is between 0.1 and 100mg/kg, preferably 1.0 to about 50mg/kg, per day relative to body weight. The dosage administered will also depend on the type and extent of the condition being treated, as well as the general health of the patient, the relative bioavailability of the compound administered, the formulation of the drug, the carrier in the formulation, and the route of administration. Also, it should be understood that the initial dose administered should be raised to the upper limit capable of rapidly achieving the desired blood or tissue level, or the initial dose administered may be less than the optimum dose and the daily dose may be gradually increased during the treatment period according to specific conditions. If desired, the daily dose may be divided into multiple administrations, for example two or four times a day.

Many disease states and conditions in humans and other mammals are found to be caused or regulated by nonsense or missense mutations. Examples of disease states and conditions found to be caused or regulated by nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NF1 and NF2 gene), retinitis pigmentosa (human USH2A gene) cases of skin blisters such as epidermolysis bullosa (COL7a1 gene), cystic fibrosis (controlling epithelial cell transmembrane ion transport channel gene), breast and ovarian cancer (BRCA1 and BRCA2 gene), muscular dystrophy (Dystrophin gene), colon cancer (mismatch repair gene, located in MLNH1 and MLNH2), and pompe disease such as neimn-pick disease (acid sphingomyelinase gene). See Sanders CR, Myers jk. disease-related analysis of membrane proteins. annu Rev biophysis biomolstruct.2004; 33: 25-51; national Center for Biotechnology Information (U.S.)Genes and diseaseBethesda，MD：NCBI，NLM ID：101138560[Book]；and Raskó，István；Downes，C S Genes in medicine：molecular biology and human genetic disorders 1st ed.London；New York：Chapman & Hall，1995.NLM ID：9502404[Book].

The compounds of the invention can treat or prevent a disease state caused or modulated by a nonsense or missense mutation in a mammal by administering to a mammal having a disease state caused by a nonsense or missense mutation an effective amount of a compound of the invention.

6. Examples of the embodiments

Nuclear Magnetic Resonance (NMR) spectra were obtained from a Bruker Avance300 or 500 million spectrometer, or in some cases, a GE-Nicolet300 million spectrometer. The reaction solvent is usually used in the high performance liquid chromatography or American chemical society degree, unless otherwise stated is in the obtained anhydrous condition. "chromatography" or "Silica Gel purification" refers to the elution of a column using Silica Gel (EM Merck, Silica Gel 60, 230-400 mesh).

The numbering used herein in the sixth section and the section entitled "6. examples", such as the compounds of 1, 2, 3, is used only in the sixth section and is not included nor mixed with the numbering used in the third section entitled "3. synthesis of compounds of the invention".

The compounds synthesized according to the present invention are listed in table 1.

TABLE 1

Example 1 Synthesis of Compound 101-280

The following schemes 100 and 101 describe the synthesis of compounds 101-280. 3' -N-demethylazithromycin 2 is selectively produced by demethylation of azithromycin 1. Amine 2 is selectively alkylated with tosylates 11, 12, 13 to yield alkynes 3, 4,5, respectively. Alkyne 3, 4 or 5 and azide 14a-14gm selectively provide triazole 101-280 in the presence of cuprous iodide as shown in scheme 101.

The process 100 is as follows: synthesis of alkynes 3, 4 and 5.

Synthesis of 3' -N-demethylazithromycin 2

Azithromycin 1(0.80 g, 1.02 mmol) and sodium acetate (0.712 g, 8.06 mmol) were dissolved in 80% aqueous methanol (25 ml). The solution was heated to 50 degrees and then iodine (0.272 g, 1.07 mmol) was added in three portions over three minutes. The pH of the reaction was maintained between 8 and 9 by adding 1N sodium hydroxide (1ml) over a period of 10-45. The solution turned to a colorless liquid in 45 minutes, but stirring was continued for two hours. TLC (dichloromethane/methanol solution/ammonium hydroxide 10: 1: 0.05) showed a single main product after two hours (Rf ═ 0.66). The reaction solution was cooled to room temperature (rt) and poured in a solution containing NH₄Aqueous solution (75 ml) of OH (1.5 ml) and extracted with chloroform (3 × 30 ml). Mixed organic layer containing NH₄OH (1.5 mL) in water (30 mL) and Na₂SO₄Drying while the solution evaporated gave a white residue. The crude product was eluted on a silica gel column with dichloromethane/methanol/ammonium chloride 18: 1: 0.05 to give amine 2(0.41 g, 55%).

Synthesis of alkynes 5

A mixture of 3 '-N-demethylazithromycin 2(0.5 g, 0.7 mmol) and tosylate 13(0.20 g, 0.82 mmol) was stirred in N, N-diisopropylethylamine (Hunig's base) (3 ml) at 80 ℃ for 4 hours. The reaction mixture was diluted with ethyl acetate to 50ml and simultaneously with NaHCO₃And brine (1 × 30 ml). K for organic layer₂CO₃After drying and evaporation of the solution, 0.65 g of a yellow foam was obtained. The crude product was eluted on a silica gel column with dichloromethane/methanol 40: 1 to give amine 5 as a white solid (0.42 g, 74%).

Synthesis of alkynes 4

Alkyne 4 was prepared from 3' -N-demethylazithromycin 2 and tosylate 12 using the same synthetic procedure as described for compound 5.

Synthesis of alkynes 3

Alkyne 3 was prepared from 3' -N-demethylazithromycin 2 and tosylate 11 using the same synthetic procedure as described for compound 5.

TABLE 2

A process 101: synthesis of the Compounds of Table 2

Triazole 101-280 is formed from alkynes 3, 4, and 5 using azide compounds 14a-14gm under one of several similar reaction conditions, e.g., conditions a, B, C, and D below correspond to compounds 151, 155, 159, and 158, respectively. The use of conditions A and C, in which no degassing stage of the reaction mixture is involved, leads to the formation of significant amounts of iodinated by-products in addition to the desired product, thus leading to low yields. At the same time, by reducing the amount of cuprous iodide in the reaction to 0.5 molar equivalent or as in conditions B and D, the formation of iodinated by-products can also be reduced. Condition D indicates that the presence of Hunig's matrix is not essential for the success of the triazole formation stage; however, it has been shown that this substrate is included because it generally results in higher yields while relatively reducing the reaction time.

Condition A

Synthesis of triazole 151

Solution alkyne 3(30mg, 0.04 mmol), azide 14az (10mg, 0.07 mmol) and Hunig's base (10 μ L) were stirred in 0.5 ml tetrahydrofuran and CuI (5 mg, 0.03 mmol) was added. The mixture was stirred at room temperature for 16 hours and then with CH₂CL₂(10ml) diluted with 3: 1 NH₄Saturated aqueous CL solution and 28% NH₄The mixture of aqueous OH (10ml) and saline (10ml) was washed with CH₂CL₂Back-extracted (2 × 10 ml). K for mixing organic extracts₂CO₃Drying, filtering and concentrating to obtain 52 mg of crude productThe crude product was chromatographed on silica gel (using 40: 12M NH)₃In methanol solution and CH₂CL₂Middle elution) to give the compound as a white solid (22 mg, 60%). (943.4[ M + Na ]]⁺，921.3[M+H]⁺，461.3[M+2H]²⁺。

Condition B:

synthesis of triazole 155

Alkyne 3(80mg, 0.10 mmol), azide 14bd (21mg, 0.12 mmol) and Hunig's matrix solution were thoroughly degassed by alternately venting off the reaction gas while purging dry argon in 0.4 ml tetrahydrofuran. CuI (2mg, 0.01 mmol) was then added and the mixture was further degassed. The reaction was then stirred under argon for 6 hours and CH was added₂CL₂(20 ml) diluted and then saturated NH₄Aqueous CL solution and 28% NH₄OH solution (10ml) was mixed at a ratio of 3: 1, and the mixture was washed with saline solution (10ml) and CH₂CL₂Back-extracted (2 × 15 ml). K for mixing organic extracts₂CO₃Drying, filtering and concentrating to obtain 115mg of crude product, which is chromatographed on silica gel (using 2M NH)₃In methanol solution (2.5%) and CH₂CL₂(97.5%) eluted). Compound (94 mg, 0.094 mmol) was obtained as a white solid. MS (ESI) M/e999.3[ M + H ]]⁺，500.4[M+2H]²⁺。

Condition C

Synthesis of triazole 159

Alkyne 3(79mg, 0.10 mmol) and Hunig's matrix (0.2 ml) were stirred in 3 ml tetrahydrofuran solution, and azide compound 14bh (115mg, 0.50 mmol) and CuI (20 mg, 0.10 mmol) were added. The reaction mixture was then stirred under argon for 60 hours, then saturated NH was poured in₄CL solution in combination with CH₂CL₂(2 × 15ml) extraction. Na is used for organic extraction liquid₂SO₄Drying, filtering, concentrating to obtain crude product, and separating with silica gel chromatography (25: 1)1: 0.1 CH₂CL₂∶MeOH∶NH₄OH elution) and then purified by TLC (using 25: 1: 0.1 CH)₂CL₂∶MeOH∶NH₄OH elution) to yield the compound as a white solid (38 mg, 0.037 mmol). MS (ESI) M/e 1017.9[ M + H ]]⁺，509.7[M+2H]²⁺。

Condition D:

synthesis of triazole 158

Alkyne 3(120mg, 0.15 mmol) and azide 14bg (60mg, 0.25 mmol) were degassed thoroughly by alternately venting the reaction gas while purging dry argon in 2.7 ml of tetrahydrofuran. CuI (10mg, 0.05 mmol) was then added and the mixture was further degassed. The reaction was then stirred under argon for 4 hours, then concentrated in vacuo and dissolved in CH₂CL₂(1ml) and then placed directly on a silica gel column. With 2 mol of NH₃In methanol solution (3%) and CH₂CL₂(97%) to give a white solid compound (80mg, 0.08 mmol). MS (ESI) M/e1019.6[ M + H ]]⁺，510.6[M+2H]²⁺。

The residue of the compounds in table 2 was synthesized from alkyne 3, 4,5 and the appropriate azide compound 14a-14gm as one of the conditions shown in table 2 analogous to the four reaction conditions shown above. The time required for each reaction varies depending on several factors, including: a specific substrate; the amount of Cu (I) salt used; absence or presence of Hunig's matrix; and the concentration of the reactants. Since the disappearance of starting material was monitored by TLC and/or LCMS, the reaction was typically allowed to proceed for 2-72 hours. The reaction was stopped when the analysis showed that the starting alkyne species was largely consumed. Purification and assay set-up in conditions A-D are typical of these applications in all assays. Minor modifications to the process have also been used (these modifications include the use of different rinse solutions, different organic extraction solutions, the use of other anhydrous salts for drying the organic extracts, chromatographic purification of compounds with different mixed solutions). In all experiments, the manner of establishing the reaction mixture, the extracted product, the drying of the organic extract, and the isolation and purification of the compounds are typical processes designed for organic synthesis schemes. There is no particular or unusual experimental design for the isolation and purification of the reaction products, but they are critical in the course of the reaction. The separation rates for the synthetic compounds 101-280 were different and are shown in the penultimate column 2 of Table 2.

Example 2 Synthesis of Compound 301-357

The following; schemes 103 and 104 are for the synthesis of compounds 301-357. 3' -N-demethylerythromycin A20 is selectively produced by demethylation of erythromycin A. Similarly, demethylation of clarithromycin results in 3' -N-demethyl clarithromycin 21. Selective N-alkylation of amines 20 and 21 with propargyl bromide or with tosylate 11 or 12 yields alkynes 23, 24, 25, 26, 27, or 28, respectively. Alkyne 23-28 and azide 14a-14eb selectively provide triazole 301-357 in the presence of cuprous iodide as shown in scheme 2.

Synthesis of 3' -N-demethylerythromycin A20

Compound 20 was prepared by erythromycin using the method described in U.S. patent No.3,725,385.

Synthesis of 3' -N-desmethylclarithromycin 21

In clarithromycin (1.00 g, 1.3 mmol) and NaOAc. H₂O (0.885 g, 6.5 mmol) mixture to MeOH-H₂O (20ml, 4: 1), the mixture was heated to 55-60 ℃. Iodine (0.330 g, 1.3 mmol) was added and the reaction was stirred at 55-60 ℃ for 3 hours. The reaction mixture was poured into 50ml of CHCl₃Containing 1ml of ammonia solution. With CHCl₃(4X50 ml) and dissolved in an aqueous solution containing 5ml of ammoniaThe solution was washed with 70 ml of water and dried (anhydrous Na)₂SO₄) Concentrating, and purifying by flash chromatography (silica gel, CHCl)₃∶MeOH∶NH₄OH 100: 10: 0.1) gave 21. Yield: 0.9 g (92%).

Synthesis of alkyne 24

3 '-N-desmethyl erythromycin A20(1.0 g, 1.4 mmol) and tosylate 11(1.25 g, 5.6 mmol) were mixed in dry THF (15ml) and Hunig's base (2.2 ml, 11.9 mmol) and stirred at 55 deg.C for 48 hours. The reaction mixture was poured into CH₂CL₂(50 ml) with 2% anhydrous NH₄OH (3x30 ml) and saturated brine (1x30 ml) and the organic layer was extracted with Na₂SO₄Dry and evaporate the solution. Purification of the crude product on a silica gel column, CH₂CL₂MeOH: 10: 1, 24 was obtained. (0.35 g, 32%).

Synthesis of alkyne 23

Alkyne 23 was prepared from 3' -N-desmethyl erythromycin a20 and propargyl bromide using the same synthetic procedure as described for compound 24.

Synthesis of alkyne 25

Alkyne 25 was prepared from 3' -N-desmethyl erythromycin a20 and tosylate 12 using the same synthetic procedure as described for compound 24.

Synthesis of alkyne 26

Alkyne 26 is prepared from 3' -N-desmethylclarithromycin a21 and propargyl bromide using the same synthetic procedure as described for compound 24.

Synthesis of alkyne 27

Alkyne 27 was prepared from 3' -N-desmethylclarithromycin a21 and tosylate 11 using the same synthetic procedure as described for compound 24.

Synthesis of alkyne 28

Alkyne 28 was prepared from 3' -N-desmethylclarithromycin a21 and tosylate 12 using the same synthetic procedure as described for compound 24.

TABLE 3

The process 104 is as follows: synthesis of the Compounds of Table 3

Triazole 301-357 is generated from alkyne 23-28 using azide compounds 14a-14gm under the reaction conditions a, B, C and D above for the synthesis of compound 101-280 in example 1. As described above, the use of conditions A and C, excluding the degassing stage of the reaction mixture, results in the formation of a significant amount of iodinated by-product, thereby resulting in a low yield. In addition, by reducing the amount of copper salt in the reaction to 0.5 molar equivalent or the amount as in conditions B and D, the formation of iodinated by-products can be reduced.

The compounds of table 2 were synthesized under reaction conditions similar to conditions a, B, C and D as described above, with the time required for each reaction varying depending on several factors, including: a specific substrate; the amount of Cu (I) salt used; absence or presence of Hunig's matrix; and the concentration of the reactants. Since the disappearance of starting material was monitored by TLC and/or LCMS, the reaction was typically allowed to proceed for 2-72 hours. The reaction was stopped when the analysis showed that the starting alkyne species was largely consumed. The purification and experimental set-up in conditions A-D are typical applications for all the products in Table 2. Minor changes to the process are shown in table 2.

Example 3 Synthesis of Compound 401-

The compound 401-417 shown in Table 4 was derived from telithromycin by a method similar to those described in tables 2 and 3 above. Telithromycin is similar to azithromycin, erythromycin and clarithromycin described above, is selectively demethylated and then alkylated with tosylate. As a result, the alkyne is added to the corresponding triazole by the same copper cycloaddition catalyzed [3+2] action as described above for azide 14.

Synthesis of 3' -N-demethyltelithromycin 30

To an anhydrous acetonitrile solution containing telithromycin 29(3.0 g, 3.60 mmol) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions and argon was bubbled through at 0 deg.C for 30 minutes. The mixture was warmed to room temperature and stirred overnight. Adding CH₂CL₂(250 ml) and 5% Na₂S₂O₃(80 ml) the two layers were separated. The organic layer was coated with 5% Na₂S₂O₃(1X80 ml) extraction with NH₄CL (1X80 mL) diluted and Na₂SO₄And (5) drying. Evaporating the solution, and using 0-8% ammonia (2N NH) to obtain the crude product₃) And CH₂CL_{2 of}Purification by silica gel elution gave compound as a white solid (1.95 g, 68%). MS (ESI) M/E; m + H⁺798.6。

Scheme 105 Synthesis of alkyne 31

Synthesis of 3' -N- (but-3-ynyl) telithromycin 31

Scheme A: amine 30(0.66 g, 0.83 mmol), toluene sulfonic acidSalt 11(0.33 g, 1.49 mmol) was mixed in solution THF (15ml) and Hunig's base (3 ml) and heated at 90 ℃ for 5 days. The solution was evaporated and the residue was dissolved in 1N HCL (50 ml) and stirred at room temperature for 1 hour. Adding CH₂CL₂(30 ml) the two layers were separated. CH for aqueous layer₂CL₂Extraction (2 × 30 ml) was performed while basifying with NaOH (1N) to form a white suspension. CH for suspension₂CL₂(3X30 ml) and the organic layer was extracted with Na₂SO₄And (5) drying. Evaporating the solution, and using 0-6% ammonia (2N NH) to obtain the crude product₃) And CH₂CL₂Purification by silica gel elution gave compound 31 as a white solid (0.12 g, 17%). MS (ESI) M/e 850.8(M + H)⁺。

Synthesis of 3' -N- (but-3-ynyl) telithromycin 31

Scheme B: amine 30(0.66 g, 0.83 mmol), tosylate 11(0.40 g, 1.84 mmol) were mixed in solution acetonitrile (10ml) and Hunig's base (0.18 ml, 1.0 mmol), heated to 90 ℃ with a microwave over 10 minutes and maintained at 90 ℃ for 1.5 hours. The reaction was vented for 15 minutes and the solution evaporated. The residue was dissolved in 1N HCl (60 mL) and stirred at room temperature for 2 hours. Adding CH₂CL₂(30 ml) the two layers were separated. CH for aqueous layer₂CL₂Extraction (2 × 30 ml) was performed while basifying with 5% KOH (1N) to form a white suspension. CH for suspension₂CL₂(3X30 ml) and the organic layer was extracted with Na₂SO₄And (5) drying. The solution was evaporated and the crude product obtained was purified by TLC (2000 micron plates), CH₂CL₂Aqueous ammonia (2N NH)₃) Purification by elution 12: 1 gave compound 31 as a white solid (0.19 g, 27%). MS (ESI) M/e 850.8(M + H)⁺。

TABLE 4

Triazole 401-417 is formed from alkyne 31 using azide compounds 14a-14gm under similar reaction conditions to those described in tables 4 and 5 above, as described earlier, the employment of reaction conditions that do not include a degassing stage of the reaction mixture, resulting in the formation of iodinated by-products, thus resulting in low yields. Meanwhile, the formation of iodinated by-products can be reduced by reducing the amount of copper salt used in the reaction to 0.5 molar equivalent or less.

