Immune-regulating azalay

Abstract

Immunomodulating compounds of formula (1) 0 , R 1 , R 2 and W are as defined herein), its stereoisomers, and pharma- ceutically acceptable salts thereof, and compositions comprising said compounds are defined herein. The invention also includes a method for treating or preventing an inflammatory and / or immunological disease or disorder in an animal by administering a therapeutically effective amount of a compound of formula (1), its stereoisomer, or a pharma- ceutically acceptable salt thereof, or the use of said compound of formula (1) for the preparation of a medicament for treating or preventing an inflammatory and / or immunological disease or disorder in an animal. [Formula 1] JPEG2024535760000110.jpg59127

Description

[Technical Field]

[0001] Anti-inflammatory and immunomodulatory compounds, non-antibacterial anti-inflammatory and immunomodulatory compounds, their stereoisomers, and pharmaceutically acceptable salts thereof are defined herein. The present invention includes each 13-membered macrolide ring compound in equilibrium with a 15-membered macrolide ring compound. The present invention also includes pharmaceutical compositions comprising the compounds of the present invention, and methods for treating inflammatory and / or immunological diseases or disorders in animals. The compounds of the present invention are azalides. [Background technology]

[0002] Macrolides are antibacterial compounds consisting of a macrocyclic lactone ring containing 12 to 16 atoms, linked via glycosidic bonds to at least one or two deoxysugars. Azalides are a class of macrolides in which the lactone ring contains a nitrogen atom. Draxxin® is a semisynthetic macrolide (azalide) antibiotic sold as a ready-to-use sterile parenteral preparation containing tulathromycin. The preparation consists of an equilibrated mixture of two isomers of tulathromycin in a 9:1 ratio (Tula-A:Tula-B). Tula-A has a 15-membered lactone ring structure, and Tula-B has a 13-membered lactone ring structure. The equilibration is pH- and time-dependent. Tulathromycin is commercially available under the trade name Draxxin® for bovine respiratory disease (BRD) and swine respiratory disease (SRD).

[0003] Macrolides are known to inhibit protein synthesis in bacteria (both Gram-positive and Gram-negative) by reversibly binding to the P site of the 50S unit of the ribosome. Macrolides tend to be bacteriostatic and can be bactericidal against some pathogens. Their activity against Gram-negative pathogens of BRD and their ability to concentrate in lung tissue make them excellent therapeutic agents. They are the first line of treatment for BRD and are also used to treat respiratory infections in humans.

[0004] Known macrolide antibiotics include, for example, erythromycin, tilmicosin, azithromycin, clarithromycin, gamithromycin, fidaxomicin, roxithromycin, and tulathromycin. Additionally, some macrolides have been shown to have anti-inflammatory and immunomodulatory effects. For example, the broad-spectrum antibiotic azithromycin suppresses the expression of interleukin-12p40 in lipopolysaccharide (LPS)- and interferon-gamma-stimulated macrophages, attenuates the LPS-induced induction of CXCL8 (IL-8) and GM-CSF from primary bronchial epithelial cells, and downregulates the release of transcription factors AP-1, NFκB, inflammatory cytokines, and mucins in epithelial cells through its interaction with phospholipids and Erk1 / 2. US Patent Publication No. 2016-0031925 describes certain azithromycin analogs that are immunomodulatory but modified to reduce or eliminate their antibiotic effects. Clarithromycin has immunomodulatory effects on ERJ-mediated inflammation induced by Pseudomonas aeruginosa flagellin. Erythromycin inhibits the expression of interleukin-6 and interleukin-8 and promotes apoptosis of in vitro activated human neutrophils. Tilmicosin regulates COX-2 and iNOS gene expression and cytokine production in LPS-stimulated macrophages and monocytes. Roxithromycin downregulates Th2 chemokine production by keratinocytes and chemokine receptor expression in Th2 cells. Tulathromycin promotes apoptosis, downregulates proinflammatory mediators such as leukotriene B4 and CXCL8, and induces the production of the anti-inflammatory and pro-resolving lipid lipoxin A4. Research results demonstrate that these antibacterial macrolides modulate certain excessive immune responses, which cascade to produce specific anti-inflammatory effects.

[0005] Inflammation and pro-inflammatory mediators adversely affect production in the food animal industry by reducing growth, feed and water intake, reproduction, milk production, and metabolic health. The increased clinical use of macrolide antibiotics is associated with increased pneumococcal macrolide resistance and resistance among BRD pathogens. Recent concerns from government agencies and the general public worldwide about antibiotic use in food-producing animals (e.g., cattle and pigs) are thought to result in cross-resistance to human pathogens. Bovine respiratory disease (BRD) remains a major problem in modern cattle production, and wise management is crucial for both animal welfare and human food safety. In fact, Mannheimia haemolytica is the primary bacterium isolated from respiratory disease in feedlot cattle and is an important component of endemic pneumonia in newborn calves. One of the hallmarks of BRD is an enhanced host inflammatory response, which promotes progression to the complete BRD complex. Inhibiting or reversing inflammation in the host has the potential to prevent or suppress the development of bovine BRD and other inflammatory diseases or disorders in animals. Thus, there is an unmet need to develop new anti-inflammatory and immunomodulatory agents that lack the antibacterial effects of known macrolides. The compounds of the present invention are non-antibacterial in multiple bacterial species and have been shown to have 5-20 times greater immunomodulatory activity at lower doses than current macrolides (e.g., azithromycin, erythromycin, and tulathromycin). Thus, the compounds can be used to control or prevent the onset of bacterial or viral infections enabled by inflammation and / or immune responses due to stressful events or other environmental factors(s), thereby preventing or mitigating the progression of the pathobiological cascade to a full disease complex. Several other non-antibiotic immunomodulatory azalide analogs have been developed, most recently published in WO2021 / 183758, WO2021 / 183754, WO2021 / 183759, and WO2021 / 183762. The compounds of the invention presented herein are non-antibacterial, anti-inflammatory and immunomodulatory macrolides for the relief of inflammatory conditions in animals, with the potential to reduce the use of antibiotics in animals. Summary of the Invention

[0006] In one aspect of the invention, there is provided an anti-inflammatory and immunomodulatory compound of formula (1), or a non-antibacterial anti-inflammatory and immunomodulatory compound of formula (1), [ka] wherein W is H or a compound of formula (A), [ka] In the formula, X is R a , -(CH2) m NR 5 R 6 , -(CH2) m OR 7 , -(CH2) m SR 7 , -(CH2) m N3, -(CH2) m CN or -(CH2) m X', X' is F, Cl, I, or Br; R is H, phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl ring, or a 9- or 11-membered fused heteroaryl ring, each of which contains at least one heteroatom selected from N, O, and S, wherein phenyl (R 9 ) n , each of the heteroaryl rings contains at least one heteroatom selected from N, O, and S, and the phenyl, naphthyl, and heteroaryl rings are (R 9 ) n are respectively replaced by R a , R 0 and R 1 are each independently H or C1-C6 alkyl, or R 1 However, (R 9 ) n or benzyl substituted with or R 1is —CH2Het, where Het is a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S, and the heteroaryl ring is 9 ) n is replaced by or R 1 However, (R 9 ) n is a C3-C6 cycloalkyl substituted with R b is H, C1-C4 alkyl, C1-C4 haloalkyl, C0-C3 alkylphenyl, C0-C3 alkylC3-C6 cycloalkyl, C0-C3 alkylheterocycle, C0-C3 alkylheteroaryl, wherein the heterocycle is a 5- or 6-membered saturated or partially saturated monocyclic ring, the heteroaryl is a 5- or 6-membered monocyclic ring, the heterocycle and heteroaryl ring each contain at least one heteroatom selected from N, O, and S, and the cycloalkyl, phenyl, heterocycle, and heteroaryl ring each are (R 9 ) n is replaced by R c is C1-C4 alkyl, R 2 is H, C1-C6 alkyl, -R c OR b , C1-C6 haloalkyl, C0-C3 alkyl, C3-C6 cycloalkyl, -R c NR a R b , -NR a R c S(O) p R 8 , -NR a R c C(O)NR a R c , R c CN, -R c S(O) p R 8 , -NR a R b , -NR b R b, C0-C3 alkylaryl, C0-C3 alkylheterocycle which is a 5- or 6-membered saturated or partially saturated heterocycle, C0-C3 alkylheteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl ring, the heterocycle and the heteroaryl ring each contain at least one heteroatom selected from N, O, and S, and the cycloalkyl, aryl, heterocyclic, and heteroaryl ring each are (R 9 ) n and each ring is optionally fused to Y; or or R and R 2 are linked together to form a bond to form a fused dioxo-oxathiazole ring, [ka] R 5 and R 6 each independently represents H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 , -C(O)NR a R 8 , -C(O)R c NR a R b , -C(O)OR c R 8 , -C(O)ONR a R b , -R c NR a C(O)R 8 , -R c C(O)R b , -R c C(O)OH, -R c C(O)NR a R b , -R c NR a C(O)H, -R c S(O) p R 8 , -R c NR a R b , -R c OR b , -S(O) p R 8, -S(O) p R 8 NR a R b , -R c S(O) p NR a R b or -R c NR a S(O) p R 8 or C0-C4 alkylaryl, C0-C4 alkylC3-C6 cycloalkyl, C0-C4 alkylheterocycle, and C0-C4 alkylheteroaryl, wherein the heterocycle and heteroaryl rings are each a 5- or 6-membered monocyclic ring or a 9- or 10-membered fused ring containing at least one heteroatom selected from the group consisting of N, O, and S, and the aryl, cycloalkyl, heterocycle, and heteroaryl ring are each selected from (R 9 ) n is replaced by or R 5 and R 6 together with the nitrogen atom to which they are attached form Ring B, a 4- to 8-membered heterocyclic ring, or a 5-membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O, and S, and each ring is 9 ) n and each ring is optionally fused to Y; R 7 H, C1-C6 alkyl, phenyl, -R c NR a R b , -R c OR b , -R c S(O) p R a , -R c NR a C(O)R b , -R c C(O)NR a R b , -R c NR a C(O)NR a R b , or -R c NR a C(O)OR band R 8 is C1-C6 alkyl, C1-C6 haloalkyl, C0-C4 alkyl, C3-C6 cycloalkyl, -NR a R b , phenyl, and a 5- or 6-membered heterocyclic or heteroaryl ring each containing at least one heteroatom selected from N, O, and S, and wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, and —OCHF (R 9 ) n is replaced by R 9 are independently selected from C1-C6 alkyl, C1-C6 alkoxy, C0-C4 alkyl, C3-C6 cycloalkyl, halo, oxo, nitro, hydroxy, -R c OR b , Cyano, -NR a R b , C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 , -SF5, phenyl, and 5- or 6-membered heterocyclic or heteroaryl rings each containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the phenyl, heterocyclic, and heteroaryl rings are optionally further substituted with F, Cl, cyano, or -CF3; Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, or tetrahydrothiophenyl, each optionally substituted with methyl, F, Cl, cyano, oxo, or —CF3; m is an integer 1, 2, or 3; n is an integer 0, 1, 2, or 3, and when n is 2 or 3, each R 9 The substituents may be the same or different, a compound in which p is an integer 0, 1, or 2; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] In another embodiment, a composition comprising a compound of formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0008] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response is due to a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of this method, the method for treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of this method, the animal is a livestock animal. In another aspect of this method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, the method for treating or preventing an inflammatory response in an animal downregulates TNFα and IL-6 in the animal.

[0009] In another aspect, there is provided a use of a compound of formula (1), its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to prevent or alleviate the progression of a respiratory disease or disorder. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to prevent or alleviate the progression of a respiratory disease or disorder. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to downregulate TNFα and IL-6 in the animal.

[0010] In another aspect of the invention, R a and Rb are each independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, or t-butyl. a and R b are each independently H, methyl, ethyl, propyl, or isopropyl. a and R b are each independently H, methyl, ethyl, or propyl. a and R b are each independently H or methyl.

[0011] In another aspect of the invention, R c is methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl. c is methyl, ethyl, propyl, isopropyl, or t-butyl. c is methyl, ethyl, propyl, or isopropyl. In another aspect of the invention, R c is methyl, ethyl, or propyl. c is methyl. In another embodiment, R c is ethyl. In another embodiment, R c is propyl.

[0012] In another embodiment, X' is F, Cl, or Br. In another embodiment, X' is F or Cl. In another embodiment, X' is F. In another embodiment, X' is Cl.

[0013] In another aspect of the invention, R 0 and R 1 are each independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, or t-butyl, or R 1 are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R9 ) n In another embodiment, R is benzyl, cyclopentyl, cyclohexyl, -CH2 pyridinyl, -CH2 pyrimidinyl, -CH2 pyridazinyl, -CH2 pyrazinyl, -CH2 pyrrolyl, -CH2 furanyl, -CH2 thiophenyl, -CH2 pyrazolyl, -CH2 imidazolyl, -CH2-triazolyl, -CH2 tetrazolyl, -CH2 oxazolyl, -CH2 isoxazolyl, -CH2 thiazolyl, -CH2 isothiazolyl, or -CH2 oxadiazolyl substituted with 0 and R 1 are each independently H, methyl, ethyl, propyl, isopropyl, or isobutyl, or R 1 are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is benzyl, cyclopentyl, cyclohexyl, -CH2 pyridinyl, -CH2 pyrimidinyl, -CH2 pyrazolyl, -CH2 imidazolyl, -CH2 triazolyl, -CH2 tetrazolyl, -CH2 oxazolyl, -CH2 isoxazolyl, -CH2 thiazolyl, -CH2 isothiazolyl, or -CH2 oxadiazolyl substituted with 0 is H, methyl, ethyl, or propyl, and R 1 is methyl, ethyl, propyl, or isobutyl, or R 1 are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is benzyl, cyclopentyl, cyclohexyl, —CH2 pyridinyl, —CH2 pyrimidinyl, —CH2 pyrazolyl, —CH2 thiazolyl, or —CH2 imidazolyl substituted with 0is H, methyl, ethyl, or propyl, and R 1 is methyl, ethyl, propyl, or isobutyl, or R 1 are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is cyclohexyl, benzyl, —CH2 pyridinyl, or —CH2 thiazolyl substituted with 0 is H or methyl, and R 1 is methyl, propyl, or isobutyl. 0 is H or methyl, and R 1 is methyl.

[0014] In another aspect of the invention, R is H, or each (R 9 ) n In another embodiment, R is H, or each of (R 9 ) n In another embodiment, R is H, or each (R 9 ) nIn another embodiment, R is H or, each independently, selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is H or, each independently, selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another aspect, R is H or independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another aspect, R is H or independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R9 ) n is a phenyl substituted with