The following compound 406 is a typical use of the compound described in table 4 via a specific synthetic procedure for azide 14 ad. As shown in example 1, the time required for each reaction varies depending on several factors, including: a specific substrate; the amount of Cu (I) salt used; absence or presence of Hunig's matrix; and the concentration of the reactants. Since the disappearance of starting material was monitored by TLC and/or LCMS, the reaction was typically allowed to proceed for 6-24 hours. The reaction was stopped when the analysis showed that the starting alkyne species was largely consumed. The purification and experimental set-up in conditions A-D of example 1 are typical applications for the synthesis of the compounds of Table 4 in example 1.

The process 106 is as follows: synthesis of Compound 406

Synthesis of Compound 406

This compound was obtained by reacting alkyne 31(0.06 g, 0.07 mmol) with azide 14ad (0.030 g, 0.14 mmol) under argon atmosphere in the presence of CuI (0.030 g, 0.14 mmol) in a mixed solution of THF (5 ml) and Hunig's base (0.05 ml) at room temperature overnight. The crude product obtained was purified by TLC (2000 micron plates), CH₂CL₂Aqueous ammonia (2N NH)₃) Elution purification at 12: 1 gave triazole 406 as a white solid (0.025 g, 34%). MS (ESI) M/e 533.7(M +2H)²⁺。

Example 4: synthesis of Compound 425-451

The oximes 425-433 of Table 5 were synthesized from alkynes 400a to 400i by cycloaddition catalysis of Cu (I) with azide compounds 14a-14gm under the foregoing procedure.

Process 107

Synthesis of alcohol 27a

To alkyne 27(0.700 g) was added 10ml of 0.9N HCL and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with sodium chloride and NH₄The pH of the OH solution was adjusted to 8. The solution was extracted with ethyl acetate (3 × 30 ml) and dried (over Na)₂SO₄) And concentrating under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 60% ethyl acetate hexanes) to give 0.200 g (35% yield) of the desaturanose sugar derivative 27 a. Data of 27 a:¹HNMR(300MHz，CDCL₃.partial)：δ0.82(t，3H)，2.25(s，3H)，3.00(s，3H)，3.25(dd，1H)，3.55(m，2H)，3.70(s，1H)，3.85(s，1H)，3.95(s，1H)，4.40(d，1H)，5.15(dd，1H)

synthesis of acetate salt 27b

To a solution of 27a (0.200 g, 0.32 mmol) in acetone (2 ml) was added anhydrous acetic acid (0.05 ml, 0.5 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and then extracted with ethyl acetate (3 × 50 ml), the combined organic components were washed with saturated sodium bicarbonate (3 × 50 ml), dried (anhydrous Na)₂SO₄) And concentrating under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate hexanes) to afford 0.100 g (50% yield) of acetate 27 b. Data of 27 b:

¹HNMR(300MHz，CDCl₃，partial)：δ0.84(t，3H)，2.00(s，3H)，2.20(s，3H)，2.90(s，3H)，3.00(q，1H)，3.25(s，1H，3.47(m，2H)，3.70(bs，1H)，3.82(bs，1H)，3.97(s，1H)，4.60(d，1H)，4.77(dd，1H)，5.15(dd，1H).

synthesis of ketolide 27c

In CH with acetate 27b (0.090 g, 0.134 mmol), EDC & HCl (0.172 g, 0.90 mmol), and dimethyl sulfoxide (DMSO) (0.171 ml, 2.41 mmol)₂CL₂(1.5 ml) solution was added dropwise to CH containing pyridine trifluoroacetate (0.174 g, 0.90 mmol) at 15 deg.C₂CL₂(1ml) solution. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (2 ml) and stirred slowly for 30 minutes. The mixture was then poured into CHCl₃In (50 ml), the organic layer was washed with water (2 × 50 ml), dried (anhydrous Na)₂SO₄) And concentrating under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 30% ethyl acetate hexanes) to afford 0.070 g (78% yield) of acetate 27 c. Data of 27 c:

MS(ESI)m/e 668(M+H)⁺；¹HNMR(300MHz，CDCl₃，partial)：δ0.86(t，3H)，2.00(s，3H)，2.24(s，3H)，2.70(s，3H)，2.95-3.10(m，1H)，3.15-3.05(m，1H)，3.45-3.65(m，1H)，3.80(q，1H)，3.90(s，1H)，4.28(d，1H)，4.40(d，1H)，4.76(dd，1H)，5.10(dd，1H).

synthesis of oxime 400a

To a solution of 27c (2.0 g, 2.9 mmol) in MeOH (10ml) was added (R) -N-piperidin-3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). The reaction mixture was stirred at room temperature for 14 hours. The mixture (50 ml) was then poured into water (50 ml) by adding NH₄OH to pH 11, after separation of the organic layer, washed with brine (50 ml) and dried (over anhydrous Na)₂SO₄) And concentrating under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 12: 1 CH)₂CL₂And 2M aqueous ammonia) to obtain2 g (78% yield) of a 1: 1 mixture of oxime 400a and E/Z isomer. Data of 400 a: MS (ESI) M/e 724.7(M + H)⁺。

Synthesis of oxime 400b

Oxime 400b was synthesized from ketolide 27c and (R) -N-pyronaridin-3-yl-hydroxylamine using the conditions described for oxime 400a above. Data for oxime 400 b: MS (ESI) M/e 710.6(M + H)⁺。

Process 108

Synthesis of oxime 400c

Oxime 400c from ketolide 27c and N- [ 2-dimethylaminoethyl]Hydroxylamine hydrobromide was synthesized using the conditions described above for oxime 400 a. Data for oxime 400 c: MS (ESI) M/e 726.5(M + H)⁺。

Synthesis of oxime 400d

Oxime 400d was synthesized from ketolide 27c and N-piperidin-4-yl-hydroxylamine hydrobromide using the conditions described above for oxime 400 a. Data for oxime 400 d: MS (ESI) M/e 724.6(M + H)⁺。

Synthesis of oxime 400e

Oxime 400e was synthesized from ketolide 27c and cis-4-aminocyclohexyl-hydroxylamine hydrobromide using the conditions described for oxime 400a above. Data for oxime 400 e: MS (ESI) M/e 738.7(M + H)⁺。

Synthesis of oxime 400f

In CHCl containing oxime 400f (20 mg, 0.02 mmol)₃To the solution (0.2 ml) was added formaldehyde (5 mg of 37% anhydrous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The reaction mixture was heated continuously to 50 ℃ in a sealed tube for 12 hours. Reaction mixture in anhydrous NaHCO₃(10ml) and chloroform (10ml) and the organic fraction was fractionated with K₂SO₄Drying throughConcentration by filtration afforded oxime 400f (18 mg) as a white solid. Data for oxime 400 f: MS (ESI) M/e 766.7(M + H)⁺。

Synthesis of Oxime triazole 425-

These triazoles were all synthesized from alkyne 400a and the azide compounds shown in table 6 under the conditions of copper-catalyzed cycloaddition described previously.

Synthesis of oxime triazole 432-434 and 444-445

These triazoles were all synthesized from alkyne 400b and the azide compounds shown in table 6 under the conditions of copper-catalyzed cycloaddition described previously.

Synthesis of Oxime triazole 437 and 438

These triazoles were all synthesized from alkyne 400c and the azide compounds shown in table 6 under the copper-catalyzed cycloaddition conditions described previously.

Synthesis of Oxotriazoles 440 and 441

These triazoles were all synthesized from alkyne 400d and the azide compounds shown in table 6 under the conditions of copper-catalyzed cycloaddition described previously.

Synthesis of Oxotriazol 443

These triazoles were all synthesized from alkyne 400e and azide 14w under the copper-catalyzed cycloaddition conditions described previously.

Synthesis of Oxotriazol 448

These triazoles were all synthesized from alkyne 400f and azide 14w under the conditions of copper-catalyzed cycloaddition described previously.

Synthesis of Compounds 448 and 449

Compound 449 was synthesized from alkyne 400 g. The alkyne is derived from 27c and intermediate 39 as shown in scheme 109 below. O-Rhodomyces deoxyglucamine hydroxylamine 39 is formed by the protection of 2' OH groups by benzyl ester in 4 stages of synthesis from deoxyglucamine hydrochloride, and undergoes Mitsunobu reaction with N-hydroxyphthalimide, debenzylation and reduction of phthalimide groups.

Process 109

Synthesis 34

Rhodomyces desoxysamine hydroxylamine can be prepared according to the method described in the literature (JACS, 1954, 76, 3121-3131).

Synthesis of 35

To a suspension of 34(3.5 g, 16.5 mmol) in acetone was added K₂CO₃(4.6 g, 33.1 mmol) and stirred for 30 minutes. Benzoic anhydride (4.5 g, 19.8 mmol) was then added and stirred at ambient temperature for 16 hours. Reacting the mixture with CH₂CL₂(100 ml) and water (100 ml). After the organic layer separated, the aqueous layer was treated with CH₂CL₂(2 × 100 ml) extraction. The combined organic layers were dried, concentrated and purified by flash chromatography (silica gel, 50% ethyl acetate hexanes). 2 g (61% yield) of product are obtained. Compound 35 was used as a mixed isomer as the next step without further purification. Data for 35 (mixed isomers):

¹HNMR(300MHz，CDCl₃)：δ1.22(d，1.5H)，1.30(d，1.5H)，1.40-1.54(m，1H)，1.80(m，1H)，2.32(s，3H)，2.34(s，3H)，2.95-3.04(m，1H)，3.31-3.40(m，0.5H)，3.63-3.72(m，0.5H)，4.19-4.27(m，0.5H)，4.67(d，0.5H)，4.98(dd，0.5H)，5.16(dd，0.5H)，5.43(d，0.5H)，7.43(t，2H)，7.57(t，1H)，8.07(t，2H).

synthesis of 36-37:

at 0 ℃ in a mixture containing 35(2.7 g, 9.7 mmol), N-hydroxyphthalimide (1.7 g, 10.7 mmol) and Ph₃P (2.8 g, 10.7 mmol) in THF was added DIAD (2.1 mmol)L, 10.7 mmol) was stirred at ambient temperature for 12 hours. The resulting solution was concentrated under reduced pressure and the crude product was redissolved in EtOAc (100 ml). The organic layer was washed with 1N NaOH (2x75 ml), water (1x75 ml) and brine (2x75 ml). Drying (anhydrous Na)₂SO₄) Concentration and purification by flash chromatography on silica gel (30% ethyl acetate hexanes) gave 36(0.9 g) and 37(1.8 g) (61% yield) product. Data:

¹H NMR(300MHz，CDCl₃)：δ1.33(d，3H)，1.69(dd，1H)，1.84(ddd，1H)，2.34(s，6H)，3.02(ddd，1H)，3.67(dq，1H)，5.16(d，1H)，5.45(dd，1H)，7.50(t，2H)，7.55(d，1H)，7.71(dd，2H)，7.81(dd，2H)，8.19(d，2H).

38 Synthesis of

A solution containing 37(1.8 g) of MeOH (50 ml) was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel (50% ethyl acetate hexanes) to give 0.6 g of 38.

39 Synthesis of

Hydrazine (0.514 ml, 16.4 mmol) was added to a solution of 38(0.55 g, 1.64 mmol) in EtOH (5 ml) and heated to 60 ℃ for 1 hour. The white suspension was then stirred at room temperature for 12 hours. The white product was filtered and washed with MeOH (3 × 20 ml). The combined filtrates were concentrated and purified by flash chromatography on silica gel (CH)₂CL₂∶2％NH₃-MeOH ═ 9: 1) to give 0.155 g of pure product, hydrochloride 39 was modified with 2M HCL.

Synthesis of 400g

A solution of 39(0.82 g) and macrolide alkyne 27c in EtOH (3 ml) was heated at 60 ℃ for 72 hours. The solution was concentrated and purified by flash chromatography on silica gel (CH)₂CL₂∶2％NH₃-MeOH 10: 1) to give 400d (0.08 g) as a white solid. MS (ESI) M/e 799(M + H)⁺，400(M+2H)⁺。

449 Synthesis of

A mixed solution of 400d (0.0275 g, 0.034 mmol), 14w (0.001 g, 0.052 mmol) and CuI (0.007 g, 0.034 mmol) was purged with argon and THF (2 mL) was added. A small amount of Hunig's base was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was diluted with a solution containing 20% NH₄Saturated NH of OH (10mL)₄The OH solution was cooled and stirred at room temperature for 30 minutes. Subjecting the mixture to CH₂CL₂(3 × 20 ml) and the combined organic extracts were washed with a saturated solution of ammonium chloride containing 10% aqueous ammonia (1 × 50 ml). The obtained solution was treated with anhydrous Na₂SO₄Dried, concentrated and purified by flash Chromatography (CH)₂CL₂∶2％NH₃-MeOH 10: 1) yielding 0.023 g.

449.MS(ESI)m/e 496(M+2H)²⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.85(t，3H)，1.05(d，3H)，1.15(d，3H)，3.33(t，2H)，3.81(d，1H)，4.10-4.28(m，3H)，4.58(d，2H)，4.84(d，1H)，5.20(d，1H)，7.08(s，1H)，7.24(d，2H)，8.14(d，2H).

448 Synthesis

Compound 448 was synthesized from intermediate 36 using the same chemical steps as described for 449. 448 of the data: MS (ESI) M/e 496(M +2H)²⁺。

Oximes 434 and 435 are synthesized from compound 425 by the nitrogen alkylation of piperidinyl oxime with 3-bromo-1-fluoropropane or 2-bromofluoroethanol, respectively, as shown in scheme 110 below.

Process 110

434 Synthesis of

The mixture containing oxime 425(0.04 g, 0.04 mmol) and 3-bromo-1-fluoropropane (0.012 ml)0.13 mmol) of DMF was heated to 60 ℃ for 14 hours. The reaction mixture was diluted with water (20 ml) and brine (10ml) and then with CH₂CL₂(3X30 ml) and the combined organic extracts were dried (Na)₂SO₄) Filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 3: 100: 0.1 MeOH/CH)₂CL₂/NH₄0H) To yield 0.023 g of oxime 434. 434 of the data: MS (ESI) M/e 489.1(M +2H)²⁺。

435 Synthesis

Compound 435 is synthesized from compound 425 and 2-bromofluoropropane under the synthesis conditions described previously for compound 434. Data of 435: MS (ESI) M/e 482.1(M +2H)²⁺。

Compound 436 is prepared by oximation followed by cycloaddition as described in scheme 110.

Synthesis of Compound 436

The synthesis of compound 436 of scheme 111 below begins with alkyne 27 c. 27c in methanol to obtain alkyne 27d through deacylation, and obtaining triazole 436a through treatment of azide compound 14 au. The triazole reacts with 3(R) -hydroxyamino-piperidine-1-carboxylic acid phenyl ester to give the carbobenzoxy group (CBZ) -protected oxime as a mixture of E/Z isomers. The CBZ group is moved by hydrogenolysis to compound 436.

Process 111

Synthesis of alkyne 27d

A solution of ketolide 27c (0.230 g) in MeOH (10mL) was heated to 50 deg.C for 48 hours. The solution was removed under reduced pressure to give pure deacetylated product 27d (0.190 g, 88%). Data for 27 d:

MS(ESI)m/e 626(M+H)⁺；¹HNMR(300MHz，CDCl₃，partial)：^TM 0.85(t，3H)，2.25(s，3H)，2.70(s，3H)，2.97(q，1H)，3.10(t，1H)，3.18(dd，1H)，3.5(m，1H)，3.80-3.97(m，2H)，4.32(m，2H)，5.15(dd，1H).

436a Synthesis

Triazole 436a was synthesized from alkyne 27d and azide compound 14au under the copper-catalyzed cycloaddition conditions of the compounds of table 1.

436 of the following Synthesis

A solution of the alkoxyamine 33(0.13 g, 0.50 mmol) in anaesthetic ether (1.0 ml) was reacted with 2.0M HCl in ether (1.5 ml, 3.0 mmol), stirred at 23 ℃ for 1h and evaporated to give a white foam. The hydrochloride solution was reacted with 436a (0.15 g, 0.17 mmol) in ethanol (3.5 ml) and the reaction mixture was stirred at 55 ℃ for 16 h, then cooled to room temperature and diluted with water (30 ml). Addition of NH₄OH to adjust the pH to 10, the reaction mixture was extracted with ethyl acetate (3X30 ml) and dried (Na)₂SO₄) After evaporation, a yellow oil was obtained.