[0015] In another aspect of the invention, R 2 is H, C1-C6 alkyl, -CH2CN, -R c OR b , -R c S(O) p R a , C1-C6 haloalkyl, C0-C3 alkyl, C3-C6 cycloalkyl, -R c NR a R b , -NR a R b, pyrrolyl, -CH2 pyrrolyl, -CH2CH2 pyrrolyl, tetrahydrofuranyl, -CH2 tetrahydrofuranyl, -CH2CH2 tetrahydrofuranyl, tetrahydrothiophenyl, -CH2 tetrahydrothiophenyl, -CH2CH2 tetrahydrothiophenyl, tetrahydropyranyl, -CH2 tetrahydropyranyl, -CH2CH2 tetrahydropyranyl, tetrahydrothiopyranyl, -CH2 tetrahydrothiopyranyl, -CH2CH2 tetrahydrothiopyranyl, pyrrolidinyl, -CH2 pyrrolidinyl -yl, -CH2CH2pyrrolidinyl, piperidinyl, -CH2piperidinyl, -CH2CH2piperidinyl, piperazinyl, -CH2piperazinyl, -CH2CH2piperazinyl, morpholinyl, -CH2morpholinyl, -CH2CH2morpholinyl, furanyl, -CH2furanyl, -CH2CH2furanyl, thiophenyl, -CH2thiophenyl, -CH2CH2thiophenyl, pyrazolyl, -CH2pyrazolyl, -CH2CH2pyrazolyl, imidazolyl, -CH2imidazolyl, -CH2CH2imidazolyl, isoxazolyl, -CH2 isoxazolyl, -CH2CH2 isoxazolyl, oxazolyl, -CH2 oxazolyl, -CH2CH2 oxazolyl, isothiazolyl, -CH2 isothioazolyl, -CH2CH2 isothiazolyl, thiazolyl, -CH2 thiazolyl, -CH2 CH2 thiazolyl, triazolyl, -CH2 triazolyl, -CH2CH2 trizolyl, oxadiazolyl, -CH2 oxadiazolyl, -CH2 CH2 oxadiazolyl, thiadiazolyl, -CH2 thiadiazolyl, -CH2CH2 thiadiazolyl, tetrazolyl, -CH2 tetrazolyl, -CH2CH2 tetrazolyl, phenyl, -CH2 phenyl (benzyl), -CH2CH2 phenyl, pyridinyl, -CH2 pyridinyl, -CH2 CH2 pyridinyl, pyrimidinyl, -CH2 pyrimidinyl, -CH2 CH2 pyrimidinyl, pyridazinyl, -CH2 pyridazinyl, -CH2 CH2 pyridazinyl, pyrazinyl, -CH2 pyrazinyl, or -CH2 CH2 pyrazinyl; and the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each (R 9 ) n and each ring is optionally fused to Y. In another embodiment, R 2is H, C1-C6 alkyl, -CH2OCH3, -(CH2)2OCH3, -CH2CN, -CH2F, -CHF2, -CH2CF3, -CF3, -CH2S(O)2CH3, cyclopropyl, -CH2cyclopropyl, cyclobutyl, -CH2cyclobutyl, cyclopentyl, -CH2cyclopentyl, cyclohexyl, -CH2cyclohexyl, -R c NR a R b , -NR a R b , pyrrolyl, -CH2 pyrrolyl, tetrahydrofuranyl, -CH2 tetrahydrofuranyl, tetrahydrothiophenyl, -CH2 tetrahydrothiophenyl, tetrahydropyranyl, -CH2 tetrahydropyranyl, tetrahydrothiopyranyl, -CH2 tetrahydrothiopyranyl, pyrrolidinyl, -CH2 pyrrolidinyl, piperidinyl, -CH2 piperidinyl, piperazinyl, -CH2 piperazinyl, morpholinyl, -CH2 morpholinyl, furanyl, -CH2 furanyl, thiophenyl, -CH2 thiophenyl, pyrazolyl, -CH2 pyrazolyl, imidazolyl, -CH2 imidazolyl, isoxazolyl , -CH2 isoxazolyl, oxazolyl, -CH2 oxazolyl, isothiazolyl, -CH2 isothioazolyl, thiazolyl, -CH2 thiazolyl, triazolyl, -CH2 triazolyl, oxadiazolyl, -CH2 oxadiazolyl, thiadiazolyl, -CH2 thiadiazolyl, tetrazolyl, -CH2 tetrazolyl, phenyl, -CH2 phenyl(benzyl), pyridinyl, -CH2 pyridinyl, pyrimidinyl, -CH2 pyrimidinyl, pyridazinyl, -CH2 pyridazinyl, pyrazinyl or -CH2 pyrazinyl, and the cycloalkyl, phenyl, heterocyclic and heteroaryl rings are each (R 9 ) n and each ring is optionally fused to Y, which is cyclopentyl, cyclohexyl, thiophenyl, or phenyl. 2is H, C1-C6 alkyl, -CH2OCH3, -(CH2)2OCH3, -CH2CN, -CH2F, -CHF2, -CH2CF3, -CF3, -CH2S(O)2CH3, cyclopropyl, -CH2cyclopropyl, cyclobutyl, -CH2cyclobutyl, cyclopentyl, -CH2cyclopentyl, cyclohexyl, -CH2cyclohexyl, -R c NR a R b , -NR a R b , pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each (R 9 ) n and each ring is optionally fused to Y, which is cyclopentyl, cyclohexyl, thiophenyl, or phenyl. 2 is H, C1-C6 alkyl, -CH2OCH3, -(CH2)2OCH3, -CH2F, -CH2CF3, -CF3, -CH2S(O)2CH3, -CH2CN, -NHR b , -NCH2R b , cyclopropyl, -CH2cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each independently (R 9 ) nand each ring is optionally fused to Y, which is a cyclopentyl, cyclohexyl group, thiophenyl, or phenyl. 2 is H, C1-C6 alkyl, -CH2OCH3, -(CH2)2OCH3, -CH2CN, -CH2CF3, -CF3, -CH2S(O)2CH3, -NHR b or -NCH2R b where R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 is cyclopropyl, -CH2cyclopropyl, cyclohexyl, furanyl, piperidinyl, piperazinyl, pyrrolodinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and when fused with Y, is benzofuranyl, 6,7-dihydro-5H-pyrrolo[1,2a]imidazolyl, benzo[b]thiophenyl, dihydroimidazo[1,2a]pyridinyl, tetrahydroisoquinolinyl, or isoindolinyl, and the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n or substituted with R 2 is phenyl or pyridinyl, each substituted with morpholine. 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -CH2S(O)2CH3, -NHR b or -NCH2R b where R bis methyl, cyclohexyl, phenyl, or pyridinyl, the phenyl and pyridinyl rings being optionally substituted with F, Cl, cyano, or —CF3, or R 2 is cyclopropyl, -CH2cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl; The heterocyclic and heteroaryl rings are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n or substituted with R 2 is phenyl or pyridinyl, each substituted with morpholine. 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -CH2S(O)2CH3, -NHR b or -NCH2R b where R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2is cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl, and the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH, -N(CH), -CF, -CHF, -OCHF, -S(O)NH, -SCH, -S(O)CH, and -S(O)CH (R 9 ) n or substituted with R 2 are phenyl or pyridinyl each substituted with morpholine.

[0016] In another aspect of the invention, R and R 2 are linked together to form a bond to form a di-oxo-oxathiazolyl ring, [ka] In the formula, R 1 are as defined herein. In another embodiment, R and R 2 are joined together to form a bond to form a di-oxo-oxathiazolyl ring, wherein R 1 is H, methyl, phenyl, or benzyl, and the phenyl moiety is (R 9 ) n In another embodiment, R and R are substituted with 2 are joined together to form a bond to form a di-oxo-oxathiazolyl ring, wherein R 1 is H, methyl, phenyl, or benzyl, and the phenyl moieties are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) nIn another embodiment, R and R are substituted with 2 are joined together to form a bond to form a di-oxo-oxathiazolyl ring, wherein R 1 is H, methyl, phenyl, or benzyl, and the phenyl moieties are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R and R are substituted with 2 are joined together to form a bond to form a di-oxo-oxathiazolyl ring, wherein R 1 is H, methyl, phenyl, or benzyl, and the phenyl moieties are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n is replaced by .

[0017] In another aspect of the invention, R 5 and R 6 each independently represents H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 , -C(O)NR a R 8 , -C(O)R c NR a R b , -C(O)OR c R 8 , -C(O)ONR a R b , -R c NR a C(O)R 8 , -R c C(O)OH, -R c C(O)NRa R b , -R c NR a C(O)H, -R c S(O) p R 8 , -R c NR a R b , -R c OR b , -S(O) p R 8 , -S(O) p R 8 NR a R b , -R c S(O) p NR a R b , -R c NR a S(O) p R 8 , C0-C4 alkylphenyl, C0-C4 alkylC3-C6 cycloalkyl, C0-C4 alkylheterocycle, C0-C4 alkylheteroaryl, wherein the heterocycle and heteroaryl ring are each 5-6 membered monocyclic rings, each heterocycle and heteroaryl ring contains at least one heteroatom selected from the group consisting of N, O, and S, and the phenyl, cycloalkyl ring, heterocycle, and heteroaryl ring are each (R 9 ) n In another embodiment, R 5 and R 6 each independently represents H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 , -C(O)NR a R 8 , -C(O)R c NR a R b , -C(O)OR c R 8 , -C(O)ONR a R b , -R c NR a C(O)R 8 , -R c C(O)OH, -Rc C(O)NR a R b , -R c NR a C(O)H, -R c S(O) p R 8 , -R c NR a R b , -R c OR b , -S(O) p R 8 , -S(O) p R 8 NR a R b , -R c S(O) p NR a R b , -R c NR a S(O) p R 8 , phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, C1-C2 alkylcyclopentyl, C1-C2 alkylcyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, C1-C2 alkyltetrahydro-furanyl, C1-C2 alkyloxazolidinyl, C1-C2 alkyltetrahydropyranyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkyltriazolyl, C1-C2 alkyltetrazolyl, C1-C2 alkyloxazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyridazinyl, C1-C2 alkylpyrimidinyl or C1-C2 alkylpyrazinyl, and phenyl, cycloalkyl ring, heterocycle and heteroaryl ring are each (R 9 ) n In another embodiment, R5 and R 6 each independently represents H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 , -C(O)NR a R 8 , -C(O)R c NR a R b , -C(O)ONR a R b , -R c NR a C(O)R 8 , -R c C(O)NR a R b , -R c NR a C(O)H, -R c S(O) p R 8 , -R c NR a R b , S(O) p R 8 , -S(O) p R 8 NR a R b , -R c S(O) p NR a R b, phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, C1-C2 alkyloxazolidinyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, C1-C2 tetrahydrofuran, C1-C2 tetrahydropyran, pyrazolyl, imidazolyl, pyridinyl, pyridinyl and R is an alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH. 9 ) n In another embodiment, R 5 and R 6 are each independently H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 , -C(O)NR a R 8 , -C(O)R c NR a R b , -R c S(O) p R 8 , -R c NR a R b , -R c OR b , -S(O) p R 8, phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2 alkyloxazolidinyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, C1-C2 morpholinyl, C1-C2 piperazinyl, C1-C2 tetrahydropyranyl, C1-C2 tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyrimidinyl, or C1-C2 alkylpyrazinyl; and the phenyl, cycloalkyl, heterocycle, and heteroaryl ring are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH2, —N(CH3)2, —CF3, —CHF2, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3 (R 9 ) n In another embodiment, R 5 and R 6 are each independently H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, -OCF3, or -C(O)NR a R 8 , -R c S(O) p R 8 , -R c NR a R b , -R c OR b , -S(O) p R 8, phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2 alkyloxazolidinyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, C1-C2 tetrahydropyranyl, C1-C2 tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl phenyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyrimidinyl, or C1-C2 alkylpyrazinyl; and the phenyl, cycloalkyl, heterocycle, and heteroaryl rings are each independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl, Br, I, oxo, hydroxy, cyano, nitro, —NH2, —NHCH3, —N(CH3)2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3 (R 9 ) n In another embodiment, R 5 is H, C1-C6 alkyl, morpholinyl, piperazinyl, -CH2 morpholinyl, -CH2 piperazinyl, -(CH2)2 morpholinyl, or (CH2)2 piperazinyl. 5 is H, methyl, ethyl, propyl, isopropyl, -CHmorpholinyl, -CHpiperazinyl, -(CH)morpholinyl, or -(CH)piperazinyl. 5 is H, methyl, ethyl, propyl, or isopropyl. 6 is H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, -OCF3, -C(O)NR a R 8 , -R c S(O) p R 8 , -Rc NR a R b , -R c OR b , -S(O) p R 8 , phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2 alkyloxazolidinyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, C1-C2 tetrahydropyranyl, C1-C2 tetrahydrofuranyl, pyrazolyl, midazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyrimidinyl, or C1-C2 alkylpyrazinyl, and the phenyl, cycloalkyl ring, heterocycle, and heteroaryl ring are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH2, —N(CH3)2, —CF3, —CHF2, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3 (R 9 ) n In another embodiment, R 6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, -CH2CF3, -CF3, -OCF3, -C(O)NR a R 8 (In the formula, R a is H or methyl, and R 8 is H, methyl, cyclopropyl, phenyl optionally substituted with F, Cl, or CF), —(CH)S(O)R 8 (In the formula, R 8 is methyl or phenyl), -CHNR a R b or -(CH2)2NR a Rb (In the formula, R a and R b are each independently H or methyl), -(CH2)2OCH3, -(CH2)3OCH3, phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2 alkylpyrrolidinyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 morpholinyl, C1-C2 tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyrimidinyl, or C1-C2 alkylpyrazinyl; and the phenyl, cycloalkyl ring, heterocycle, and heteroaryl ring are each independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH2, —N(CH3)2, —CF3, —CHF2, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3 (R 9 ) n is replaced by .

[0018] In another aspect of the invention, R 5 and R 6 together with the nitrogen atom to which they are attached form Ring B, a 4- to 8-membered heterocyclic ring, or a 5-membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O, and S, and each ring is 9 ) n and each ring is further optionally fused to Y, which is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, or triazolyl. 5 and R 6together with the nitrogen atom to which they are attached form Ring B, a 4- to 8-membered heterocyclic ring, or a 5-membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O, and S, and each ring is 9 ) n and each ring is further optionally fused to Y, which is phenyl, pyridinyl, or pyrimidyl. 5 and R 6 together with the nitrogen atom to which they are attached form a ring B which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n and each ring is further optionally fused to Y, which is phenyl or pyridinyl. 5 and R 6 together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is substituted with R 5 and R 6together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n In another embodiment, R is substituted with R 5 and R 6 together with the nitrogen atom to which they are attached form a ring B that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n or when fused to Y which is phenyl, Ring B is indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or dihydrobenzoxazinyl. 5 and R 6 together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH (R 9 ) n is replaced by .

[0019] In another aspect of the invention, R 7is H, C1-C6 alkyl, phenyl, -(CH2) m NH2, -(CH2) m NHCH3, -(CH2) m N(CH3)2, -(CH2) m C(O)H, -(CH2) m C(O)CH3, -(CH2) m S(O) p CH3, -(CH2) m NHC(O)CH3, -(CH2) m NHC(O)NHCH3, -(CH2) m NHC(O)N(CH3)2, or -(CH2) m NHC(O)CH3, where m is an integer 1, 2, or 3. In another embodiment, R 7 is H, C1-C6 alkyl, phenyl, -(CH2) m NH2, -(CH2) m NHCH3, -(CH2) m N(CH3)2, -(CH2) m C(O)CH3, -(CH2) m S(O) p CH3 or -(CH2) m NHC(O)CH3, where m is an integer 1 or 2. In another aspect of the invention, R 7 is H, C1-C6 alkyl, phenyl, -(CH2)NH2, -(CH2)NHCH3, -(CH2)N(CH3)2, -(CH2)C(O)CH3, -(CH2)S(O) p CH3, or —(CH2)NHC(O)CH3. In another embodiment, R 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, -(CH2) m NH2, -(CH2)NHCH3, -(CH2)N(CH3)2, -(CH2)C(O)CH3, -(CH2)S(O) p CH3, or —(CH2)NHC(O)CH3. In another embodiment, R 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CHNH, —CHNHCH, or —CHN(CH). 7is H, methyl, ethyl, propyl, isopropyl, or —CHN(CH). In another embodiment, R 7 is H, methyl, ethyl, or propyl.

[0020] In another aspect of the invention, R 8 are each independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, and —OCHF (R 9 ) n C1-C6 alkyl, C1-C6 haloalkyl, -NR a R b or C0-C4 alkyl, C3-C6 cycloalkyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl, or pyrimidinyl. 8 are each independently selected from the group consisting of methyl, ethyl, propyl, or methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, and —OCHF (R 9 ) n In another embodiment, R is cyclopropyl, C alkylcyclopropyl, phenyl, or pyridinyl substituted with 8 is methyl, ethyl, or cyclopropyl or phenyl, each optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxy, F, Cl, Br, oxo, cyano, and —CF.