The crude CBZ-protected intermediate solution in ethanol was reacted with 10% Pd/C (100 ml) while the reaction mixture was stirred in a hydrogen chamber at 23 ℃ for 12 hours. The crude product obtained is filtered and evaporated and purified by thin layer chromatography (SiO)₂，10％ 2M NH₃Methanol/dichloromethane) to yield 436 as a white solid (80mg, 0.080 mmol): LCMS (ESI) M/e 550(M +2H)²⁺。

The process 112 is as follows: synthesis of intermediate 400h

Synthesis of Compound 27e

In the presence of roxithromycin (850 mg, 0.914 mmol, 90%) and NaAc (828 mg, 10.000 mmol) MeOH (6.0 ml) and water (1.5 ml) and I was added in four portions over 30 minutes at 48 deg.C₂(per part: 63.5 mg) in each part I₂1N NaOH (400. mu.l) was then added. The reaction was continued for 30 minutes. The solution was removed and EtOAc (100 ml) was added followed by water (20 ml). The organic portion was washed with brine (40 ml x2), Na₂SO₄And (5) drying. The residue was isolated by Flash Chromatography (FC) (6/94/0.2 MeOH/CH)₂CL₂/NH₄CL) to give compound 27e600 mg, 80% yield.

LCMS(ESI)m/e 824(M+H)⁺

Synthesis of Compound 400h

A mixed solution of THF (5.4 mL) containing compound 27e (500 mg, 0.608 mmol) and but-3-ynyl toluene-4-sulfonate and Hunig's base (1.6 mL) was refluxed for 48 hours. The reaction mixture was concentrated, then EtOAc (100 ml) was added. The organic layer was washed with saturated NaHCO₃The solution (20 ml) and saline (50 ml) were washed. Compound 400h through FC (3/100/0.2 MeOH/CH)₂CL₂/NH₄CL) was isolated to give 316 mg of product in 59% yield. LCMS (ESI) M/e 876(M + H)⁺

Synthesis of Compound 447

This compound was synthesized from alkyne 400h and azide 14bt under the conditions of example 1.

Process 113

Synthesis of Compounds 450 and 451

Containing 9-Oxime Compound 27f (100 mg, 0.125 mmol), NaCO₃(106 mg, 0.998 mmol) and 2-chloroethylenedimethylamine hydrochloride (109 mg, 0.749 mmol) in acetoneThe tube was then stirred at 70 ℃ for 5 days, then EtOAc (30 mL) was added and rinsed with 1N NaOH (2 mL) and water (15 mL). Compound 400h through FC (3/100/0.2 MeOH/CH)₂CL₂/NH₄CL) was isolated to give 75 mg of product in 70% yield. MS (ESI) M/e 859(M + H)⁺

Triazole 450 was synthesized from alkyne 400i and azide compound 14w under the conditions of example 1.

Synthesis of alkyne 400j

In a solution containing 9-oxime compound 27f (180 mg, 0.229 mmol), 3-fluoropropyl bromide (161 mg, 1.144 mmol) and Bu₄NBr (37 mg, 0.115 mmol) CH₂CL₂To the mixed solution was added 50% NaOH (3.0 ml). The mixture was stirred at room temperature for 45 minutes, then water (20 ml) was added. CH for aqueous layer₂CL₂(20ml x 2). The combined organic layers were washed with brine (50 ml). Compound 400j was purified by FC (25/75/0.2 acetone/hexane/NH)₄OH) was isolated to yield 94 mg of product in 48% yield. MS (ESI) M/e 848(M + H)⁺。

Triazole 451 was synthesized from oxime alkyne 27f and alkyne 400i by alkylation with 3-fluoro-1-propyl bromide and azide compound 14w under conditions to synthesize compound 450.

TABLE 5

Example 5: synthesis of 460-466 Compound

Alkyne 41 in scheme 114 is synthesized from 9' -N-desmethyl azithromycin under the synthesis conditions for alkyne 4 in example 1. The alkynes are general intermediates for the compounds listed in table 6. Compound 466 is directly derived from alkyne 41 and azide 14w by copper catalyzed [3+2] cycloaddition under the conditions of example 1.

Process 114

Synthesis of alkyne 41

5.0 g (6.93 mmol) of 3 ', 9 ' -bis-N-norazithromycin 40 and 3.107 g (13.80 mmol) of tosylate 11 are heated to 100 ℃ for 24 hours in 60 ml of Hunig's matrix and 8 ml of acetonitrile solution. After cooling, the solution was removed by rotary evaporation and the residue was purified by column chromatography on silica gel to give 1.70 g of the final product. MS (ESI) M/e 774(M + H)⁺

Synthesis of Compound 42

Containing 0.200 g (0.26 mmol) 41, 0.262 g (1.29 mmol) 3- (N-phthalamide) -propionaldehyde, and 0.110 g (0.52 mmol) NaB (OAc)₃A1.5 ml solution of H in DMF was stirred at 25 ℃ for 4 hours. The reaction mixture was diluted with water and CH₂CL₂(50 ml x3) extraction, combined organic layers washed with brine, MgSO₃Drying, concentrating and purifying by silica gel column chromatography to obtain 0.200 g of product. MS (ESI) M/e 961(M + H)⁺

Synthesis of triazole 460

A mixed solution of 0.200 g (0.20 mmol) of alkyne 42, 0.080 g (0.41 mmol) of azide compound 14w and 0.040 g (0.20 mmol) of CuI in 15ml of THF was degassed and then purged with argon. 0.2 ml Hunig's matrix was added. The reaction mixture was stirred at 25 ℃ for 6 hours. Then 40 ml of 10% NH were added to the reaction mixture₄OH, stirring for 10 minutes, using CH₂CL₂(50 ml)x3), the combined organic layers were washed with brine, dried, concentrated, and purified by TLC to give 4600.098 mg of compound. MS (ESI) M/e 1153(M + H)⁺

Synthesis of triazole 461

A mixed solution of 2.0 ml of ethanol containing 0.025 g (0.02 mmol) of RX-460 and 0.002 g (0.04 mmol) of hydrazine was heated under reflux for 6 hours. Cool, remove ethanol, and place the remaining suspension in 5.0 ml of CH₂CL₂In (b), the organic solution was collected by filtration through a cotton-tipped pipette and concentrated. This procedure was repeated several times as necessary until MS and proton NMR showed 0.020 g of pure final product. MS (ESI) M/e 1023(M + H)⁺

Synthesis of Compounds 462 and 463

Compound 462 is synthesized from alkyne 41 and 2- (N-phthalamide) -acetaldehyde under the conditions previously described for the preparation of compound 460.

Compound 463 was synthesized from compound 462 using the conditions described above for the synthesis of compound 461 from 460.

Synthesis of Compounds 464 and 465

Compound 464 is synthesized from alkyne 41 and 4- (N-phthalamide) -butyraldehyde under the conditions described previously for the preparation of compound 460.

Compound 465 was synthesized from compound 464 using the conditions described above for the synthesis of compound 461 from 460.

TABLE 6

EXAMPLE 6 Synthesis of Compound 475-

TABLE 7

As shown in scheme 115 below, precursors 44 and 46 of carboxylic acid derivatives are generated from amine 2 by alkylation following saponification with the corresponding omega bromo ester. These carboxylic acids give the final product compounds 475-477 and 480 by reacting with the corresponding amines

Process 115

Synthesis of Compound 43

A solution of diisopropylethylamine (25 ml) containing demethylazithromycin 2(3.7 g, 5 mmol) was reacted with ethyl 5-bromobutyrate (7.2 g, 50 mmol) and stirred at 105 deg.C for 5 hours. The reaction mixture was cooled to room temperature, poured off slowly and the liquid portion evaporated to a yellow oil. By the fast color-general method (SiO)₂，6％2M NH₃Methanol/dichloromethane) gave a white foamy solid 43(2.7 g, 3.2 mmol). LCMS (ESI) M/e 850(M + H)⁺

Synthesis of Compound 44

A solution of 43(0.60 g, 0.70 mmol) in methanol (16 mL) and water (2.4 mL) was reacted with 1.0M aqueous sodium chloride (2.0 mL, 2.0 mmol) and stirred at 50 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, acetic acid (0.12 ml, 2.0 mmol) was added and evaporated to a white powder. By the fast color-general method (SiO)₂，10％2M NH₃Methanol/dichloromethane) to yield a white powdery solid 44(0.40 g, 0.49 mmol). LCMS (ESI) M/e 836(M + Na)⁺

Synthesis of Compound 45

A solution of diisopropylethylamine (25 mL) containing demethylazithromycin 2(3.7 g, 5 mmol) and ethyl 5-bromobutyrate (5.2 g, 25 mmol)Mole) and stirred at 105 ℃ for 4 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (100 ml), washed with water (100 ml), dried (Na)₂SO₃) And evaporated. By the fast color-general method (SiO)₂，6％2M NH₃Methanol/dichloromethane) gave a colorless oil 45(0.55 g, 0.64 mmol). LCMS (ESI) M/e 864(M + H)⁺

Synthesis of Compound 46

A solution of 45(0.54 g, 0.62 mmol) in methanol (10ml) and water (1.25 ml) was reacted with a 1.0M aqueous solution of sodium chloride (1.25 ml, 1.25 mmol) and stirred at 45 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, 1.0M acetic acid (1.25 ml, 1.25 mmol) was added, extracted with dichloromethane (3 × 30 ml), dried (Na)₂SO₃) And evaporated to give white powder 46. LCMS (ESI) M/e 836(M +2H)⁺

Process 116

Synthesis of Compound 477

A solution of 46(30 mg, 0.035 mmol) in dichloromethane (0.5 mL) was reacted with 4-nitrophenylethylamine hydrochloride (14 mg, 0.070 mmol), diisopropylethylamine (0.018 mL, 0.11 mmol) and 1-ethyl-3- (3-dimethylaminopropylamine) carbodiimide (10mg, 0.053 mmol) and stirred at 23 ℃ for 12 hours. The reaction mixture was evaporated to a yellow thin sheet and purified by thin layer chromatography (SiO)₂，5％2M NH₃Methanol/dichloromethane) to give white flakes 477(7.0 mg, 0.0071 mmol) LCMS (ESI) M/e 493(M +2H)⁺

Process 117

A solution of DMF (0.4 mL) containing 46(31 mg, 0.037 mmol) was reacted with D- (-) isobide-2-amino-1- (4-nitrophenyl) -1, 3-propanediol (7.9 mg, 0.037 mmol) and 1-ethyl-3- (3-dimethylaminopropylamine) carbodiimide (8.5 mg, 0.037 mmol) and stirred at 23 ℃ for 16 h. The reaction mixture was evaporated to a yellow thin sheet and purified by thin layer chromatography (SiO)₂，5％2M NH₃Methanol/dichloromethane) to yield white flakes 476(10 mg, 0.0097 mmol) LCMS (ESI) M/e 516(M +2H)²⁺

Process 118

Containing 46(40 mg, 0.048 mmol) of CH₂CL₂(0.7 mL) was reacted with Flofenicol amine 47(12 mg, 0.048 mmol) and 1-ethyl-3- (3-dimethylaminopropylamine) carbodiimide (10mg, 0.053 mmol) and stirred at 23 ℃ for 16 h. The reaction mixture was evaporated to a yellow thin sheet and purified by thin layer chromatography (SiO)₂，5％2M NH₃Methanol/dichloromethane) to give white solid 475(10 mg, 0.0097 mmol) LCMS (ESI) M/e 532.1(M +2H)²⁺

Synthesis of Compounds 478 and 479

Compound 462 is synthesized from clarithromycin amine 21 ethyl 4-bromobutyrate or ethyl 3-bromopropionate and 4-fluorophenethylamine under the chemical action of compound 477 as described previously.

Synthesis of Compound 480

Compound 480 was synthesized from amine 2 and bromide 48 as depicted in scheme 117 using alkylation under the conditions of synthesis of amine 3 in example 1.

Process 119

Example 7: synthesis of Compound 501-515

TABLE 8

The derivatives related to the amide, aminobenzene sulfonamide and urea groups in table 8 were synthesized by adding the corresponding carboxylic acid, sulfonyl chloride, or acylimidazole to the amines 500a and 500b under appropriate conditions. Amines 500a-b are synthesized by scheme 120.

Process 120

Synthesis of amine 500a

Hunig's (5 mL) solution containing amine 2(2.0 g, 2.7 mmol) was added N- [ 2-bromoethane]Phthalimide (0.76 g, 3 mmol). The mixture was heated to 100 ℃ in a closed tube for 1.5 hours. The reaction mixture was diluted with water (100 ml) and CH₂CL₂(50 ml x 3). The mixed organic extracts are dried (K)₂CO₃) And (4) concentrating. The crude product was purified by silica gel chromatography (using a column containing 1-4% methylethanolamine (2M NH)₃) CH (A) of₂CL₂Elution) gave the phthalimide derivative as a white solid (1.8 g, 1.9 mmol).

To EtOH (10ml) containing phthalimide (1.0 g, 1.1 mmol) was added hydrazine (1ml of 80% aqueous solution). The mixture was stirred at room temperature for 8 hours, and then the solid reaction residue was dissolved in CH₂CL₂(100 ml) and rinsed with water (3 × 50 ml). Organic layer through K₂CO₃After drying, filtration and concentration 0.82 g of a white solid was obtained without further purification.

Synthesis of amine 500b

Compound 500b was synthesized from amine 2N- [ 3-bromopropane ] -phthalimide under the conditions described for compound 500a above.

Compound 503 was synthesized from amine 500a and the N-acylimidazole derivative of the disilylether of D- (-) -isobide-2-amino-1- (4-nitrophenyl) -1, 3-propanediol.

Process 121

Synthesis of Compound 503

Dimethylformamide (200 ml) containing D- (-) -isobide-2-amino-1- (4-nitrophenyl) -1, 3-propanediol (2.1 g, 10 mmol) was reacted with imidazole (2.0 g, 30 mmol) and tert-butyldimethylchlorosilane (3.0 g, 20 mmol), and the reaction mixture was stirred at 23 ℃ for 16 hours. The reaction mixture was diluted with ether (300 ml), washed with water (3 × 300 ml), and dried (Na)₂SO₃). By flash chromatography (SiO)₂20% ethyl acetate/hexanes) to give bis-silyl 50 as a yellow oil (2.6 g, 5.9 mmol)

A solution of bis-silyl 50(44 mg, 0.10 mmol) in dichloromethane (1.0 ml) was reacted with triethylamine (0.028 ml, 0.20 mmol) and 1, 1-carbonyldiimidazole (16 mg, 0.10 mmol) and the reaction mixture was stirred at 23 ℃ for 3 hours. Amine 500a (78 mg, 0.10 mmol) was added and the reaction mixture was stirred at 23 ℃ for 12 hours and evaporated to give a yellow sheet which was purified by thin layer chromatography (SiO₂，10％2M NH₃Methanol/dichloromethane) to yield white flakes 503 a: LCMS (ESI) m/e 623(M+2H)²⁺

A tetrahydrofuran (0.8 ml) solution containing 503a (50 mg, 0.040 mmol) was reacted with tetrabutylammonium fluoride (0.16 ml of a 1.0M solution, 0.16 mmol) and acetic acid (0.005 ml, 0.08 mmol), and the reaction mixture was stirred at 23 ℃ for 4 hours. Diluted with water (20 ml), extracted with dichloromethane (3 × 20 ml), dried (Na)₂SO₃) Evaporated and purified by thin layer chromatography (SiO)₂，5％2M NH₃Methanol/dichloromethane) gave white flakes 503(19 mg, 0.019 mmol): LCMS (ESI) M/e 509(M +2H)²⁺

Synthesis of Compound 502

Compound 502 was synthesized from amine 500b and D- (-) -isobide-2-amino-1- (4-nitrophenyl) -1, 3-propanediol under the conditions of compound 503.

Synthesis of Compound 501

Process 122

A methanol solution (30 ml) containing CBZ amine 51 (U.S. Pat. No.5,164,402) (1.5 g, 5.2 mmol) was reacted with 10% Pd/C (0.15 g), purged with hydrogen and stirred at 23 ℃ for 2 hours. The reaction mixture was filtered through a silica gel pump and evaporated to give crude yellow oleylamine 52.

Acetonitrile (5.0 ml) containing amine 52 was reacted with diisopropylethylamine (2.0 ml, 12 mmol) and 4-fluoro-nitrobenzene (0.60 ml, 5.7 mmol) and stirred at 70 ℃ for 16 h. The reaction mixture was evaporated and purified by flash chromatography (SiO)₂20-50% ethyl acetate/hexanes) to give ethyl ester 503(0.76 g, 2.8 mmol) as a yellow oil

Process 123

Tetrahydrofuran (12 ml) containing ethyl ester 53(0.43 g, 1.6 mmol) was reacted with a solution of methanol (4.0 ml) with a 1.0M aqueous solution of sodium hydroxide (3.1 ml, 3.1 mmol) and stirred at 50 ℃ for 6 hours. The reaction mixture was cooled to room temperature and 1.0M hydrochloric acid (3.1 ml, 3.1 mmol) was added, extracted with dichloromethane (3 × 20 ml), dried (Na)₂SO₃) The reaction mixture was evaporated to give carboxylic acid 54(0.32 g, 1.1 mmol) as a yellow powder

Process 124

A solution of 500a (78 mg, 0.10 mmol) in dichloromethane (1.0 mL) was reacted with carboxylic acid 54(25 mg, 0.10 mmol) and triethylamine (0.042 mL, 0.3 mmol) and O- (7-acetazolamidobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluoro-propyl-ene (57 mg, 0.15 mmol) and the reaction mixture was stirred at 23 ℃ for 4 hours. Evaporation gives a yellow flake which is purified by thin layer chromatography (SiO)₂，5％2M NH₃Methanol/dichloromethane) gave yellow flakes 501(20 mg, 0.02 mmol): LCMS (ESI) M/e 505(M +2H)²⁺

Synthesis of Compounds 504, 505, 507, 508, and 512-515

These compounds were synthesized from amines 500a and 500b and the corresponding carboxylic acids using similar experimental conditions as previously described for compound 501.