[0021] In another aspect of the invention, each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, halo, oxo, hydroxy, -CH2OH, nitro, cyano, -NR a R b , C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8or phenyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolyl, furanylthiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyridinyl, and pyrazinyl, each of which is optionally further substituted with fluoro, chloro, cyano, or —CF. 9 are independently C1-C6 alkyl, C1-C6 alkoxy, halo, oxo, hydroxy, -CH2OH, nitro, cyano, -NR, each optionally substituted with fluoro, chloro, cyano, or -CF3. a R b , C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 or phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. 9 are independently C1-C6 alkyl, C1-C6 alkoxy, halo, oxo, hydroxy, -CH2OH, nitro, cyano, -NR a R b , C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 or phenyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl, each optionally substituted with fluoro, chloro, cyano, or —CF. 9is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, oxo, hydroxy, -CH2OH, cyano, nitro, -NH2, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -CH2F, -OCHF2, -OCF3, -S(O)2NH2, -SCH3, -S(O)CH3, -S(O)2CH3, or phenyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl, each optionally substituted with fluoro, chloro, cyano, or -CF3. 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH; or phenyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl, each optionally substituted with fluoro, chloro, cyano, or —CF. 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH. 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH. 9 is independently selected from the group consisting of methyl, methoxy, F, Cl, Br, I, oxo, cyano, —NHCH 3 , —N(CH 3 ) 2 , and —CF 3 .

[0022] In another aspect of the invention, X is R a , -(CH2) m NR 5R 6 , -(CH2) m OR 7 , -(CH2) m SR 7 , -(CH2) m N3, -(CH2) m CN or -(CH2) m X', where m is an integer 1 or 2. In another embodiment, X is R a In another embodiment, X is -CHNR 5 R 6 In another embodiment, X is -CHOR 7 In another embodiment, X is -CHSR 7 In another embodiment, X is -CH2N3. In another embodiment, X is -CH2CN. In another embodiment, X is -CH2X'.

[0023] In another aspect of the invention, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, imidazolyl, or tetrahydrothiophene, each optionally substituted with methyl, F, Cl, cyano, oxo, or -CF. In another aspect, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, or tetrahydrothiophene, each optionally substituted with methyl, F, Cl, cyano, oxo, or -CF. In another aspect, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, thiophenyl, thiazolyl, or tetrahydrothiophene, each optionally substituted with methyl, F, Cl, cyano, oxo, or -CF. In another embodiment, Y is cyclopentyl, phenyl, or thiophenyl, each optionally substituted with methyl, F, Cl, cyano, oxo, or -CF. In another embodiment, Y is cyclopentyl, phenyl, or thiophenyl. In another embodiment, when Y is fused to a 5- or 6-membered heterocyclic or heteroaryl ring, the fused moiety is selected from benzofuranyl, 6,7-dihydro-5H-pyro[1,2-a]imidazolyl, thieno[3,2b]pyridinyl, 3,4-dihydroisoquinolinyl, isoindolinyl, and imidazo[1,2α]pyridinyl.

[0024] In another embodiment of the invention, p is the integer 0. In another embodiment, p is the integer 1. In another embodiment, p is the integer 2. In another embodiment of the invention, n is the integer 0, 1, or 2. In yet another embodiment, n is the integer 0 or 1. In yet another embodiment, n is the integer 0. In yet another embodiment, n is the integer 1. In yet another embodiment, n is the integer 2.

[0025] In another embodiment, there is provided a compound of formula (1) wherein W is a compound of formula (A) of formula (1A): [ka] In the formula, R, R 0 , R1 , R 2 and X are as defined herein. In another aspect, the compounds of formula (1A) are compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein R 0 is H, methyl, ethyl, or propyl; R is H, phenyl, or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S; and the phenyl and heteroaryl ring are 9 ) n is substituted with R 1 is C1-C6 alkyl or cyclohexyl, or R 1 is benzyl, -CH2 pyridinyl, or -CH2 thiazolyl, each of which is independently selected from methyl, fluoro, chloro, methoxy, cyano, and -CF3 (R 9 ) n is substituted with R 2 , n, and X are as defined herein, or R and R 2 are linked to form a bond to form a di-oxo-oxathiazolyl ring, its stereoisomers, and pharmaceutically acceptable salts thereof. In another embodiment, the compound of formula (1A) is 0 is H, methyl, ethyl, or propyl, and R is H or each (R 9 ) n phenyl, pyridinyl or thiophenyl substituted with R 1 is C1-C6 alkyl or cyclohexyl, or R 1 is benzyl, -CH2 pyridinyl, or -CH2 thiazolyl, each of which is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH2, -N(CH3)2, -CF3, -CHF2, -OCHF2, -S(O)2NH2, -SCH3, -S(O)CH3, and -S(O)2CH3 (R 9 ) n is substituted with R 2 , n, and X are as defined herein, their stereoisomers, and pharmaceutically acceptable salts thereof.

[0026] In another embodiment, a composition comprising a compound of formula (1A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0027] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1A), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of this method, the method for treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of this method, the animal is a livestock animal. In another aspect of this method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, the method for treating or preventing an inflammatory response in an animal downregulates TNFα and IL-6 in the animal.

[0028] In another aspect, there is provided a use of a compound of formula (1A), its stereoisomers, and pharmaceutically acceptable salts thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to prevent or alleviate the progression of a respiratory disease or disorder. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to prevent or alleviate the progression of a respiratory disease or disorder. In another aspect, there is provided a use of the medicament for treating or preventing an inflammatory response in an animal to downregulate TNFα and IL-6 in the animal.

[0029] In another aspect of the present invention, formula (A) is selected from the group consisting of formula (A0), formula (A1), formula (A2), formula (A3), formula (A4), formula (A5), or formula (A6); [ka] and stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another embodiment, the compound of formula (A) is formula (A0). In another embodiment, formula (A) is formula (A1). In another embodiment, formula (A) is formula (A2). In another embodiment, formula (A) is a compound of formula (A3). In another embodiment, formula (A) is formula (A4). In another embodiment, formula (A) is formula (A5). In another embodiment, formula (A) is formula (A6). In another embodiment, a preferred formula (A) is formula (A1).

[0030] In another aspect of the invention, there are provided compounds of formula (1) wherein W is H, i.e. compounds of formula (1.1) wherein R 0 , R, R 1 and R 2 is defined herein, [ka] In another aspect, a compound of formula (1.1) wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1.1) are provided, wherein R is H or (R 9 ) n is phenyl substituted with R 0 is H, methyl, ethyl, ethyl, or propyl, and R 1 is methyl, ethyl, propyl, isopropyl, isobutyl, or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 9are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH; R 2 and n is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1.1) are provided, wherein R is H, or (R 9 ) n is phenyl substituted with R 0 is H, methyl, ethyl, or propyl, and R 1 is methyl, ethyl, propyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl or -CH2 thiazolyl substituted with R 2 is cyclopropyl, cyclopentyl, cyclohexyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or R 2 However, each (R 9 ) n phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9 is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, —S(O)CH, and morpholine, and n is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1.1) are provided, wherein R is H, or (R 9 ) n is phenyl substituted with R 0 is H or methyl, and R 1is methyl, and R 2 is cyclopropyl, cyclohexyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or R 2 However, each (R 9 ) n phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9 is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, and n is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1.1) are provided, wherein R is H, or (R 9 ) n is phenyl substituted with R 0 is H or methyl, and R 1 is methyl, and R 2 is cyclopropyl, cyclohexyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or R 2 However, each (R 9 ) n phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl, or -NHphenyl substituted with 9 are independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, —NO2, cyano, —NH2, —N(CH3)2, —CF3, —CHF2, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3; or R 2 is phenyl or pyridinyl, each substituted with morpholine, and n is an integer 0, 1, or 2. In another aspect, compounds of formula (1.1), wherein R is H, or (R 9) n is phenyl substituted with R 0 is H or methyl, and R 1 is methyl, and R 2 However, (R 9 ) n and each R 9 are independently selected from methyl, methoxy, F, Cl, Br, cyano, and —CF3, and n is an integer 0, 1, or 2, their stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of Formula (1.1) are compounds of Table A, their stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of Table A are non-antibacterial compounds of Formula (1.1), their stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of Formula (1) are compounds of Formula (1.1) that are Example A-9, their stereoisomers, and pharmaceutically acceptable salts thereof.

[0031] In another embodiment, the composition comprises a compound of Formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of Table A of Formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Table A of Formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Table A of Formula (1.1), which is Example A-9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0032] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1.1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1.1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table A of Formula (1.1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table A of formula (1.1), i.e., Example A-9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response in the animal is due to a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or reduces the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0033] In another aspect, there is provided the use of a compound of formula (1.1), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1.1), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1.1) of Table A, i.e., Example A-9, its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is due to bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament to treat or prevent an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is a livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, the use of administering the medicament to an animal to treat or prevent an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0034] In another aspect of the invention, W is of formula (A) and formula (A) is R a is H, i.e., a compound of formula (1-A0), [ka] In the formula, R, R a , R 0 , R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A0), wherein R a is H, methyl, or ethyl, and R 0is H, methyl, ethyl, or propyl, and R, R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A0), wherein R a is H or methyl, and R 0 is H, methyl, ethyl, or propyl, and R, R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A0), wherein R a is H and R 0 is H, methyl, ethyl, or propyl, and R, R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (1-A0), wherein R a is H and R 0 is H, methyl, ethyl, or propyl, and R 1 is C1-C6 alkyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with, R is H, or R is each 9 ) n phenyl, thiophenyl, or pyridinyl substituted with R 2 , R 9 and n are as defined herein, or R and R 2 are linked to form a bond to form a di-oxo-oxathiazolyl ring, its stereoisomers, and pharmaceutically acceptable salts thereof. In another embodiment, the compound of formula (1-A0) is a is H and R 0 is H, methyl, ethyl, or propyl, and R 1 is C1-C6 alkyl or cyclohexyl, or R1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with, R is H, or R is each 9 ) n phenyl, thiophenyl, or pyridinyl substituted with R 2 is as defined herein, and each R 9 are independently selected from halo, methyl, ethyl, isopropyl, methoxy, —CF, cyano, nitro, oxo, amino, —N(CH), —S(O)CH, —S(O)CH, —SCH, and —S(O)NH; n is an integer 0, 1, or 2; or R and R 2 are linked to form a bond to form a di-oxo-oxathiazolyl ring, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (1-A0), wherein R a is H and R 0 is H, methyl, ethyl, or propyl, and R 1 is C1-C6 alkyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl or -CH2 thiazolyl substituted with R, where R is H or R is each 9 ) n phenyl, thiophenyl, or pyridinyl substituted with R 2 However, each (R 9 ) n phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, and n is an integer 0, 1, or 2. In another aspect, compounds of formula (1-A0), wherein R a and R 0 But both are H and R 1 is methyl and R is H, or R is each (R 9 ) n phenyl, thiophenyl, or pyridinyl substituted with R 2 However, each (R 9 ) n phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9 is independently selected from halo, methyl, ethyl, isopropyl, methoxy, -CF3, cyano, nitro, oxo, amino, -N(CH3)2, -S(O)CH3, -S(O)2CH3, -SCH3, and -S(O)2NH2, and n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0035] In another embodiment, the composition comprises a compound of formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0036] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1-A0), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1-A0), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response in the animal is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal, and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0037] In another aspect, there is provided a use of a compound of Formula (1-A0), its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided a use of a non-antibacterial compound of Formula (1-A0), its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of use, the animal is a livestock animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, the use of administering the medicament to an animal for treating or preventing an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0038] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is formula (A1), i.e., a compound of formula (1-A1), [ka] In the formula, R, R 0 , R 1 , R 2 , R 5 , and R 6 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (1-A1), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , R 2 , R 5 and R 6 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0039] In another embodiment, there is provided a compound of formula (1-A1), wherein R 0 is H, methyl, ethyl, or propyl, and R is H or each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is C1-C6 alkyl, cyclohexyl, or R 1 are respectively (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 )n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and R 5 and R 6 each independently represents H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, -OCF3, or -C(O)NR a R 8 , -R c S(O) p R 8 , -R c NR a R b , -R c OR b , or -S(O) p R 8 , or each (R 9 ) n or C0-C3 alkylphenyl, C0-C3 alkylC3-C6 cycloalkyl, C0-C3 alkyloxazolidinyl, C0-C3 alkylpyrrolidinyl, C0-C3 alkylpiperidinyl, C0-C3 alkylpiperazinyl, C0-C3 alkylmorpholinyl, C0-C3 alkyltetrahydropyranyl, C0-C3 alkyltetrahydrofuranyl, C0-C3 alkylpyrazolyl, C0-C3 alkylimidazolyl, C0-C3 alkylpyridinyl, C0-C3 alkylpyrimidinyl, C0-C3 alkylpyridazinyl, C0-C3 alkylthiazolyl, or C0-C3 alkylpyrazinyl substituted with R 5 and R 6 together with the nitrogen atom to which they are attached, each (R 9 ) nor Ring B is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl optionally substituted with at least one oxo, wherein each R 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. 0 is H, methyl, ethyl, or propyl, and R is H or each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is methyl or R 1 are respectively (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) ncyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and R 5 is H or C1-C6 alkyl, and R 6 is H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, -OCF3, -C(O)NR a R 8 , -R c S(O) p R 8 , -R c NR a R b , -R c OR b , or -S(O) p R 8 , or each (R 9 ) n or C0-C3 alkylphenyl, C0-C3 alkylC3-C6 cycloalkyl, C0-C3 alkylpyrrolidinyl, C0-C3 alkylpiperidinyl, C0-C3 alkylpiperazinyl, C0-C3 alkylmorpholinyl, C0-C3 alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridazinyl, C0-C3 alkylpyridinyl, or C0-C3 alkylthiazolyl substituted with R 5 and R 6 together with the nitrogen atom to which they are attached, each (R 9 ) n and forming ring B which is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, or tetrazolyl substituted with each R 9is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the present invention provides compounds of formula (1-A1), wherein R 0 is H, R is H, each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is methyl and R 2 H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and R 5 is H or C1-C6 alkyl, and R 6 is H, C1-C6 alkyl, methoxy, ethoxy, C1-C6 haloalkyl, -OCF3, -CH2OCF3, -(CH2)2OCF3, -CH2CN, -R c S(O) p CH3, -R c S(O) p NR a R b , -R c S(O)p Phenyl, -R c NR a R b , R c OR b , -R c NHC(O)CH3, wherein R a and R b are each independently H, methyl and ethyl, or R 6 However, each (R 9 ) n and each R is a C0-C3 alkylphenyl, a C0-C3 alkylC3-C6 cycloalkyl, a C0-C3 alkylpyrrolidinyl, a C0-C3 alkylpiperidinyl, a piperazinyl, a morpholinyl, a C0-C3 alkyltetrahydropyranyl, a pyrazolyl, an imidazolyl, a pyridazinyl, a C0-C3 alkylpyridinyl, or a C0-C3 alkylthiazolyl substituted with 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the present invention provides compounds of formula (1-A1), wherein R 0 is H, and R is H, (R 9 ) n is phenyl substituted with R 1 but , methyl, and R 2 imidazole optionally substituted with methyl, phenyl, -NHR b , -NCH2R b and R b is cyclohexyl or phenyl, each optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, (R 9 phenyl substituted with R 2is imidazolyl optionally substituted with methyl, and R 5 is H and R 6 is propyl, and each R 9 are independently selected from the group consisting of methyl, methoxy, F, Cl, cyano, and -CF3, and n is an integer 0, 1, or 2, as well as their stereoisomers and pharmaceutically acceptable salts. In another aspect, the compounds of Table B of Formula (1-A1), their stereoisomers, and pharmaceutically acceptable salts. In another aspect, the compounds of Table B of Formula (1-A1) that are non-antibacterial, their stereoisomers, and pharmaceutically acceptable salts. In another aspect, the compounds of Table B of Formula (1-A1) selected from the group consisting of Examples B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, or B-148, as well as their stereoisomers and pharmaceutically acceptable salts.

[0040] In another embodiment, the present invention relates to a composition comprising a compound of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a composition comprising a non-antibacterial compound of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a composition comprising a compound of Table B of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a composition comprising a non-antibacterial compound of Table B of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a composition comprising a non-antibacterial compound of Table B of Formula (1-A1), selected from the group consisting of B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, or B-148, or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0041] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table B of Formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table B of Formula (1-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, or B-148. In another aspect of the method, the inflammatory response in the animal is due to bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing an inflammatory response in the animal prevents or reduces the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is a livestock animal and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in the animal.