Synthesis of Compound 506

To a solution of 500a (50 mg, 0.056 mmol) in dichloromethane (10ml) and Hunig's matrix (0.1 ml) was added 8-nitronaphthalenesulfonyl chloride (0.07 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was allowed to standFollowed by placing on a silica gel column and passing through CH containing 1-3% 2M aqueous ammonia₂CL₂Elution afforded white solid 506(52 mg, 0.052 mmol). LCMS (ESI) M/e535(M +2H)²⁺

Synthesis of Compounds 509, 510 and 511

Compounds 509, 510 and 511 were synthesized from amines 500a and 500b using conditions similar to those of compound 506.

Example 8 Synthesis of Compounds 525-529

TABLE 9

Thiazoles related to the compounds of Table 9 were prepared from alkylated 3' -N-demethylazithromycin 2 with 4- [ 2-bromoethane ] thiazole via scheme 125 and the synthetic method of compound 529, described below.

Process 125

Synthesis of 4-aminophenylacetamide 55a

To a solution of 4-nitrophenylacetamide 55(3.2 g, 1.78 mmol) in methanol (50 ml) was added 10% Pd-C (0.32 g), and the reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen for 24 hours. Pd-C was removed by filtration. The filtrate was evaporated to give 55 a.

¹HNMR(300MHz，CDCl₃-CD₃OD)：δ7.06(d，J＝8Hz，2H)，6.72(d，J＝8Hz，2H)，3.41(s，2H).

Synthesis of Azide 55b

Azide 55b was prepared from 55a by the procedure for the preparation of azide 14 au. The yield is 44%;

¹HNMR(300MHz，CDCl₃-CD₃OD)：δ7.20(d，J＝6Hz，2H)，6.94(d，J＝63.45(s，2H).

synthesis of Azide 55c

A solution of azide 55b (640 mg, 3.64 mmol) and trimethylacetylene (700 mg, 7.14 mmol) in DMF (25 ml) was heated to 90 ℃ for 48 hours. The reaction mixture was evaporated and dried in vacuo. The residue was dissolved in THF (15 ml). TBAF (1.0M in THF, 7.5 ml, 7.5 mmol) and acetic acid (220 ml, 3.6 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. The residue after THF removal was a suspension in water and stirred for 15 minutes. Filtration afforded 55c as a white solid (596 mg, 81% yield).

¹HNMR(300MHz，CDCl₃-CD₃OD)：δ8.01(d，J＝1Hz，1H)，7.69(d，J＝1Hz，1H)，7.57(d，J＝8Hz，2H)，7.33(d，J＝8Hz，2H)，3.45(s，2H).

Synthesis of thiocarboxamide 55d

A mixed solution of 55c (180 mg, 0.89 mmol) and Lawesson's reagent (288 mg, 0.71 mmol) in THF (3 ml) was refluxed under argon for 2 hours. Then the reaction mass is taken up with CH₂CL₂Diluting, washing with brine and MgSO₄Dried and concentrated in vacuo. By chromatography (25: 1: 0.1/CH)₂CL₂∶MeOH∶NH₃·H₂O) gave crude 55d (150 mg, 77% yield).

¹HNMR(300MHz，CDCl₃-CD₃OD)：δ8.01(s，1H)，7.75(s，1H)，7.62(d，J＝8Hz，2H)，7.44(d，J＝8Hz，2H)，3.96(s，2H).

Synthesis of thiazole 55e

In the presence of 55dTo a solution of (165 mg, 0.72 mmol) in THF (8 ml) and MeOH (2 ml) was added 1, 4-bromobutanone (130 mg, 0.60 mmol). After refluxing for 2 hours with CH₂CL₂Diluted and saturated NaHCO₃Rinsing (MgSO)₄Dried and concentrated. By chromatography (25: 1: 0.1/CH)₂CL₂∶MeOH∶NH₃·H₂O) gave crude 55e (165 mg, 79% yield).

¹HNMR(300MHz，CDCl₃-CD₃OD)：δ7.92(d，J＝1Hz，1H)，7.76(d，J＝1Hz，1H)，7.64(d，J＝9Hz，2H)，7.39(d，J＝9Hz，2H)，6.87(s，1H)，4.29(s，2H)，3.63(t，J＝7Hz，2H)，3.22(t，J＝7Hz，2H).

Synthesis of 529

A solution of 55e (150 mg, 0.43 mmol), N-demethylazithromycin 2(276 mg, 0.363 mmol), Hunig's matrix (4 ml) and KI (300 mg, 1.81 mmol) in THF (10ml) was refluxed for 8 hours. THF was removed in vacuo and the residue was dissolved in CH₂CL₂In (1). The solution was washed with brine, MgSO₄Dried and concentrated. By chromatography (25: 1: 0.1/CH)₂CL₂∶MeOH∶NH₃·H₂O) gave product 529(255 mg, 71% yield).

MS(ESI)：1003.4(M+H)⁺，502.5(100％).¹HNMR(300MHz，CDCl₃，partial)δ7.92(s，1H)，7.78(s，1H)，7.64(d，J＝8Hz，2H)，7.42(d，J＝8Hz，2H)，6.78(s，1H)，4.38(d，J＝7Hz，1H)，4.29(s，2H)，3.26(s，3H)，2.28(s，3H)，2.25(s，3H).

The remaining compounds in Table 9 were prepared from 3' -N-demethylazithromycin 2 with the corresponding 4- [ 2-bromoethyl ] thiazole substituent using the procedure described above for compound 529.

EXAMPLE 9 Synthesis of Compound 550-556

Process 126

Synthesis of 2-azidoethanol (56)

2-Bromoethanol (2 mL, 26.8 mmol) and NaN₃The mixed solution (3.48 ml, 53.6 mmol) was heated to 70 ℃ for 12 hours, and then poured into a mixed solution of ether and water (150 ml, 1: 1). The organic layer was separated and the aqueous layer was extracted with ether (2 × 30 ml). The organic layer was washed with water (1 × 100 ml), dried and carefully reduced in volume, without further purification, for further use.

Synthesis of 2-azidoethylmethanesulfonate (57)

Methanesulfonyl chloride (3.1 ml, 40.2 mmol) was added to solution 2(26.8 mmol) and triamine (5.6 ml, 40.2 mmol) in dichloromethane (50 ml) at 0 ℃ and stirred at room temperature for 12 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with saturated bicarbonate solution (2 × 100 ml). The solution is treated with anhydrous Na₂SO₄Dried, filtered and carefully concentrated until the volume is reduced and ready for further use without further purification.

58 Synthesis

A solution of amine 2(2 g, 2.7 mmol) and 57(8.2 mmol) in THF and Hunig's base (40 mL, 1: 1) was mixed and refluxed for 24 hours. The reaction mixture was concentrated and dissolved in CH₂CL₂(100 ml). The organic layer was washed with brine (2 × 100 ml), dried and concentrated under reduced pressure. By flash chromatography on silica gel (CH)₂CL₂∶2％NH₃MeOH) gave 1 g 58. MS (ESI) M/e 805(M + H)⁺。

Synthesis of 59a-c, 59d and 59 g:

alkynes 59a-c were prepared by methods described in the literature (J.Med.chem, 1996, 39, 904. multidot. 917).

Data of 59 a:¹H NMR(300MHz，CDCl₃)：δ2.29(t，1H)，4.04(dd，2H)，4.68(brs，1H)，6.65(d，2H)，8.14(d，2H).

data of 59 b:¹H MR(300MHz，CDCl₃)：δ2.32(t，1H)，4.09(dd，2H)，4.90(brs，1H)，6.79(t，1H)，7.93(dd，1H)，8.06(dd，1H).

data of 59 c:¹H NMR(300MHz，CDCl₃)：δ2.27(t，1H)，3.02(s，3H)，4.01(dd，2H)，4.53(brs，1H)，6.73(d，2H)，7.75(d，2H).

alkyne 59d reaction by 4-dimethyl sulfoxide phenol with propargyl bromide in K₂CO₃The alkylation synthesis in (1).

¹H NMR(300MHz，CDCl₃)：δ2.58(t，1H)，3.04(s，3H)，4.78(d，2H)，7.11(d，2H)，7.89(d，2H).

59g of alkyne: 4-Nitrophenol (1 g, 7.2 mmol), 4-pentyne-1-ol (0.775 mL, 7.9 mmol) and Ph at 0 deg.C₃P (2.2 g, 8.28 mmol) in THF was added DIAD (2 ml, 7.9 mmol) and stirred at room temperature for 24 h. The solution was concentrated and the residue was dissolved in diethyl ether (75 ml). The ether layer was washed with brine (1x50 ml), 1N NaOH (1x50 ml) and water (1x50 ml). Drying the remaining solution (anhydrous NaSO)₄) Concentrated, then purified by flash chromatography on silica gel (20% EtOAc-hexanes). After titration with diethyl ether, 1 g of an off-white solid 59 was isolated.

¹H NMR(300MHz，CDCl₃)：δ1.99(t，1H)，2.03-2.09(m，2H)，2.44(dt，2H)，4.18(t，2H)，6.97(d，2H)，8.22(d，2H).

Synthesis of 550-556

The general method is as follows:

to a mixed solution containing 59a-g (0.0746 mmol), 58(0.0622 mmol) and CuI (0.0746 mmol) was added THF (5 ml) under argon. Then a small amount of Hunig's matrix was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was diluted with a solution containing 20% NH₃NH of OH₃The saturated solution of OH (25 ml) was cooled and stirred at room temperature for 30 min. The mixture was extracted with dichloromethane (3 × 50 ml) and the combined organic extracts were extracted with 10% NH₃NH of OH₃Saturated solution of CL (2 × 50 ml) was rinsed. Using anhydrous NaSO for the rest solution₄Dried, concentrated and purified by TLC (first using: CH)₂CL₂∶2％NH₃-MeOH 10: 1 followed by EtOAc: Et₃N8: 2) gave pure 550-556.

Data of 555: yield 50%. MS (ESI) M/e 981(M + H)⁺，491(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.91(m，6h)，0.94(d，2H)，3.21(t，1H)，3.3(s，3H)，4.05(t，1H)，4.26(brs，1H)，4.36(d，1H)，4.44(t，2H)，4.51(d，2H)，4.68(d，2H)，5.12(d，2H)，5.2(brs，1H)，6.61(d，2H)，7.67(s，1H)，8.14(d，2H).

551 data: yield 60%. MS (ESI) M/e999 (M + H)⁺，500(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.90(m，6H)，0.91(d，3H)，3.29(s，3H)，4.57(d，2H)，5.15(d，1H)，5.30(brs，1H)，6.76(t，1H)，7.70(s，1H)，7.89(dd，1H)，7.99(dd，1H).

Data of 550: yield 50%. MS (ESI) M/e 1014(M + H)⁺，507(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.87(d，3H)，0.91(d，3H)，1.09(d，3H)，3.32(s，3H)，3.61(d，1H)，4.66(d，1H)，4.99(t，1H)，5.11(d，1H)，6.68(d，2H)，7.63(s，1H)，7.70(d，2H).

552 of data: yield 55%. MS (ESI) M/e 1015(M + H)⁺，508(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.91(m，6H)，0.99(d，3H)，3.28(s，3H)，3.64(d，1H)，3.67(s，1H)，4.05(m，1H)，4.25(d，1H)，4.38(d，1H)，4.45(t，1H)，4.70(d，1H)，5.11(d，1H)，5.27(s，2H)，7.12(d，2H)，7.81(s，1H)，7.86(d，2H).

553 of the data: yield 50%. MS (ESI) M/e 935(M + H)⁺，468(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.92(m，6H)，0.99(d，3H)，3.48(s，3H)，3.62(d，1H)，3.66(s，1H)，4.02-4.07(m，1H)，4.35-4.41(m，3H)，4.67(dd，1H)，5.09(d，1H)，7.17-7.31(m，6H).

554 data: yield 40%. MS (ESI) M/e 908(M + H)⁺，455(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.91(m，6H)，0.97(d，3H)，3.25(s，3H)，3.62(d，1H)，3.66(s，1H)，4.05(brt，1H)，4.23(brs，1H)，4.38(d，1H)，4.50(t，2H)，4.67(d，1H)，5.11(d，1H)，7.35(dd，1H)，8.17(s，1H)，8.20(d，1H)，8.56(d，1H)，8.98(s，1H).

Data of 556: yield 90%. MS (ESI) M/e 1010(M + H)⁺，505.5(M+2H)⁺；¹H NMR(300MHz，CDCl₃，partial)：δ0.86-0.91(m，6H)，0.94(d，3H)，3.30(s，3H)，4.12(t，2H)，4.26(t，2H)，4.27-4.42(m，3H)，4.67(dd，1H)，5.05(d，1H)，6.96(d，2H)，7.42(s，1H)，8.20(d，2H).

Synthesis of Azide 14a-14gm

The azide compounds 14a-14gm shown in Table 11 were generally synthesized from several compounds of the present invention including 101-280, 301-357, 401-417, 425-451 and 460-466. These azide compounds are synthesized by known methods described in the literature. Specific examples are listed below. The remaining compounds of table 11 were synthesized by similar methods from the corresponding commercially available starting materials.

TABLE 11

Scheme 127 Synthesis of Azide 14au

Synthesis of 14au

An acetic acid solution (3.0 ml) containing florfenicol (0.090 g, 0.25 mmol) was reacted with sulfuric acid (10%, 15ml) and heated to 110 ℃ for 12 hours. The reaction mixture was then cooled to room temperature, adjusted to pH 14 by the addition of 10M aqueous sodium hydroxide and extracted with dichloromethane (3X30 ml) and NaSO₄Drying and evaporation gave florfenicol amine 60(65 mg, 0.25 mmol) as a yellow oil.

A solution of florfenicol amine 60(0.90 g, 3.6 mmol) in water (10mL) and methanol (30 mL) was reacted with triethylamine (1.5 mL, 10.8 mmol) and methylsulfonyl trifluoro ether azide (13.4 mmol dissolved in 20mL of dichloroethane; the solution was prepared according to the procedure described in J.Am.chem.Soc.2002, 124, 10773) and stirred at 0 deg.C for 3 hours and then heated to 23 deg.C for 1 hour. The reaction mixture was diluted with water (30 ml), extracted with dichloroethane (30 ml) and evaporatedAnd (4) sending. Purification by flash chromatography (SiO)₂50-100% ethyl acetate/hexanes) gave azide 14au (0.65 g, 2.4 mmol) as a yellow solid.

Scheme 128 Synthesis of Azide 14s

Synthesis of Azide 14s

A solution of D- (-) -isobide-2-amino-1- (4-nitrophenyl) -1, 3-propanediol (0.42 g, 2.0 mmol) in water (5 ml) and methanol (17 ml) was reacted with triethylamine (0.84 ml, 6 mmol) and methylsulfonyl trifluoro-ether azide (3 mmol dissolved in 5ml of dichloroethane; this solution was prepared according to the method described in J.Am.chem.Soc.2002, 124, 10773) and stirred at 23 ℃ for 3 hours. The reaction mixture was diluted with water (30 ml), extracted with dichloroethane (30 ml) and evaporated. Purification by flash chromatography (SiO)₂50-100% ethyl acetate/hexanes) gave azide 14s (0.28 g, 1.2 mmol) as a yellow solid.

Scheme 129 Synthesis of Azide 14bq

Synthesis of Azide 14bq

In a solution containing 4-nitrophenylalanine (4.6 g, 20 mmol) and NaBH₄(3.2 g, 84 mmol) in THF (50 mL) was added BF₃OEt (14.8 ml, 106 mmol) stirred at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was then cooled to 0 ℃ and quenched with methanol. The reaction mixture was filtered and concentrated by filtration to give a solid residue. Dissolve 10% of the residue in water (5 ml), methanol (methanol20 ml) and triethylamine (0.9 ml). Azidotrifluoromethanesulfonic acid (triflic azide) solution (3.5 mmol dissolved in 7 ml dichloroethane; prepared according to the method described in J.Am.chem.Soc.2002, 124, 10773) was added and stirred at room temperature for 14 hours. The reaction mixture was diluted with aqueous dichloroethane (30 ml) and saturated NaCO₃And a saline flush. The organic extracts were dried, filtered and concentrated to give 14bq (150 mg) as a white solid.

Synthesis of Azide 14ed

Process 130

A solution of acetonitrile (15.0 mL) containing florfenicol (0.494 g, 1.38 mmol) was reacted with carbon tetrabromide (0.594 g, 1.66 mmol) and triphenylphosphine (0.434 g, 1.66 mmol) and stirred at 23 deg.C for 12 h. The reaction mixture was then evaporated to give a yellow residue which was purified by flash chromatography (SiO)₂10% ethyl acetate/dichloromethane) to yield 61(0.28 g, 0.67 mmol) as a white powder.

Process 131

A solution of 61(0.20 g, 0.41 mmol) in methanol (5.0 mL) was reacted with 10% palladium on charcoal (20 mg) and stirred in a hydrogen chamber at 23 deg.C for 2 hours. The reaction mixture is then filtered, evaporated and purified by thin layer chromatography (SiO)₂10% ethyl acetate/dichloromethane) to yield white flake 62(90 mg, 0.67 mmol).

Process 132

An acetic acid solution (3.0 ml) containing 62(90 mg, 0.26 mmol) was reacted with a 10% sulfuric acid (15ml) solution and heated to 110 ℃ for 12 hours. The reaction mixture was then cooled to room temperature, adjusted to pH 14 by the addition of 10M aqueous sodium hydroxide and extracted with dichloromethane (3X30 ml) and NaSO₄Drying and evaporation gave crude 63 as a yellow oil. A solution of the crude amine (83 mg) in methanol (3.6 ml) and dichloromethane (3.0 ml) was cooled to 0 ℃ and heated to 23 ℃ with triethylamine (0.14 ml, 1 mmol) and azidotrifluoromethanesulfonic acid (1.2 ml of 0.3M dichloromethane). After 2 hours, the reaction mixture is then evaporated and purified by thin layer chromatography (SiO)₂10% ethyl acetate/dichloromethane) to yield colorless oil 63(60 mg, 0.23 mmol).

Synthesis of Azide 14ag

Azide 14ag was synthesized from 1S, 2S 2-amino-1- (4-methylsulfonyl-phenyl) -propane-1, 3-diol using the procedure described for azide 14 bq.

Azide compounds 14a, 14t, 14u, 14at, 14aw, 14ax, 14ay, 14df, 14ds, 14dv, 14dw, and 14dz were synthesized using the Mitsunobu pathway of scheme 133 and the method of azide compound 14dw described in the examples below.

Scheme 133 Synthesis of Azide 14dw

To a mixed solution (10ml) of THF containing ethyl salicylate (1.0 g, 6.0 mmol), 2-bromoethanol (0.445 ml, 6.06 mmol), and triphenylphosphine (1.8 g, 6.9 mmol) was added DIAD (1.4 ml, 6.60 mmol) at 0 ℃. The reaction mixture was slowly warmed to room temperatureAnd stirred for 2 hours. The reaction mixture was concentrated and dissolved in diethyl ether (50 ml). Then washed with brine (3 × 50 ml) and dried (NaSO)₄) Concentration and purification by flash chromatography (silica gel, 5% ethyl acetate/hexanes) gave 0.8 g of intermediate bromoethyl ether. Bromoethyl ether (0.678 g, 2.4 mmol) was dissolved in DMF (5 ml) and sodium azide (0.473 g, 7.2 mmol) was added. The mixture was heated to 70 ℃ for 2-3 hours with an oil bath. Diluted with ether (50 ml), washed with water (4X50 ml), anhydrous NaSO₄Drying, and concentrating under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 0.52 g of pure azide 14dw (89%).

Synthesis of Azide Compounds 14a, 14t, 14u, 14at, 14aw, 14ax, 14ay, 14df, 14ds, and 14dz

These compounds were synthesized by the method described for azide compound 14 dw.

Synthesis of Azide 14dv

The compound is synthesized by ethyl salicylate and azide 14dw, except that 3-bromopropanol is replaced by 2-bromoethanol.

Synthesis of Azide Compounds 14dg, 14dh, 14di, 14dj, and 14dn

These azide compounds are synthesized from the corresponding aminobenzenes by diazotization of 14dg as shown in scheme 134 and the examples below.

The process 134: synthesis of Azide 14dg

Synthesis of Azide 14dg

3-Nitro aniline 4(2.00 g, 14.20 mmol) was stirred vigorously at room temperature under 10% HCl (80 mL) until completely dissolved. The solution is added inCooling to 0 deg.C in ice-water bath, and adding NaNO₂(1.13 g, 16.33 mmol) and stirred for 30 minutes. Will contain NaN₃An aqueous solution (20 ml) (1.39 g, 21.3 mmol) was added dropwise and stirred for an additional 1 hour. EtOAc (120 ml) was added to the suspension and the two layers separated. The organic layer was washed with 10% HCl (100 mL), saturated NaHCO₃(100 ml), extracted once with saturated brine (100 ml) and then with NaSO₄And (5) drying. Evaporation of the solution gave 14dg (2.27 g, 97%)

Synthesis of Azide Compounds 14dg, 14di, 14dj, and 14dn

These azides were synthesized from the corresponding aminobenzenes by conditions of 14 dg.

Azide 14z was synthesized from azide 14v by the sequence depicted in scheme 135.

The process 135: synthesis of Azide 14z

Synthesis of Azide 14z

Azide compound 14(0.66 g, 3.43 mmol) and 1-butyn-4-ol (0.32 ml, 4.12 mmol) were subjected to cycloaddition in THF (20 ml) and Hunig's base (10ml) in the presence of CuI (0.668 g, 3.43 mmol) to give compound 15 within 3 hours at room temperature. The crude product 15 was reacted with EtOH (15mL) containing Pd/C (0.10 g, 10% wt, Degussa) under hydrogen 9 (gas cell) and then with NaNO-containing solution₂(0.14ke, 2.0 mmol) 10% HCl (20 mL) and reacted with NaN₃(0.17 g, 2.6 mmol) of water (1.0 ml) was subjected to the azide reaction using the method described for azide 14dg to give crude azide 14 z.

Azide 14aa was synthesized according to the procedure outlined in scheme 136.

The process 136: synthesis of Azide 14 aa.

Synthesis of Azide 14 aa:

4-Azidophenethyl alcohol (0.6 g, 3.68 mmol) was dissolved in anhydrous THF (15mL), DMF (5 mL) and triethylamine (Et)₃N) (0.54 ml, 3.7 mmol). The solution was cooled to 0 ℃ in an ice-water bath, MsCL (0.30 ml, 3.7 mmol) was added and stirring was continued for 2h at 0 ℃. The reaction was cold-soaked with water (1ml) and concentrated in vacuo. Then EtOAc (60 mL) and saturated NaHCO were added₃(40 ml) the two layers were separated. The aqueous layer was washed with EtOAc (2X40 mL) and the combined organic layers were NaSO₄Drying and evaporation of the solution gave the methanesulfonic acid derivative as a brown solid. The crude mesylate product was reacted with propargylethanol (0.40 ml, 6.83 mmol) in the presence of CuI (0.54 g, 2.84 mmol) in THF (10ml) and Hunig's base (1ml) at rt for 12 h. The reaction was carried out as described for 14 v. To the crude DMF solution (10mL) was added NaN₃(0.96 g, 14.7 mmol) and the mixture was heated to 85 ℃ for 6 hours. The solution was filtered and evaporated. The residue was azide reacted with water (30 ml) and 5% MeOH in EtOAc (40 ml). The aqueous layer was extracted with EtOAc (5 × 20 ml) containing 5% MeOH, and the combined organic layers were NaSO₄The solution was dried and evaporated. The crude product was purified on silica gel, CH₂CL₂Elution with MeOH 17: 1 afforded 14aa (0.51 g, 57%) as a solid azide.

Flow 137: synthesis of Azide 14af

Synthesis of Azide 14 af:

cyanoethanol 65(0.65 g, 4.42 mmol), imidazole (0.67 g, 9.73 mmol) and DMAP (0.05 g, 0.44 mmol) were dissolved in anhydrous THF (20 ml). TBSCI (0.70 g, 4.65 mmol) was added to the solution and stirring continued for 3 hours, TLC indicated the consumption of 65. Will CH₂CL₂(60 mL) was added to the mixture and saturated NaHCO₃(1X30 ml) and saturated brine (1X30 ml) and extracted with NaSO₄And (5) drying. The solution was evaporated and a colorless oil was obtained.

To an isopropanol (15ml) solution containing the crude product were added potassium carbonate (0.28 g, 2.04 mmol) and hydroxylamine hydrochloride (0.29 g, 4.08 mmol), and then the mixed solution was heated under gentle reflux (about 100 ℃ C.) for 24 hours. The actual structure of the baseline product is indicated by TLC, except for the new product (Rf ═ 3.1, CH)₂CL₂MeOH 30: 1). The reaction was filtered and the solution was evaporated to give a white solid. MS (ESI) analysis confirmed carboxami-doxime 66(M + N)⁺295.1) and the corresponding TBS-deprotected product (M + N)⁺181.0) is about 1: 1.

Half of the crude product 66 (ca. 2.2 mmol according to 65) was dissolved in THF (10ml) and Hunig's matrix (5 ml). Anhydrous acetic acid (1.05 ml, 11.0 mmol) was added to the solution and the mixture was heated to reflux for 3 hours. The solution was evaporated, the residue was in CH₂CL₂(40 mL) and saturated NaHCO₃(30 ml) in a medium. The two layers were separated and the organic layer was saturated NaHCO₃(2 × 30 ml), extracted with saturated brine (1 × 30 ml) and extracted with NaSO₄And (5) drying. The solution was evaporated and the crude product was purified on silica gel eluting with EtOAc/Hexanes 1: 8 to 1: 6 to 1: 4 to 1: 3 to give oxadiazole 67(0.040 g, 6%). To a solution of oxadiazole 67(0.039 g, 0.12 mmol) in THF (3 ml) was added BF₃∶0Et₂(0.16 ml, 1.26 mmol) and stirred at 0 ℃. The reaction mixture was warmed to room temperature and stirred continuously overnight. Ethanol addition to consume excess BF₃∶OEt₂And the solution was evaporated. Residue(s)Quilt CH₂CL₂(40 ml) absorb with saturated NaHCO₃(2X25 ml) and extracted with NaSO₄And (5) drying. The crude product obtained after evaporation of the solution was not further purified. The crude product is dissolved in CH₂CL₂(2 mL) and Et₃N (0.05 ml, 0.36 mmol). To the solution was added MsCL (0.04 ml, 0.48 mmol) and stirred at room temperature. Stirring was continued for 2 hours while the reaction solution was in CH₂CL₂(40 mL) and saturated NaHCO₃(30 ml) in a medium. The two layers were separated and the organic layer was saturated NaHCO₃(2 × 30 ml), extracted with saturated brine (1 × 20 ml) and extracted with NaSO₄And (5) drying. The solution was evaporated and the crude product was dissolved in DMF (3 mL), NaN₃(0.10 g, 1.5 mmol) and heated to 55 deg.C overnight. Diethyl ether (50 ml) was added and the solution was saturated NaHCO₃(3 × 30 ml), extracted with saturated brine (1 × 30 ml) and extracted with NaSO₄And (5) drying. The solution was evaporated. The crude product was purified on silica gel, CH₂CL₂MeOH s 120: 1 elution afforded 14af (0.018 g, 66% yield) as a colorless, concentrated oil azide.

The process 138: synthesis of Azide 14x

Synthesis of Azide 14x

Containing α -bromo-p-tolylcyanide (196 mg, 1 mmol), NH₄CL (107 mg, 2 mmol) and NaN₃A solution of (260 mg, 4 mmol) in DMF (2 ml) was heated to 120 ℃ for 8 h. Reacting with CH₂CL₂And (4) eluting. The inorganic salts are removed by filtration and the remaining solution is concentrated and purified by flash chromatography (10: 1: 0.1/CH)₂CL₂∶MeOH∶NH₃·H₂O) gave azide 20(180 g, 90% yield).

Flow 139: synthesis of azide 14bp

Synthesis of azide 14bp

Contains acutangula 68(700 mg, 3.1 mmol), NH₄CL (332 mg, 6.2 mmol) and NaN₃A solution of (808 mg, 12.4 mmol) in DMF (5 ml) was heated to 120 ℃ for 4 h. Reacting with CH₂CL₂And (4) eluting. The inorganic salts are removed by filtration and the remaining solution is concentrated and purified by flash chromatography (10: 1: 0.1/CH)₂CL₂∶MeOH∶NH₃·H₂O) gave azide 14dp (600 g, 90% yield).

The process 140: synthesis of Azide 14bd

Synthesis of Azide 14bd

A solution of p-toluenesulfonamide (6.84 g, 40 mmol), N-bromosuccinimide (7.12 g, 40 mmol) and benzoyl peroxide (0.29 g, 1.2 mmol) in carbon tetrachloride (100 mL) was refluxed for 3 hours. The reaction mixture was concentrated and the residue was extracted with EtOAc. The obtained crude product is added into CH₂CL₂Obtained by crystallization was 69(2.60 g, 26% yield). Will contain 69(150 mg, 0.6 mmol) and NaN₃A solution of (156 mg, 2.4 mmol) in DMF (2 ml) was heated to 80 ℃ for 6 h. The reaction was then eluted with ethyl acetate, washed with brine, and then with NaSO₄Drying and evaporation gave azide 14bd (110 mg, 86% yield).

The process 141: synthesis of Azide 14bz

Synthesis of Azide 14bz

Azide 14bz was prepared by 14bd synthesis from the reaction of bromide 28 and sodium azide in 90% yield. Bromide 28 was prepared by 17 synthetic methods from the reaction of N- (2-hydroxyethyl) -p-toluenesulfonamide and N-bromosuccinimide, in 23% yield.

Synthesis of Azide 14bm

Azide 14bm was synthesized from 2-fluoro-sulfonamido toluene according to the preparation method of 14bd described above.

Synthesis of Azide 14bh

Azide 14bh was synthesized from 3-fluoro-4-sulfonamido toluene according to the preparation method of 14bd described above.

Synthesis of Azide 14bo

Azide 14bo was synthesized from 1-p-tolyl-acetyltoluene according to the preparation method of 14bd described above.

Synthesis of Azide 14cm

Azide 14cm was synthesized from 4-dimethylaminosulfonyltoluene according to the preparation method of 14bd described above.

Synthesis of Azide 14cn

Azide 14cn was synthesized from 4-methylaminosulfonyltoluene according to the above preparation method of 14 bd.

Synthesis of Azide 14cr

Azide 14cn was synthesized from 3- (2-fluoro-4-methyl-phenyl) -5-hydroxymethyl-oxyphenbutazone-2-1 according to the preparation of 14bd above.

Synthesis of Azide Compound 14cp

Azide 14cp was synthesized from N- [3- (2-fluoro-4-methyl-phenyl) -2-oxo-hydroxy-phenylbutazone-5-monomethyl ] -acetazolamide according to the preparation of 14bd above.

Synthesis of Azide 14bl

Azide 14bl was synthesized from 3-methoxy-4-sulfinylaminotoluene according to the preparation method of 14bd described above.

Synthesis of Azide 14ca

Azide 14ca was synthesized from p-toluamide and N-bromosuccinimide with sodium azide according to the preparation method of 14bz described above. The yield was 40%.

The process 142: synthesis of Azide 14cb

Synthesis of Azide 14cb

Methanesulfonyl chloride (1.7 ml, 22 mmol) was added to a solution containing 4-aminophenethylethanol (1.37 g, 10ml) and Et at 0 deg.C₃N (2.5 g, 25 mmol) CH₂CL₂(20 ml). The reaction mixture was stirred at 0 ℃ for 2 hours, and the reaction mixture was washed with brine, MgSO₄Dried and concentrated to give 69b (2.6 g, 89% yield).

Azide 14cb was synthesized from di-sensitized rana 69b and sodium azide according to the preparation method of 14bd described above. The yield was 90%.

Synthesis of 14cq azide

Azide 14cq was synthesized from acetic acid 3- [ 2-fluoro-4- (2- (hydroxy-ethyl) -phenyl) -2-oxo-hydroxy-phenylbutazone-5-monomethyl ester by the previously described preparation of azide 14 cb.

Azidation 14cs was synthesized from 4-bromomethylphenylacetic acid by the method of scheme 143.

Flow 143: synthesis of Azide 14cs

Synthesis of 14cs Azide

4-Bromomethylphenylacetic acid (1.15 g, 5 mmol) with NaBH₄BF3-OEt was reacted under conditions for the synthesis of azide 14 b. Crude p-bromomethylphenylethanol was reacted with propargylamine hydrochloride (0.85 g, 9.3 mmol) in Hunig's matrix at room temperature for 2 hours. The reaction mixture was concentrated and the crude residue was dissolved in a 2: 1TF mixture of water (30 mL) and then reacted with t-butoxycarbonyl (Boc) anhydride (1.1 g) and K₂CO₃The reaction was carried out for 12 hours. The reaction mixture was partitioned between water and EtOAc, the organic layer was dried, filtered and concentrated to give a residue which was purified by TLC (15: 1: 0.1 CH)₂CL₂∶MeOH∶NH₄OH elution) to yield 0.89 g of intermediate 13 cs. Alkyne 13cs (0.62 g, 2.15 mmol) is the corresponding triazole by reaction with sodium azide and NHCL under the aforementioned synthesis conditions of 14 dp. Triazole was synthesized with methanesulfonyl chloride and azide under the following conditions for 14dx synthesis as colorless oil azides 14 cs.

The azide 14o-14r was synthesized from the corresponding phenyl isocyanate with 2-bromoethanol by ionic substitution of the azide. A typical preparation of 14o azide follows.

Process 144

Synthesis of 14o azide

Bromoethanol (2 ml, 29.2 mmol) was added to a stirred toluene containing 3-fluorophenyl isocyanate (2 g, 14.6 mmol). Adding the reaction mixtureHot reflux for 7 hours. It was then eluted with ether (100 ml) and washed with water (3 × 100 ml). After organic extraction, drying, filtration and concentration, the residue was dissolved in DMF (30 ml). Adding NaN₃(2.5 g, 30.5 mmol) and the reaction mixture was stirred at 70 ℃ for 4 hours. The reaction mixture was partitioned between ether and water. The organic layer was separated and washed with water (3 × 100 ml), then dried and concentrated. The crude product was purified by silica gel chromatography (eluting with 9: 1 Hexane EtOAc) to give 14o (2.4 g) as a white solid.

Azides 14p, 14q, 14r were synthesized from the corresponding isocyanates under the same conditions as azide 14 o.

Azide 14ar was synthesized from 4- (2-bromoethyl) benzoic acid in the manner described in scheme 145.

The process 145: synthesis of Azide 14ar

Synthesis of Azide 14ar

DMF (10mL) containing 4- (2-bromoethyl) benzoic acid (1.0 g, 4.40 mmol) and sodium azide (0.72 g, 11.0 mmol) was heated to 80 ℃ and stirred for 12 hours. After evaporation of the solution, the residue was suspended and acidified by adding a small amount of acetic acid dropwise to cold water (40 ml). The suspension was filtered and the residue was washed with cold water (40 ml), acidified by addition of a small amount of acetic acid and dried in vacuo at 40 ℃ to give the carboxylic acid as a white solid (0.8 g, 95%) (Rf ═ 0.51, EtOAc/Hexanes/MeOH 4: 1: 0.02).