[0042] In another aspect, there is the use of a compound of formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is the use of a non-antibacterial compound of formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is the use of a non-antibacterial compound of Table B of formula (1-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided use of a therapeutically effective amount of a non-antibacterial compound of Table B of Formula (1-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, or B-148, to prepare a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of use, the animal is a livestock animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, the use of administering a medicament to an animal to treat or prevent an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0043] In another aspect of the invention, R 5 and R 6 are linked together with the nitrogen atom they share, forming (R 9 ) n Compounds of formula (1-A1), i.e., compounds of formula (1-A1a), which form ring B substituted with [ka] In the formula, R, R 0 , R 1 , R 2 , R 9In another aspect, the present invention provides compounds of formula (1-A1a), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , R 2 , ring B, R 9 and n are as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0044] In another embodiment, there is provided a compound of formula (1-A1a), wherein R 0 is H, methyl, ethyl, or propyl, and R is H or each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is C1-C6 alkyl or cyclohexyl, or R 1 are respectively (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and ring B is each (R 9 ) nor ring B, when fused to Y, is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, wherein each R 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. 0 is H, methyl, ethyl, or propyl, and R is H or each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is methyl or R 1 are respectively (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) ncyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and ring B is each (R 9 ) n and each R is an azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, or tetrazolyl substituted with 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1-A1a), wherein R 0 is H, and R is H, or each (R 9 ) n phenyl, pyridinyl, or thiophenyl substituted with R 1 is methyl and R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) ncyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and ring B is each (R 9 ) n and each R is an azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, or tetrazolyl substituted with 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (1-A1a), wherein R 0 is H, R is H, each (R 9 ) n phenyl or piperidinyl substituted with R 1 is methyl, and R 2 However, each (R 9 ) n ring B is piperidine, and each R 9 are independently selected from the group consisting of methyl, methoxy, F, Cl, Br, cyano, —NH2, —N(CH3)2, and —CF3, and n is an integer 0, 1, or 2, their stereoisomers, and pharmaceutically acceptable salts. In another aspect, the compounds of Table C of Formula (1-A1a), their stereoisomers, and pharmaceutically acceptable salts. In another aspect, the compounds of Table C of Formula (1-A1a), which are non-antibacterial, their stereoisomers, and pharmaceutically acceptable salts. In another aspect, the compounds of Table C of Formula (1-A1a), i.e., Examples C-4 or C-11, their stereoisomers, and pharmaceutically acceptable salts.

[0045] In another embodiment, the composition comprises a compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of Table C of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Table C of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of Table C of Formula (1-A1a), i.e., Example C-4 or C-11, its stereoisomer, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0046] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table C of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Table C of Formula (1-A1a), i.e., Example C-4 or C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response in the animal is due to bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0047] In another aspect, there is provided the use of a compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of Table C of Formula (1-A1a), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, there is provided the use of a non-antibacterial compound of Table C of Formula (1-A1a), i.e., Example C-4 or C-11, its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is due to bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament to treat or prevent an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is a livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, the use of administering the medicament to an animal to treat or prevent an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0048] In another aspect of the invention is a compound selected from the group consisting of: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (A-9), N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide (B-26), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[(4-chlorophenyl)methyl-methylsulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-41), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-48), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-49), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-50), 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (B-58), 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (B~60), N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide (B-107), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-113), N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide (B-148), 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (C-4), and (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (C-11), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0049] In another embodiment, the compound is selected from the group consisting of: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-50), N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide (B-107), (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-113), and 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (C-4), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0050] In another aspect is the compound (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-50), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0051] In another aspect is the compound N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide (B-107), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0052] In another aspect is the compound (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-113), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0053] In another aspect is the compound 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (C-4), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0054] In another aspect, the composition includes an exemplary compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4, and C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition includes an exemplary compound selected from the group consisting of B-50, B-107, B-113, and C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition includes Example B-50, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition includes Example B-107, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition includes Example B-113, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, a composition comprising Example C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0055] In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of an exemplary compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4, and C-11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of an exemplary compound selected from the group consisting of B-50, B-107, B-113, and C-4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of Example B-50, its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of Example B-107, its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of Example B-113, its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of Example C-4, its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect of this method, treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0056] In another aspect, there is provided the use of an exemplary compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4, and C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for preventing or treating an inflammatory response in an animal. In another aspect, there is provided the use of an exemplary compound selected from the group consisting of B-50, B-107, B-113, and C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for preventing or treating an inflammatory response in an animal. In another aspect, there is provided the use of Example B-50, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for preventing or treating an inflammatory response in an animal. In another aspect, there is the use of Example B-107, its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing or treating an inflammatory response in an animal. In another aspect, there is the use of Example B-113, its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing or treating an inflammatory response in an animal. In another aspect, there is the use of Example C-4, its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing or treating an inflammatory response in an animal. In another aspect, the use of the medicament for use in treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder in the animal. In another aspect of use, the animal is a livestock animal, and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, IL-6 and TNF-α are downregulated in the animal.

[0057] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is formula (A2), i.e., a compound of formula (1-A2): [ka] In the formula, R, R 0 , R 1 , R 2 , and R 7is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A2), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , R 2 , and R 7 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A2), wherein R 0 is H or methyl, and R 1 is methyl and R is H or (R 9 ) n phenyl optionally substituted with R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , or -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, as well as stereoisomers and pharmaceutically acceptable salts thereof.

[0058] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is formula (A3), i.e., a compound of formula (1-A3): [ka] In the formula, R, R 0 , R 1 , R 2 , and R 7 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A3), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , R 2 , and R 7 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A3), wherein R 0 is H or methyl, and R 1 is methyl and R is H or (R 9 ) n phenyl optionally substituted with R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , or -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2are each phenyl or pyridinyl substituted with morpholine, and each R 9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH; n is an integer 0, 1, or 2; R 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH 2 NH 2 , —CH 2 NHCH 3 or —CH 2 N(CH 3 ) 2 , its stereoisomers, and pharmaceutically acceptable salts thereof. In another embodiment, a non-antibacterial compound of formula (1-A3), i.e., 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((phenylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (Example No. A3-1, [M+H] + = 1018, i.e., R 0 is H and R 1 is methyl, and R 2 is 4-chlorophenyl, and R 7 is phenyl), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0059] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is (A4), i.e., a compound of formula (1-A4): [ka] In the formula, R, R 0 , R 1 , R2 and X' are as defined herein. In another aspect, the compounds of formula (1-A4) are compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , R 2 and X' are as defined herein, their stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A4), wherein R 0 is H or methyl, and R 1 is methyl and R is H or (R 9 ) n X' is F or Cl, and R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , or -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, as well as stereoisomers and pharmaceutically acceptable salts thereof. In another embodiment, a non-antibacterial compound of formula (1-A4), i.e., 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (Example No. A4-1, [M+H] + = 944, i.e., R 0 is H and R 1 is methyl, and R 2 is 4-chlorophenyl and X' is chloro), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0060] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is (A5), i.e., a compound of formula (1-A5): [ka] In the formula, R, R 0 , R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A5), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , and R2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A5), wherein R 0 is H or methyl, and R 1 is methyl and R is H or (R 9 ) n phenyl optionally substituted with R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , or -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, as well as stereoisomers and pharmaceutically acceptable salts thereof.

[0061] In another embodiment of the present invention, there is provided a compound of formula (1) wherein W is formula (A) and formula (A) is formula (A6), i.e., a compound of formula (1-A6): [ka] In the formula, R, R 0 , R 1 , and R 2 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (1-A6), wherein R 0 is H, methyl, ethyl, or propyl, and R, R 1 , and R 2 is as defined herein, or R and R 2 are linked to form a bond to form a di-oxo-oxathiazolyl ring, its stereoisomers, and pharmaceutically acceptable salts thereof. In another embodiment, the compound is represented by formula (1-A6), wherein R 0 is H or methyl, and R 1 is methyl and R is H or (R 9 ) n phenyl optionally substituted with R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH2OCH3, -(CH2)2OCH3, -CH2CF3, -CF3, -NHR b , or -NCH2R b and R b is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano, or —CF3, or R 2 However, each (R 9 ) n cyclopropyl, -CHcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl substituted with R 2 are each phenyl or pyridinyl substituted with morpholine, and each R 9are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, where n is an integer 0, 1, or 2, as well as stereoisomers and pharmaceutically acceptable salts thereof. In another embodiment, the non-antibacterial compound of formula (1-A6), i.e., 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (Example Nos. A6-1, [M+H] + 935, i.e., R 0 is H and R 1 is methyl, and R 2 is 4-chlorophenyl), its stereoisomers, and pharmaceutically acceptable salts thereof.