To an aqueous solution of the carboxylic acid (0.70 g, 3.87 mmol) in THF (8 mL) at 0 deg.C was added 1M BH₃THF (12 ml, 12.0 mmol). After stirring at 0 ℃ for 2 hours, the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 14 hours. TLC (visualization with ninhydrin stain) shows azide compound reductionThis occurs. Then NaBH is added₄(0.46 g, 12 mmol) and BF₃∶OEt₂(1.6 ml, 12 mmol) and stirring continued for 18 hours to ensure complete reduction of the azide. Excess boron trifluoride etherate was consumed by ethanol and the mixture was filtered. The filtrate was evaporated to a semi-solid. The crude product was reacted with fresh azide trifluoride (12 ml) by azide 14s synthesis. The crude product was purified on silica gel eluting with 2: 3 EtOAc/Hexane to give 4- (2-azidoethyl) -phenyl alcohol (0.56 g, 82%) as a clean oil (Rf ═ 0.53, EtOAc/Hexane 2: 3).

The resulting mixture was washed with azido alcohol (0.40 g, 2.26 mmol) and Dess-Martin reagent (1.25 g, 2.93 mmol) in CH₂CL₂(15ml) stirred at room temperature overnight. The reaction mixture was washed with 10% Na₂S₂O₃Saturated NaHCO₃(1: 1) (30 ml) cooled and CH added₂CL₂(30 ml) the two layers were separated. The organic layer was treated with 10% Na₂S₂O₃∶NaHCO₃(1: 1) (2X30 mL), saturated NaHCO₃(2X30 ml) Wash with NaSO₄And (5) drying. The residue after evaporation of the filtrate was purified on silica gel eluting with 1: 6 EtOAc/Hexane to give 4- (2-azidoethyl) -phenyl alcohol (0.23 g, 58%) as a clean oil (Rf ═ 0.46, EtOAc/Hexane 1: 4).

DMF (4 mL) and THF (10mL) containing azidoacetaldehyde (0.23 g, 1.31 mmol) and 3-fluoropropylamine hydrochloride (0.25 g, 2.20 mmol) were stirred at room temperature for 30 minutes. Add NaBH (Oac)₃(0.51 g, 2.40 mmol) and stirring at room temperature was continued for 18 h. MeOH (20 ml) was added, the suspension was filtered, and the filtrate was evaporated to give an oily residue. The residue was in CH with 10% MeOH₂CL₂(40 ml) and water (25 ml) and the organic layer was passed over NaSO₄And (5) drying. The filtrate was evaporated and the residue was purified by TLC (2000 micron plates) with 18: 1CH₂CL₂/MeOH(2N NH₃) Elution afforded 14ar azide (0.077 g, 25%) as a yellow oil (Rf ═ 0.34, CH)₂CL₂/MeOH(2NNH₃)18∶1)。MS(ESI)M/E；M+H⁺237.0。

The process 146 is as follows: synthesis of Azide 14dt and 14cz

Synthesis of alcohol 70

In CH containing chloramphenicol (6.26 g, 20 mmol) and t-butyldimethylsilyl chloride (3.32 g, 22 mmol)₂CL₂To (40 ml) was added imidazole (1.70 g, 25 mmol). After stirring at room temperature for 4 hours, the reaction mixture was washed with saturated NaHCO₃The solution was cooled. The organic layer was washed with brine, anhydrous MgSO₄Dried and concentrated under reduced pressure. Purification by flash chromatography (silica gel, hexane: ethyl acetate/6: 1) gave 8.85 g of 70 as white crystals in 96% yield.

Synthesis of Francisella 71

Methanesulfonic chloride (0.32 g, 2.75 mmol) was added dropwise to the solution 70(1.09 g, 2.5 mmol) and Et at 0 deg.C₃N (0.51 g, 5.0 mmol) CH₂CL₂In solution (5 ml). The reaction mixture was stirred continuously at 0 ℃ for 2 hours and at room temperature for 12 hours. The solution was removed under reduced pressure and the residue was dissolved in EtOAc. EtOAc solution was washed with brine, anhydrous MgSO₄Drying and concentration under reduced pressure gave 1.22 g of 71 as a pale yellow oil in 95% yield.

Synthesis of Azide 14dt

A mixed solution (5 ml) of Pquisqual 71(1.32 g, 2.5 mmol) and sodium azide (0.65 g, 10 mmol) in DMF was stirred at 50-60 deg.C for 5 hours. The reaction mixture was cooled with water. The solution was extracted with EtOAc, washed with brine, anhydrous MgSO₄Dried and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane: ethanol)Ethyl acetate/15: 1) to yield 0.75 g of a pale yellow oil 53 in 65% yield. MS (ESI) M/e 460(M-H)⁺。

Synthesis of acetate salt 72

Triethylamine (2.5 mL, 17.9 mmol) was added to CH containing solution 70(3.3 g, 7.6 mmol), anhydrous acetic acid (2.4 g, 23.3 mmol) and 4-dimethylaminopyridine (60mg, 0.49 mmol) at 0 deg.C₂CL₂(30 ml). After stirring at the same temperature for 2 hours, the reaction mixture was taken up with CH₂CL₂Diluted and saturated NaHCO₃Rinsing with anhydrous MgSO₄Dried and concentrated. Purification by flash chromatography (silica gel, hexane: ethyl acetate/6: 1) gave 3.4 g of crude 73 as a white crystalline product in 94% yield.

Synthesis of alcohol 73

To a solution of solution 72(3.59 g, 7.5 mmol) in THF (50 ml) was added THF (7.5 mg, 7.5 mmol) containing 1.0M TBAF. Stir at room temperature under argon for 2 hours. The solution was evaporated and concentrated under reduced pressure, and the residue was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO₄Drying, concentration and purification by chromatography (silica gel, hexane: ethyl acetate/4: 1) gave 2.40 g of 73 as a pale yellow oil in 88% yield.

Synthesis of Pythagorean 74

Triethylamine (1.8 mL, 12.7 mmol) was added to CH containing solution 73(2.32 g, 6.36 mmol) and methanesulfonyl chloride (0.8 g, 7.0 mmol) at 0 deg.C₂CL₂(30 ml). After stirring at the same temperature for 2 hours, the solution was removed under reduced pressure and the residue was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO₄Drying and concentration under reduced pressure gave 2.8 g of 74 as a pale yellow oil in 99% yield.

Synthesis of Azide 14cz

A mixture of Pyland 74(3.0 g, 6.8 mmol) and sodium azide (1.76 g, 27.1 mmol) in DMF was dissolvedThe solution (15ml) was stirred under argon at 60 ℃ for 2 hours. The reaction mixture was cooled with water and the solution was diluted with EtOAc. The organic layer was washed with brine, anhydrous MgSO₄Dried and purified by chromatography (silica gel, hexane: ethyl acetate/4: 1) to give 1.65 g of 57 as a pale yellow solid in 63% yield. MS (ESI) M/e 388(M-H)⁺。

Synthesis of Azide 14cx

The azide was synthesized by the method described in patent application WO2004029066A 3.

Most of the azides shown in Table 11, including those whose details of synthesis are not described in the present text, were synthesized according to known procedures using reactions according to the foregoing schemes. The specific synthetic method for each azide is determined by the commercially available starting materials. When the possible azide formation is substitution by direct displacement of the corresponding bromoalkyl group with an azide ion, the procedure used is an example of the synthesis of azide 14c described below. When the desired bromoalkyl group is not readily available, the compound is derived from substituted alkenols: to achieve this, the alcohols are first substituted as derivatives of their sulfonyl esters and then with azide ions. This procedure is exemplified by the synthesis of azide 14dx described below. If neither the desired bromide nor the alkene is commercially available, the corresponding carboxylic acid is reduced with borohydride to the corresponding alcohol, and the resulting alkene is treated by the above method to give the azide. The conversion of carboxylic acid to azide is achieved by the experimenter through the example of compound 14b described below. Finally, some of the azides shown in Table 11 were synthesized by substitution of the corresponding alkylamines with azidotrifluoromethanesulfonic acid. An example of this procedure provides for the synthesis of azide 14w described below.

The process 147. Synthesis of azides 14c, 14dx, 14d and 14 w.

Synthesis of Azide 14c

To a solution of 4-bromomethylsulfonylbenzene (1 g, 4.0 mmol) in DMF (20 mL) was added NaN₃(0.52 g, 8.0 mmol). The mixture was stirred at room temperature for 1 hour and then 200 ml of a 1: 1 mixture of water and diethyl ether were poured in. The aqueous layer was separated and extracted with ether (2X50 mL) and the organic extract of the mixture was MgSO₄Drying and concentration under reduced pressure gave the crude product. Purification by silica gel chromatography (eluting with 30% EtOAc in hexanes) gave pure azido white solid (0.52 g, 2.5 mmol).

Synthesis of 14dx azide

In CH with 2- (2-hydroxyethyl) pyridine (2 g, 16.2 mmol) and diisopropylethylamine (5.6 ml, 32.4 mg)₂CL₂To the solution (40 ml) methanesulfonyl chloride (1.4 ml, 17.8 mmol) was added at 0 ℃. The mixture was warmed to room temperature and stirred for 3 hours, then cooled with water and CH₂CL₂(30 ml) dilution. NaHCO for organic layer₃Rinse (2 × 50 ml) with MgSO₄Drying and concentration under reduced pressure gave 3.2 g of crude acutangula. This sensitized alvard was converted to azido 14dx by the same method as the bromoether synthesis of ethyl salicylate to 14 dw.

Synthesis of Azide 14d

To a solution of 4-methanesulfonylphenylacetic acid (1 g, 4.7 mmol) in THF (25 mL) was added NaBH₄(0.54 g, 14.1 mmol), BF was added after 5 minutes₃OEt (2.4 ml, 18.8 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was then cooled with MeOH, filtered and concentrated in vacuo, then on CH₂CL₂To form a suspension. The solid was filtered, dried, and redispersed in CH₂CL₂(10ml) to form a suspension. Triethylamine (1.3 ml, 9.4 mmol) was added, followed by MsMCL (0.6 ml,7.0 mmol). After 4 h triethylamine (1.3 ml, 9.4 mmol) was added followed by MsMCL (0.6 ml, 7.0 mmol) and stirring was continued for 16 h. Reaction mixture with CH₂CL₂Diluted (50 ml) and then saturated NaCO₃And washed with brine, MgSO₄Dried, filtered and concentrated.

The crude acutangula was dissolved in DMF (10ml) and NaN was added₃And the reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was partitioned between water and diethyl ether and the aqueous layer was further extracted with diethyl ether (3 × 30 ml). The combined organic extracts were extracted with brine (100 ml), NaSO₄Dried, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 40% EtOAc in hexanes) to give 14d (0.70 g, 12 mmol) as a white solid.

In a few examples in table 11, the synthesis of azides was prepared from the modification of other azides by the synthetic methods described above:

process 148

Synthesis of azide 14bp by azide 14 bo:

HONH was added to a solution of azide 14bo (0.18 g, 1 mmol) in MeOH₂HCL (0.35 g, 5 mmol) and triethylamine (0.35 ml, 2.5 mmol). The mixture was refluxed for 8 hours, then diluted with EtOAc, washed with water and brine. NaSO for organic extraction liquid₄Dried, filtered and concentrated to give 14bp (180 mg) as a white solid.

Synthesis of azide 14bn by azide 14 bk:

azide 14bn was prepared from 14bk by the synthetic process of azide 14 bp.

Flow 149

Synthesis of azide 14bt via azide 14 bq:

the azide 14bt (111 mg, 0.5 mmol) in CH was stirred at-78 deg.C₂CL₂To the solution was added (diethylaminosulfamethoxazole (DAST) (0.1 mL, 0.82 mmol) trifluoride, the mixture was stirred at-78 deg.C for 2 hours, then warmed to room temperature and stirred for 14 hours, the reaction mixture was poured into water and stirred with CH₂CL₂And (4) extracting. The organic extract is treated with NaSO₄Dry, filter, and concentrate to give 14bq (36 mg, 0.16 mmol) as a solid.

Process 150

Synthesis of azide 14ct by azide 14 cs:

while stirring, the mixture was stirred in CH containing azide 14ct (0.21 g)₂CL₂To the solution (10ml) was added 1, 4-dioxane (2 ml) containing 4M HCL, the mixture was stirred at room temperature for 10 hours, and the reaction mixture was concentrated under reduced pressure to give hydrochloride salt as a white solid azidation 14cz (0.15 g).

Process 151

Synthesis of 14ah by 14 ag:

azide 14ah (0.27 g, 1.1 mmol) in CH₂CL₂mCPBA (1.10 g, 4.5 mmol) was added to the solution (15ml), the mixture was stirred at room temperature overnight, the solution was evaporated and the resulting crude product was purified on silica gel with CH₂CL₂the/MeOH 20: 1 to 15: 1 to 12: 1 eluted to give a colorless paste, which was solidified by standing 14ag (0.26 g, 87%) azide.

EXAMPLE 11 Synthesis of Compound 601-630

TABLE 12

Synthesis of Compound 601

Compound 601 was synthesized by the method of scheme 152. The amine 30 of example 3 was prepared according to the procedure described in US patent 6,124,269 to give 2-fluoroamine 30 a. Alkylation with tosylate 11 then occurs under the conditions of example 3 to give fluoroamine 31 a. This compound was reacted with 14bd azide by the procedure of example 1 to obtain compound 601.

Process 152

Compound 602 was synthesized from compound 122 of example 1 and ethylene carbonate by the method of scheme 153.

Process 153

Synthesis of Compound 602

To a solution of 122(0.1 g, 0.1 mmol) in phenol (5 ml) was added K₂CO₃(0.2 g) and ethylene carbonate. The reaction mixture was heated to reflux for 12 hours and then partitioned between water and ether. The ether layer is washed with K₂CO₃Dried, filtered and concentrated to give 0.28 g of an oily residue which is further purified by chromatography on silica gel (2% methanolic ammonia elution) (2M NH)₃) 0.1 g of a white solid 601 is obtained. MS (ESI) M/e 513.2(M +2H)²⁺。

Synthesis of Compound 609

Process 154

A solution of N-demethylazithromycin 2(0.1 g, 0.136 mmol), Pquisqual (0.067 g, 0.15 mmol) and Hunig's base (1ml) in DMF (1ml) was heated to 70 ℃ for 12 hours. The reaction mixture was concentrated and purified by silica gel Chromatography (CH)₂CL₂-MeOH-NH₄OH 20: 1: 0.05) gave 0.055 g 609 (38%). MS (ESI) M/z 1086(M + H)⁺，544(M+2H)⁺。

Synthesis of Compound 610

Flow 155

A mixed solution of acetonitrile (2 ml) containing acylimidazole 75(0.74 g, 1.0 mmol) and water (3 ml) was reacted with hydrazine monohydrate (0.50 ml, 10 mmol) and stirred at 50 ℃ for 1 hour. The reaction mixture was evaporated to give a yellow foam, which was then dissolved in methanol (50 ml) and heated at reflux for 20 h. The solution was evaporated and purified by flash chromatography (silica, 50-100% ethyl acetate/hexanes) to give the alkyne carbodihydrazide 76 as a white powder (0.50 g, 0.75 mmol).

A tetrahydrofuran solution (3.0 ml) containing 76(0.10 g, 0.15 mmol) was reacted with azide 14au (62 mg, 0.22 ml), diisopropylethylamine (0.080 ml, 0.46 mmol), and copper iodide (8.0 mg, 0.042 mmol), while the reaction mixture was stirred at 23 ℃ for 24 hours. The reaction mixture was extracted with ammonium hydroxide (30 ml) and dichloromethane (3 × 30 ml), NaSO₄Drying and evaporating. Purification by thin layer chromatography (SiO)₂10% methanol/dichloromethane then ether) to yield a white solid 610(98 mg, 0.10 mmol): LCMS (ESI) M/e940(M + H)⁺。

Synthesis of Compound 611

Scheme 156 illustrates the synthesis of triazole 611. The 2-penten-4-yn-1-ol is converted to tosylate 77, which is used to alkylate amine 2 to make alkyne 78. Alkyne 78 reacts with azide 14w through cycloaddition to give triazole 611.

Process 156

Synthesis of tosylate 77

To a mixed ether solution (25 ml) containing 2-penten-4-yn-1-ol (0.821 g, 10 mmol) in ice water was added p-toluenesulfonyl chloride (2.0 g, 10.5 mmol) with stirring. Powdered KOH (1.0 g, 17.8 mmol) was added after five minutes. The mucus was stirred at 0 ℃ for 45 minutes. The reaction mixture was poured into 100 ml of water and extracted with diethyl ether (2 × 50 ml). The combined organic extracts were washed with brine, MgSO₄Dried, filtered and concentrated to give 77 as a yellow oil (2.1 g, 98% yield). Data of

¹HNMR(300MHz，CDCl₃)：δ7.80(d，J＝8Hz，2H)，7.35(d，J＝8Hz，2H)，6.12(dt，J＝16，6Hz，1H)，5.70(ddd，J＝16，2，2Hz，1H)，4.60-4.50(m，2H)，2.95(d，J＝2，Hz 1H)，2.45(s，3H)；¹³C NMR(75MHz，CDCl₃)：δ145.1，135.9，132.9，130.0，127.9，113.9，80.3，79.8，69.0，21.66.

Synthesis of enyne (enyne)78

A20 ml vial was charged with tosylate 77(0.20 g, 0.85 mmol) N-demethylazithromycin 2(0.5 g, 0.68 mmol), and Hunig's base (10ml), then purged with argon and sealed. The solution was stirred in an oil bath at 100 ℃ for 1 hour. Cooled to room temperature and the reaction mixture poured into saturated NaHCO₃Aqueous solution (50O ml) and CH₂CL₂(3 × 50 ml) was extracted. Washing the mixed organic extracts with brine, K₂CO₃Dried, filtered and concentrated to give 0.72 g of a viscous yellow oil. Flash chromatography on silica gel (25mm X6 "column, 50: 1 CH)₂CL₂/2N NH₃MeOH elution) gave 78 as a yellow solid (0.48 g, 88% yield). Data MS (ESI) M/e 400.2(M +2H)²⁺，799.3(M+H)⁺，821.2(M+Na)⁺；¹HNMR(300MHz，CDCl₃，partial)：δ8.00(bs，1H)，6.20(dt，J＝16，7，Hz，1H)，5.70-5.60(m，1H)，5.00(d，J＝4Hz，1H)，4.65(m，1H)，4.48(d，J＝7Hz，1H)，4.28(dd，J＝6，2Hz，1H)，4.15-3.99(m，1H)，3.82(d，J＝6Hz，1H)，3.65(d，J＝7 Hz，1H)，3.60-3.40(m，1H)，3.32(s，3H)，3.32-3.20(m，2H)，2.32(s，3H)，2.26(s，3H)，0.86(m，6H)；¹³C NMR(75MHz，CDCl₃)：δ179.3，144.4，111.8，103.8，96.2，85.1，82.6，79.7，79.0，78.5，77.5，75.7，75.3，74.4，73.8，71.9，71.0，69.4，66.5，65.4，62.9，57.0，50.39，45.9，43.4，42.0，37.6，37.5，35.9，31.8，31.2，28.2，27.7，22.8，22.5，22.2，22.0，19.3，17.1，16.3，12.1，10.3，8.6.

Synthesis of triazole 611

To a solution of 78(20 mg, 25. mu. mol) in THF (100. mu.L) was added Hunig's base (20. mu.L), azide 14au (16 mg, 50. mu. mol) and cuprous iodide (2.4 mg, 13. mu. mol) with stirring. The resulting mixed solution was degassed by alternately providing vacuum and introducing argon. The viscous liquid was purged with argon at room temperature and stirred for 4 hours. The whole reaction mixture was placed on top of a flash chromatography silica gel column and washed with 50: 1CH₂CL₂/2N NH₃Eluted with MeOH to give triazole 611 as a white solid (14 mg, 50% yield): MS (ESI) M/z 496.8(M +2H)⁺，992.3(M+H)⁺。

Synthesis of Compound 612

Compound 612 was synthesized from alkyne 27d of example 4 and azide 14au of table 11 using the copper-catalyzed cycloaddition reaction conditions of example 1.

Synthesis of Compound 613

Compound 613 was synthesized from alkyne 27d of example 4 and azide 14b of table 11 using the copper-catalyzed cycloaddition reaction conditions of example 1.

619 Synthesis

A solution of alkyne 611(0.05 g, 0.0504 mmol) in acetone (1.5 ml) -water (0.2 ml) was added to an aqueous solution containing N-methylmorpholine N-oxide (0.13 ml, 50% water) followed by OsO-containing₄Of (2) (0.005 mmol, 0.1M in Bu)^tOH). The remaining solution was stirred at room temperature overnight and with CH₂CL₂(50 ml) and brine (50 ml). The organic layer was separated and washed with brine (2 × 50 ml) and dried (anhydrous NaSO)₄) Concentrated and purified by TLC (CH)₂CL₂∶2％NH₃-MeOH 13: 1). Yield: 20mg (40%). MS (ESI) M/z 1026(M + H)⁺，513.5(M+2H)⁺。

Synthesis of Compounds 614 and 615

Compound 614 was synthesized from compound 411 of example 3 by reaction with hydrochloric acid. Compound 615 was synthesized as shown in scheme 158 from compound 614 by the hydrocarbylation reduction reaction with pyridine-4-carboxyaldehyde.

Process 158

A solution of 0.015 g (0.015 mmol) 614, 0.006 g (0.060 mmol) 1.0 ml DMF containing pyridine 4-carboxyaldehyde was added to 0.007 g (0.030 mmol) NaBH (OAc)₃In (1). The reaction mixture was stirred at 25 ℃ for 4 h, DMF was removed by rotary evaporation and the residue was purified by TLC to give 0.003 g of compound 615. MS (M + 1): 1097.

synthesis of Compound 616

This compound was synthesized by heating Pyvale 82(0.18 g, 0.46 mmol) and amine 2(0.43 g, 0.55 mmol) in DMF (6 mL) and Hunig's under reflux for 20 hours. The solution was evaporated. The crude residue after evaporation of the solution is in CH₂CL₂(50 ml) A suspension was formed and saturated NaHCO was used₃(2 × 30 ml) and saturated brine (1 × 30 ml). Decolorizing the organic layer with decolorizing charcoal and Na₂SO₄And (5) drying. The crude product obtained by evaporating the solution was purified by silica gel column and purified with CH₂CL₂the/MeOH 14: 1: 0.05 to 12: 1: 0.05 to 10: 1: 0.05 eluted to give 616 as a white solid (0.048 g, 10% yield). LCMS; m + H⁺1031.5。

Synthesis of Compound 82

Alcohol 80 is converted to the Ensifold derivative 81 (LC-MS; M + H)⁺322.9)。

Compound 81(0.39 g, 1.21 mmol) was reacted with THF (10ml) containing alkyne 82a (0.13 ml, 2.22 mmol), CuI (0.183 g, 0.96 mmol) and Hunig's base (1ml) at room temperature over 12 hours. The reaction mixture was washed with saturated ammonium chloride (30 ml) and EtOAc (40 ml). The aqueous layer was extracted with EtOAc (4X20 mL) and the combined organic layers were NaSO₄And (5) drying. Evaporating the solution, purifying the crude product on a silica gel column using CH₂CL₂Elution with MeOH 19: 1 to 17: 1 provided alcohol 82 as a white solid (0.171 g, 37% yield). LC-MS; m + H⁺378.8。

Synthesis of Compound 83

This compound was synthesized from compound 80 and alkyne 83a by the method of 82, except that the crude product 83 was not further purified (90% yield, white-yellow solid). LC-MS; m + H⁺392.9。

Process 159

Synthesis of Compound 617

This compound was synthesized by heating a mixture of DMF (4 mL) containing alcohol 83(0.14 g, 0.37 mmol) and amine 2(0.346 g, 0.44 mmol) and Hunig's matrix (2 mL) at 110 ℃ for 24 hThen (c) is performed. Evaporating the solution, purifying the crude product on a silica gel column using CH₂CL₂/MeOH/NH₄OH 20: 1: 0.05 to 18: 1: 0.05 to 15: 1: 0.05 to give alcohol 617 as a white solid (0.173 g, 46% yield). LC-MS; m + H⁺1017.4。

Synthesis of compound 629

Process 160

84 Synthesis of

In CH containing Boc-Hyp (Bz) -OH (321.4 mg, 1.0 mmol), Thr-Ome hydrochloride (155.6 mg, 1.0 mmol), DEC (249.2 mg, 1.3 mmol), and HOBT (202.7 mg, 1.5 mmol)₂CL₂To the solution, Et was added at room temperature with stirring₃N (0.42 ml). The mixture was stirred at room temperature for 3 hours. Water (10ml) was added and the aqueous layer was replaced with CH₂CL₂(20ml x 3). The combined organic layers were washed with brine, MgSO₄And (5) drying. The concentrated residue was purified on silica gel eluting with 1: 9 to 7: 3 EtOAc: hexane to give pure oil dipeptide 84(374.6 mg, 95%).

85 Synthesis

Dipeptide 84(775.0 mg) prepared by the above procedure was dissolved in CH₂CL₂in/TFA (5 ml/5 ml). The mixture was stirred at room temperature for 1.5 hours and concentrated to dryness. The solid residue obtained was dissolved in EtOH (70 ml) and reacted with (CH)₂O)_N(514.5 mg, 17.15 mmol), Pd/C (77.5 mg) under hydrogen (gas cylinder) overnight. The mixture was filtered. The concentrated filtrate was purified on silica gel, eluting with 1: 1 to 1: 0 EtOAc: hexanes, to provide N-methylated dipeptide 85 as a white solid (320.2 mg, 53%).

629 Synthesis

DIBAL (1.0M toluene, 2.1 mL) was added to dipeptide 85(320.2 mg, 1.05 mmol) toluene at-78 deg.C with stirring over 10 minutes. At this temperature, the mixture was cooled with methanol (0.6 ml) after two hours. The reaction mixture was diluted with EtOAc and stirred with saturated sodium potassium tartrate (5.2 ml) at 0 ℃ for 1.5 h. The aqueous solution was then extracted with EtOAc (20ml × 3). The combined organic layers were washed with brine, MgSO₄And (5) drying.

The concentrated residue obtained above was dissolved in 1, 2-dichloroethane (10ml) and combined with demethylazithromycin 2(308.7 mg, 0.42 mmol), and NaBH (OAc)₃(133.5 mg, 0.63 mmol). The mixture was stirred at room temperature for 16 h and then saturated NaHCO was used₃And (6) cooling. The organic layer was separated, washed with brine, MgSO₄And (5) drying. The residue was concentrated and purified on a silica gel column with MeOH/CH ranging from 0: 1 to 15: 85₂CL₂Elution provided 629(105.8 mg, 25%) as a white solid.

Synthesis of Compounds 603, 604, 622, 627 and 628

The synthesis of compounds 603, 604, 622, 627 and 628 is similar to that shown for compound 629, which all include the corresponding dipeptide substitution.

Compound 618 is synthesized by the method illustrated in scheme 161 below

Process 161

Synthesis of intermediate 87

Dipeptide 86(495.9 mg, 2.07 mmol) and Burgess reagent (738.6 mg, 3.10 mmol) were dissolved in THF (15 mL). The reaction mixture was heated to reflux for 3 hours. After the mixture was cooled, water (10ml) was added followed by EtOAc (3)0ml x 3). The organic layer was separated, washed with brine, MgSO₄And (5) drying. The residue was concentrated and purified on a silica gel column, eluting with 0: 1 to 3: 7 EtOAc: hexane, to give the dipeptide (348.1 mg, 76%) as a pale yellow oil, dehydrated.

Synthesis of Compound 618

Compound was prepared from intermediate 87 and amine 2 using the synthesis of intermediate 85 from compound 629 described above.

Synthesis of Compound 630

Process 162

Synthesis of Compound 89

Et was added to a solution of compound 88(2.00 g, 2.54 mmol) in THF (17 mL) at 0 deg.C₃N (1.5 ml, 10.67 mmol), followed by anhydrous acetic acid (946 μ L, 9.91 mmol) and then DMAP (34 mg, 0.25 mmol) were added. The mixture was stirred at 0 ℃ for 3 hours, then Et was added₃N (150 μ L, 1.07 mmol) and anhydrous acetic acid (95 μ L, 0.99 mmol). The mixture was stirred for 3 hours, then MeOH (2.0 ml) was added. The reaction mixture was concentrated and EtOAc (100 ml), saturated NaHCO was added₃Washed (30.0 ml) with brine (30.0 ml) and dried NaSO₄Yield 2.28 g of 89. The residue was not further purified for further reaction. MS (ESI) M/e 913(M + H)⁺。

Synthesis of Compound 90

In the presence of triacetate compound 89(913 mg, 1.00 mmol, crude product), 2-methyl-1, 3-propane- [ di- (tert-butyl) carbonate](865 mg, 3.00 mmol) and 1, 4-bis (diphenylphosphino) -butane (dppb) (305 mg, 0.70 mmol) in THF (10mL, degassed) at room temperature to which was added Pd2(dba)₃(92mg, 0.10 mmol). The reaction mixture was refluxed for 12 hours, concentrated and EtOAc (100 ml), saturated NaHCO was added₃Washed (30.0 ml) with brine (30.0 ml) and dried NaSO₄The residue was chromatographed on silica gel (2% MeOH in CH)₂CL₂Containing 0.2% of NH₄OH) in two steps to give 340 mg of 90 in 35% yield. The residue was not further purified for further reaction. MS (ESI) M/e 966(M + H)⁺。

Synthesis of Compound 91

Compound 90(330 ml, 0.34 mmol) in MeOH (6 ml) was refluxed for 5 days. The residue was passed through FC (CH with 2% MeOH)₂CL₂Containing 0.2% of NH₄OH) was isolated to give 143 mg of 91, 50% yield.

MS(ESI)m/e 839(M+H)⁺。

Synthesis of Compound 630

A solution of compound 91(58 mg, 0.07 mmol) and azide 14w (40 mg, 0.21 mmol), CuI (2 mg) and Hunig's base (3 drops) in THF was mixed and stirred at room temperature for 10 hours. The reaction mixture is reacted by adding NH₄OH (3 drops), saturated NH₄CL (1 drop), water (2 ml) and CH₂CL₂(3 ml) cool. After stirring for 20 minutes, the organic layer was separated and the aqueous layer was replaced with CH₂CL₂(10 ml. times. 3) extraction, NaSO₄Drying and passing the residue through FC (2/100/0.2 MeOH/CH)₂CL₂/NH₄OH) was isolated to give 62 mg 630 in 86% yield. MS (ESI) M/e 1031(M + H)⁺。

Synthesis of Compounds 625 and 626

Flow 163

Synthesis of Compound 92

0.26 g (1.36 mmol) of p-toluenesulfonic acid was added to an ethanol solution containing 1.00 g (1.30 mmol) of tylosin at room temperature, and the reaction mixture was stirred for 3 hours. Then saturated NaHCO₃Aqueous dilution and EtOAc extraction. The combined organic layers were washed with ethyl acetate and brine, MgSO₄Dried and concentrated to give 1.220 g of 92 without further purification.

Synthesis of Compound 93

In 10ml of MeOH/H containing 0.250 g (0.29 mmol) of 92 and 0.486 g (5.92 mmol) of NaOAc₂O (80% MeOH), 0.075 g (0.29 mmol) of solid iodine was added at 55 ℃. After the addition of iodine, the pH was maintained at 9 by adding 1N NaOH to the reaction mixture over time intervals of 10, 30 and 60 minutes. The reaction mixture was stirred at 55 ℃ for 1 hour, and finally NaOH solution was added, followed by saturated NaHCO₃Aqueous 25 ml diluted and EtOAc (50 ml x2) extracted. The combined EtOAc extracts were extracted with 15mL of 5% NaS₂O₄Washing with brine, MgSO₄Dried, filtered and concentrated to give 0.221 g 93.

Synthesis of alkyne 94

A solution of 0.200 g (0.249 mmol) of 93 and 0.270 g (1.20 mmol) of the tosylate salt 11, 0.311 g (2.41 mmol) of diisopropylethylamine and 10mg of dimethylaminopyrimidine in 5ml of THF is stirred at 55 ℃ for 48 hours. The reaction mixture was washed with saturated NaHCO₃Aqueous 20ml diluted and EtOAc (30 ml x3) extracted. The combined organic layers were washed with brine (20 ml), MgSO₄Dried, filtered and concentrated and purified by flash silica gel chromatography to give 0.065 g of product 94 and 0.063 g of reduced starting material 93.

Synthesis of Compound 625

A solution of 0.300 g (0.03 mmol) of the alkyne 94, 0.018 g (0.06 mmol) of the azide 14ez and 0.006 g (0.03 mmol) of ICu in 3 ml of THF is degassed and placed under argon. To this mixture was added 4 drops of Hunig's matrix. The reaction was stirred at 25 ℃ for 6 hours. 20ml of 10% NH was added₄OH, stirring for 10 minutes, using CH₂CL₂Extraction (30 ml x3), combined organic layers washed with brine, dried, concentrated, and purified by TLC to give 0.020 g of final product. MS (ESI) M/e 1145(M + H)⁺。

Synthesis of Compound 626

A solution of 0.0 mL of 0.2NHCL containing 0.015 g (0.013 mmol) of Compound 625 and 1.0 mL of acetonitrile was stirred at 25 ℃ for 4 hours. 15ml of saturated NaHCO was added₃15ml of aqueous solution, aqueous layer with CH₂CL₂Extraction (40 ml x3), combined organic layers washed with brine, dried and concentrated gave 0.003 g of pure product 626. MS (ESI) M/e 1172(M + H)⁺。

Synthesis of Compounds 623 and 624

These compounds were synthesized from intermediate 94 and azide 14w using the procedure described for compounds 625 and 626, above.

Example 12: synthesis of Compound 701-756

Additional compounds of the invention are shown in table 13 below. These compounds were prepared according to the procedures described in examples 1-11 above.

Watch 13

Citations of documents

The entire contents of the patent documents and scientific articles cited in this application are hereby incorporated by reference.

Equivalent content

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing examples are to be considered as further illustrative of the present invention and not in limitation thereof. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (6)

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof,

wherein

T is a 14-, 15-, or 16-membered macrocyclic lactone compound, linked through a carbon atom on the macrocyclic ring;

R¹and R³Independently selected from the group consisting of:

(a)H，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) -C (O) R⁵，(f)-C(O)OR⁵，(g)-C(O)-NR⁴R⁴R⁴R⁴，(h)-C(S)R⁵，(i)-C(S)OR⁵，(j)-C(O)SR⁵，or(k)-C(S)-NR⁴R⁴R⁴R⁴；

R²Is H OR-OR¹²；

D is selected from the following groups:

(a) a single bond, (b) C_1-6Alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) -C (O) -X-, (f) -C (O) O-X-, (g) -C (O) NR⁴R⁴-X-，(h)-C(＝NR⁴)-X-，(i)-C(＝NR⁴)O-X-，(j)-C(＝NR⁴)N-X-，(k)-SO₂-X-，(l)-C(NR⁴)NR⁴-X-，(m)-C(S)-X-，(n)-C(S)NR⁴-X-，(o)-C(NR⁴) S-X-, or (p) -C (O) S-X-,

wherein

_P ⁴(i) D from 0 to 2 carbon atoms of any one of groups (b) to (D) may be optionally substituted with a group selected from O, S (O) and NR,

⁵(ii) any one of (b) to (d) may be substituted with one or more R groups,

^{5 3 5}(iii) when R in (b) to (d) is an optional substituent, R and R may form a 3-to 7-membered ring with the atom to which they are attached, and

_{1-6 2-6 2-6} ⁵(iv) x is selected from the group consisting of (aa) C alkyl, (bb) C alkenyl, (cc) C alkynyl, wherein any of (aa) - (cc) may be optionally substituted with one or more R groups;

F is selected from the following:

_{1-6 2-6 2-6}(a) a single bond, (b) C alkyl, (C) C alkenyl, (d) C alkynyl,

wherein the content of the first and second substances,

_P ⁴(i) 0-2 carbon atoms of any one of groups (b) to (d) of F may be optionally substituted with a group selected from O, S (O) and NR,

⁵(ii) any of (b) to (d) of F may be substituted with one or more R groups,

_1-6 ⁵(iii) any one of (b) to (d) of F may be substituted with a C alkyl-R group;

e is selected from the following:

(a) a 3-to 10-membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(b)3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ring,

(c) w- [3-10 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur ],

(d) w- [3-10 membered, saturated or unsaturated, or aromatic, carbocyclic ],

^{4 4 4 4 4 4 4 4 4 4 4 4 4} _p ⁴ _{2 2} ^{4 4} ₂ ^{4 4 4 4}(e) -C (O) -, (f) -C (O) O-, (g) -C (O) NR-, (h) -C (═ NR) -, (i) -C (═ NR) O-, (j) -C (═ NR) NR-, (k) -oc (O) -, (l) -oc (O) O-, (m) -oc (O) NR, (N) -NRC (O) -, (O) -NRC (O) O-, (p) -NRC (O) NR-, (q) -NRC (═ NR) NR-, (r) -s (O) -,(s) -NRs (O) -, (t) -s (O) NR-, (u) -C (N-OR) -, (v) -CH-, (w) -C (N-NRR) -, (x) -C (S) NR-, (y) -NRC (S) -, (z) -C (S) O-, or (aa) -OC (S) -, wherein

⁵i) Any of (a) to (d) may be optionally substituted with one or more R groups, and

ii) W is selected from the group consisting of:

^{4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4} _p ⁴ _{2 2} ^{4 4 4 4 4 4}(aa)-OCO-，(bb)-OC(O)O-，(cc)-OC(O)NR-，(dd)-NRC(O)O-，(ee)-OCNOR-，(ff)-NR-C(O)O-，(gg)-C(S)(NR)-，(hh)-NR-，(ii)-OC(S)O-，(jj)-OC(S)NR-，(kk)-NRC(S)O-，(ll)-OC(S)NOR-，(mm)-C(S)O-，(nn)-，OC(S)-，(oo)-C(O)-，(pp)-C(O)O-，(qq)-C(O)NR-，(rr)-C(＝NR)-，(ss)-C(＝NR)O-，(tt)-C(＝NR)NR-，(uu)-OC(O)-，(vv)-OC(O)O-，(ww)-OC(O)NR-，(xx)-NRC(O)-，(yy)-NRC(O)O-，(zz)-NRC(O)NR-，(aaa)-NRC(＝NR)NR-，(bbb)-S(O)-，(ccc)-NRS(O)-，(ddd)-S(O)NR-，(eee)-C(N-OR)-，(fff)-C(N-NRR)-，(ggg)-C(S)NR-，or(hhh)-NRC(S)-；

g is selected from: (a) b ' and (B) B ' -Z-B ', wherein

¹¹i) Each B' and B ", independently selected from (aa) aryl, (bb) heteroaryl, (cc) biaryl, (dd) fused bicyclic or tricyclic ring system, saturated, unsaturated, or aromatic, containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (ee)3-10 membered, saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (ff)3-10 membered, saturated or unsaturated carbocyclic ring, wherein any of (aa) to (ff) may be optionally substituted with one or more R groups; and

_{1-2 2 2} ^{4 4 4 4 4} _p ^{4 4 4 4 4 4}ii) Z is selected from the group consisting of (aa) a single bond, (bb) C alkyl, (cc) C alkenyl, (dd) C alkynyl, (ee) -C (O) -, - (ff) -C (O-, (gg) -C (O-, (hh) -C (═ NR) -, (ii) -C (═ NR) O-, (jj) -C (═ NR) NR-, (kk) -S (O) -, (ll) -oc (O) -, (mm) -C (S) -, (nn) -C (S) NR, (oo) -C (NR) S-, (pp) -C (O) S-, (qq) -O-, (rr) -NR-, (ss) -nrc (O) -, (tt) -oc (NR) -, (uu) -NC (NR) -, (vv) -C (S) O-, (ww) -SC (O) -, or (xx) -OC (S) -;

⁴each occurrence of R is independently selected from the following:

_{1-6 2-6 2-6 6-10 1-6 2-6 2-6 6-10 1-6 2-6 2-6 6-10} ^{6 6}(a) h, (b) C alkyl, (C) C alkenyl, (d) C alkynyl, (e) C saturated, unsaturated, or aromatic carbocycle, (f)3-12 membered saturated(ii), unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (g) -C (O) -C alkyl, (h) -C (O) -C alkenyl, (i) -C (O) -C alkynyl, (j) -C (O) -C saturated, unsaturated, or aromatic carbocycle, (k) -C (O) -3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (l) -C (O) O-C alkyl, (m) -C (O) O-C alkenyl, (n) -C (O) O-C alkynyl, (O) -C (O) O-C saturated, unsaturated, or aromatic carbocycle, (p) -C (O) O-3-12 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, and (q) -C (O) NRR,

⁵wherein any of (b) - (p) may be optionally substituted with one or more R,

^{4 4 4 4} _P ⁸or, NRR forms a 3-7 membered, saturated or unsaturated or aromatic ring comprising the nitrogen atom to which R is attached, wherein any position of said ring other than the nitrogen atom at the position to which R is attached may be optionally substituted with a substituent selected from the group consisting of O, S (O), N, and NR;

⁵r is selected from the following:

⁷ _{1-8 2-8 2-8} ⁵(a) r, (b) C alkyl, (C) C alkenyl, (d) C alkynyl, (e) a 3-12 membered, saturated or unsaturated, or aromatic carbocyclic ring, and (f) a 3-12 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, or when two R groups are attached to the same carbon atom, they may be joined to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

⁷wherein any of said (b) - (f) may be optionally substituted with one or more R;

⁶each occurrence of R is independently selected from the following:

_{1-6 2-6 2-6 3-10}(a) h, (b) C alkyl, (C) C alkenyl, (d) C alkynyl, (e) C saturated, unsaturated, or aromatic carbocycle, (f)3-10 membered saturated, unsaturated, or aromatic carbocycleAnd, or an aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen or sulfur,

Wherein any of (b) to (f) above may be optionally substituted with one or more of the following groups:

₂ ⁸ _p ^{8 8 8 8 8 8 8 8 8 8 8 8 8 8} ₂ ^{8 8 8} _{2 r} ^{8 8 8 8 8 8 8 8 8 8 8 8 8 8} _r ^{8 8 8 8 8} ₂ ^{8 8 8 8 8 8 8 8 8 8 8 8 8 8 8}(aa) carbonyl, (bb) formate (cc) F dd) Cl, (ee) Br, (ff) I gg) CN hh NO ii) -OR jj) -S (O) R kk-C (O) R ll-C (O) OR mm-OC (O) R, (nn) -C (O) NRR, (oo) -OC (O) NRR, (pp) -C (═ NR) R, (qq) -C (R) OR, (rr) -C (R) OC (O) R, (ss) -C (R) (OR), (CH) NRR, (NRR), (uu) -NROR, (vv) -NRC (O) R, (ww) -NRC (O) OR, (xx) -NRC (O) NRR, (yy) -NRS (O) R, (zz) -C OR (OR) R, (ab) -c (R) NRR, (ac) ═ NR, (ad) -c(s) NRR, (ae) -nrc(s) R, (af) -oc(s) NRR, (ag) -nrc(s) OR, (ah) -nrc(s) NRR, (ai) -sc (o) R,

_{1-8 2-8 2-8 1-8 1-8 1-8 3 3}(aj) C alkyl, (ak) C alkenyl, (al) C alkynyl, (am) C alkoxy (an) C mercapto, (ao) C acyl, (ap) -CF, (aq) -SCF, (ar)3-10 membered, saturated, unsaturated or aromatic carbocyclic ring, (as)3-10 membered, saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur,

^{6 6 6 6} _P ⁸alternatively, NRR forms a 3-10 membered saturated, unsaturated, or aromatic ring including the nitrogen atom to which R is attached, said ring being absent fromThe nitrogen atom at the position to which R is attached may be substituted at any position other than the nitrogen atom, and the substituent is selected from the group consisting of O, S (O), N, and NR;

^{6 6}alternatively, CRR forms a carbonyl group;

⁷each occurrence of R is independently selected from the following:

_{3 3 2} ^{6 6 6} _t ^{9 9} _p ^{6 6} _t ⁹(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f)I，(g)-CF，(h)-CN，(i)-N(j)-NO，(k)-NR(CRR)R，(l)-OR，(m)-S(O)C(RR)R，

(n)-C(O)(CR⁶R⁶)_tR⁹，(o)-OC(O)(CR⁶R⁶)_tR⁹，(p)-SC(O)(CR⁶R⁶)_tR⁹，(q)-C(O)O(CR⁶R⁶)_tR⁹，(r)-NR⁶C(O)(CR⁶R⁶)_tR⁹，(s)-C(O)NR⁶(CR⁶R⁶)_tR⁹，(t)-C(＝NR⁶)(CR⁶R⁶)_tR⁹，(u)-C(＝NNR⁶R⁶)(CR⁶R⁶)_tR⁹，(v)-C(＝NNR⁶C(O)R⁶)(CR⁶R⁶)_tR⁹，(w)-C(＝NOR⁹)(CR⁶R⁶)_tR⁹，(x)-NR⁶C(O)O(CR⁶R⁶)_tR⁹，(y)-OC(O)NR⁶(CR⁶R⁶)_tR⁹，(z)-NR⁶C(O)NR⁶(CR⁶R⁶)_tR⁹，(aa)-NR⁶S(O)_p(CR⁶R⁶)_tR⁹，(bb)-S(O)_pNR⁶(CR⁶R⁶)_tR⁹，(cc)-NR⁶S(O)_pNR⁶(CR⁶R⁶)_tR⁹，(dd)-NR⁶R⁶，(ee)-NR⁶(CR⁶R⁶)，(ff)-OH，(gg)-NR⁶R⁶，(hh)-OCH₃，(ii)-S(O)_nR⁶，(jj)-NC(O)R⁶，

(kk)C_1-6alkyl, (ll) C_2-6Alkenyl, (mm) C_2-6Alkynyl, (nn)3-10 membered, saturated, unsaturated, or aromatic carbocyclic ring, and (oo)3-10 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

any of (kk) to (oo) above may optionally be substituted with one or more R⁹Substitution;

or, two R⁷form-O (CH)₂)_UO-；

R⁸Selected from the following:

(a)R⁵，(b)H，(c)C_1-6alkyl, (d) C_2-6Alkenyl, (e) C_2-6Alkynyl, (f) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (g) a 3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (h) -C (O) -C_1-6Alkyl, (i) -C (O) -C_1-6Alkenyl, (j) -C (O) -C_1-6Alkynyl, (k) -C (O) -C_3-10Saturated, unsaturated, or aromatic heterocyclic ring, and (l) -C (O) -3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

the above (c) to (k) may be optionally substituted with one or more of the following groups:

(aa)H，(bb)F，(cc)Cl，(dd)Br，(ee)I，(ff)CN，(gg)NO₂，(hh)OH，(ii)NH₂，(jj)NH(C_1-6alkyl), (kk) N (C)_1-6Alkyl radical)₂，(ll)C_1-6Alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C_1-6Alkyl, optionally substituted by one or more aryl, substituted aryl, heteroaryl, substituted heteroaryl or F, Cl, Br, CN, NO₂，CF₃，SCF₃And OH substitution;

each occurrence of R⁹Independently selected from the following:

(a)R¹⁰，(b)C_1-6alkyl, (C) C_2-6Alkenyl, (d) C_2-6Alkynyl, (e) C_3-10A saturated, unsaturated, or aromatic carbocyclic ring, (f) a 3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of the above (b) to (f) may optionally be substituted with one or more R¹⁰Substituted by groups;

each occurrence of R¹⁰Independently selected from the following:

(a)H，(b)＝O，(c)F，(d)Cl，(e)Br，(f) I，(g)-CF₃，(h)-CN，(i)-NO₂，(j)-NR⁶R⁶，(k)-OR⁶，(l)-S(O)_pR⁶，(m)-C(O)R⁶，(n)-C(O)OR⁶，(o)-OC(O)R⁶，(p)NR⁶C(O)R⁶，(q)-C(O)NR⁶R⁶，(r)-C(＝NR⁶)R⁶，(s)-NR⁶C(O)NR⁶R⁶，(t)-NR⁶S(O)_pR⁶，(u)-S(O)_pNR⁶R⁶，(v)-NR⁶S(O)_pNR⁶R⁶，(w)C_1-6an alkyl group, a carboxyl group,

(x)C_2-6alkenyl, (y) C_2-6Alkynyl, (z)3-10 membered, saturated, unsaturated, or aromatic carbocyclic ring, and (aa)3-10 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (w) - (aa) above may be optionally substituted with one or more of the following groups: r⁶，F，Cl，Br，I，CN，NO₂，OH，-NH₂，-NH(C_1-6Alkyl group), -N (C)_1-6Alkyl radical)₂，C_1-6Alkoxy radical, C_1-6Alkylthio, and C_1-6An alkanoyl group;

each occurrence of R¹¹Independently selected from the following:

(a) a carbonyl group, (b) a formate group,

(c)F，(d)Cl，(e)Br，(f)I，(g)CN，(h)NO₂，(i)OR⁸，(j)-S(O)_pR⁸，(k)-C(O)R⁸，(l)-C(O)OR⁸，(m)-OC(O)R⁸，(n)-C(O)NR⁸R⁸，(o)-OC(O)NR⁸R⁸，(p)-C(＝NR⁸)R⁸，(q)-C(R⁸)(R⁸)OR⁸，(r)-C(R⁸)₂OC(O)R⁸，(s)-C(R⁸)(OR⁸)(CH₂)_rNR⁸R⁸，(t)-NR⁸R⁸，(u)-NR⁸OR⁸，(v)-NR⁸C(O)R⁸，(w)-NR⁸C(O)OR⁸，(x)-NR⁸C(O)NR⁸R⁸，(y)-NR⁸S(O)_rR⁸，(z)-C(OR⁸)(OR⁸)R⁸，(aa)-C(R⁸)₂NR⁸R⁸，(bb)＝NR⁸，(cc)-C(S)NR⁸R⁸，(dd)-NR⁸C(S)R⁸，(ee)-OC(S)NR⁸R⁸，(ff)-NR⁸C(S)OR⁸，(gg)-NR⁸C(S)NR⁸R⁸，(hh)-SC(O)R⁸，(ii)C_1-8alkyl (jj) C_2-8Alkenyl (kk) C_2-8Alkynyl radical

(ll)C_1-8Alkoxy group, (mm) C_1-8Alkylthio, (nn) C_1-8Alkanoyl, (oo) a C-3-10 membered, saturated, unsaturated, or aromatic carbocyclic ring, and (pp) a 3-10 membered, saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

wherein any of (ii) - (kk) may optionally be substituted with one or more R⁵Substitution;

R¹²selected from:

(a)H，(b)a C_1-6alkyl group，(c)a C_2-6alkenyl group，(d)a C_2-6alkynyl group，(e)-C(O)R⁵，(f)-C(O)OR⁵，(g)-C(O)-NR⁴R⁴R⁴R⁴，(h)-C(S)R⁵，(i)-C(S)OR⁵，(j)-C(O)SR⁵，(k)-C(S)-NR⁴R⁴R⁴R⁴，

(l)C_3-10a saturated, unsaturated, or aromatic carbocyclic ring, (m) a 3-10 membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, (n) - (C)_1-6Alkyl) -3-10 membered saturated, unsaturated, or aromatic carbocyclic ring, or (o) - (C)_1-6Alkyl) -3-to 10-membered saturated, unsaturated, or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur,

any of the above (a) to (d) and (l) to (o) may optionally be substituted with one or more R⁵Substitution;

at any time that it occurs at any time,

p is 0, 1, or 2;

r is 0, 1, or 2;

t is 0, 1, or 2;

u is 0, 1, 2, 3 or 4;

with the proviso that

i) When T is a 14 or 15 membered macrolide compound, D-E is not

ii) when T is a 14 or 15 membered macrolide compound, F-B' is not

iii) when T is a 14 or 15 membered macrolide compound, B '-Z-B' is not

iv) when T is a 14 or 15 membered macrolide compound, R¹¹Is not provided with

v) when the compound is of formula I, and T is

When D is not a single bond or-CH₂-，

vi) when the compound is of formula I and T is a 14 or 15 membered macrolide compound, -D-E-F-is not-CH₂-，

vii) when the compound is of formula I and T is a 14 or 15 membered macrolide compound, -D-E-F-G-is not a group as in Table A below

TABLE A

And

viii) when the compound is of formula II, and T is a 16 membered macrolide compound,

i. -D-E is not a glucoside attached through its anomeric carbon,

ii-D-E-F-G-is not C attached to a 5-10 membered monocyclic or bicyclic carbocyclic or heterocyclic ring, or to a 5-or 6-membered carbocyclic or heterocyclic ring and further to a 5-or 6-membered carbocyclic or heterocyclic ring_1-4(alkyl group, C)_2-4(alkenyl radical), C_2-4(alkynyl) chains, where all carbocyclic or heterocyclic rings may be optionally substituted by one or more groups selected from, (aa) -OH, (bb) -F, (cc) -Cl, (dd) -I, and (ee) -NO₂And are and

iii. -D-E-F-G-is not a group selected from Table B below

TABLE B

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. Use of an effective amount of a compound of claim 1 in the manufacture of a medicament for treating or preventing a disease state in a mammal.

4. Use of an effective amount of a compound of claim 1 for the manufacture of a medicament for treating or preventing a disease state selected from the group consisting of bacterial infection, fungal infection, parasitic disease, proliferative disease, viral disease, inflammation, gastrointestinal motility disorders, and diseases caused or modulated by nonsense or missense mutations in a mammal.

5. A method of synthesizing the compound of claim 1.

6. A medical device comprising the compound of claim 1.