[0062] In another embodiment, the composition comprises a compound of formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5), or (1-A6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5), or (1-A6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a non-antibacterial compound of formula (1-A3) of Example A3-1, a non-antibacterial compound of formula (1-A4) of Example (A4-1), or a non-antibacterial compound of formula (1-A6) of Example (A6-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0063] In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), its stereoisomer, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method for treating or preventing an inflammatory response in an animal by administering to an animal in need thereof a therapeutically effective amount of a non-antibacterial compound of Formula (1-A3) of Example A3-1, a non-antibacterial compound of Formula (1-A4) of Example (A4-1), or a non-antibacterial compound of Formula (1-A6) of Example (A6-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response in the animal is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal, and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0064] In another aspect, there is the use of a compound of Formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is the use of a non-antibacterial compound of Formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided use of the non-antibacterial compound of Formula (1-A3) of Example A3-1, the non-antibacterial compound of Formula (1-A4) of Example (A4-1), or the non-antibacterial compound of Formula (1-A6) of Example (A6-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of use, the animal is a livestock animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, the use of administering the medicament to an animal for treating or preventing an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0065] In another aspect of the invention, R and R 2 are linked to form a bond to form a 2-di-oxo-oxathiazolyl ring, i.e., a compound of formula (1), 0 and R 1 is as defined herein, a stereoisomer thereof, or [ka] and pharmaceutically acceptable salts thereof. In another embodiment, a compound of formula (2) is provided, wherein R 0 is H, methyl, ethyl, or propyl, and W and R1 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (2) is 0 is H, and W and R 1 is as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0066] In another aspect of the invention, there are provided compounds of formula (2) wherein W is H, i.e., compounds of formula (2.1) wherein R 0 and R 1 is as described herein, [ka] In another aspect, a compound of formula (2.1) wherein R 0 is H, methyl, ethyl, or propyl, and R 1 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (2.1), wherein R 0 is H and R 1 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0067] In another embodiment, there is provided a compound of formula (2.1), wherein R 0 is H or methyl, and R 1 is C1-C6 alkyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 9are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH; and n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0068] In another aspect of the invention there is provided a compound of formula (2) wherein W is formula (A) and X is R a and R a is H, i.e., a compound of formula (2-A0), wherein R 0 and R 1 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. [ka] In another embodiment, there is provided a compound of formula (2-A0), wherein R a is H and R 0 is H, methyl, ethyl, or propyl, and R 1 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (2-A0), wherein R a is H and R 0 is H or methyl, and R 1 is C1-C6 alkyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 9are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH; and n is an integer 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0069] In another aspect of the invention, W is of formula (A) and X is -(CH) m NR 5 R 6 and m is an integer 1, i.e., a compound of formula (2-A1), [ka] In the formula, R 0 , R 1 , R 5 , and R 6 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (2-A1), wherein R 0 is H, methyl, ethyl, or propyl, and R 1 , R 5 , and R 6 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (2-A1), wherein R 0 is H or propyl, and R 5 is H and R 6 is propyl, and R 1 is C1-C6 alkyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with R 5 and R 6 together with the nitrogen atom to which they are attached, each (R 9 ) nforming ring B which is piperidinyl or piperazinyl optionally substituted with 9 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH2, —N(CH3)2, —CF3, —CHF2, —OCHF2, —S(O)2NH2, —SCH3, —S(O)CH3, and —S(O)2CH3, and n is an integer 0, 1, or 2. In another aspect, compounds of formula (2-A1), wherein R 0 is H or propyl, and R 5 is H and R 6 is propyl, and R 1 However, (R 9 ) n methyl or benzyl optionally substituted with R 5 and R 6 together with the nitrogen atom to which they are attached to form a piperidine, and each R 9 are independently selected from the group consisting of methyl, methoxy, F, Cl, cyano, and —CF3, and n is an integer 0, 1, or 2. In another aspect are compounds of Table D of formula (2-A1), their stereoisomers, and pharmaceutically acceptable salts thereof.

[0070] In another embodiment, the compound of Formula (2-A1) or a compound of Table D of Formula (2-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier. In another embodiment, the compound of Formula (2-A1) or a compound of Table D of Formula (2-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a composition comprising ...

[0071] In another aspect of this method, the inflammatory response in the animal is due to a bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or reduces the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0072] In another aspect, there is provided a use of a compound of Formula (2-A1) or a compound of Table D of Formula (2-A1), its stereoisomer, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal. In another aspect of use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of use, the animal is a livestock animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, the use of administering the medicament to an animal for treating or preventing an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

[0073] In another aspect of the invention, W is of formula (A) and X is -(CH) m OR 7 or X is -(CH2) m SR 7 and m is an integer 1, i.e., a compound of formula (2-A2) or (2-A3), wherein R 0 , R 1 , and R 7 are each as described herein; [ka] In another aspect, the compound is of formula (2-A2) or (2-A3), wherein R 0 is H, methyl, ethyl, or propyl, and R 1 and R 7 is as described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, the compound is of formula (2-A2) or (2-A3), wherein R 0 is H, methyl, ethyl, or propyl, and R 1 is C1-C6 alkyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2, and each R 9 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, and n is an integer 0, 1, or 2. In another aspect, compounds of Formula (2-A2) or Formula (2-A3), wherein R 0 is H and R 1 is methyl, and R 7 is H, methyl, ethyl, or propyl, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0074] In another aspect of the invention, W is of formula (A) and X is -(CH) m X' or X is -(CH2) m N3, or X is -(CH2) mCN and m is an integer 1, i.e., a compound of formula (2-A4), (2-A5) or (2-A6), wherein R 0 , R 1 , [ka] and X' are each as described herein. In another aspect, the compound is of formula (2-A4), (2-A5), or (2-A6), wherein R 0 is H, methyl, ethyl, or propyl, X' is fluoro or chloro, and R 1 is as described herein, as well as stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, compounds of formula (2-A4), (2-A5), or (2-A6), wherein R 0 is H, methyl, ethyl, or propyl, X' is fluoro or chloro, and R 1 is C1-C6 alkyl or cyclohexyl, or R 1 However, each (R 9 ) n benzyl, -CH2 pyridinyl, or -CH2 thiazolyl substituted with 9 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH, —N(CH), —CF, —CHF, —OCHF, —S(O)NH, —SCH, —S(O)CH, and —S(O)CH, and n is an integer 0, 1, or 2. In another aspect, compounds of Formula (2-A4), Formula (2-A5), or Formula (2-A6), wherein R 0 is H, methyl, ethyl, or propyl, and R 1 is methyl, its stereoisomers, and pharmaceutically acceptable salts thereof.

[0075] In another embodiment, the composition comprises a compound of Formula (2.1), Formula (2-A0), Formula (2-A2), Formula (2-A3), Formula (2-A4), Formula (2-A5), or Formula (2-A6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0076] In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to the animal in need thereof a therapeutically effective amount of a compound of Formula (2.1), Formula (2-A0), Formula (2-A2), Formula (2-A3), Formula (2-A4), Formula (2-A5), or Formula (2-A6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of this method, the inflammatory response in the animal is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of this method, treating or preventing an inflammatory response in the animal prevents or reduces the progression of a respiratory disease or disorder in the animal. In another aspect of this method, the animal is a livestock animal, and the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of this method, IL-6 and TNF-α are downregulated in the animal.

[0077] In another aspect, there is provided a use of a compound of (2.1), Formula (2-A0), Formula (2-A2), Formula (2-A3), Formula (2-A4), Formula (2-A5), or Formula (2-A6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing an inflammatory response in an animal. In another aspect of the use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and / or an environmental factor. In another aspect of the use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or alleviates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is a livestock animal. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, the use of administering the medicament to an animal for treating or preventing an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal. [Brief explanation of the drawings]

[0078] Consideration [Figure 1] Mechanisms of immunomodulators in the context of BRD progression [Figure 2] Summary of clinical and genomic time data [Figure 3] Plasma cytokine (IL-6, IL-8, IL-10, and IFN-γ) levels at arrival in feedlot calves at risk for BRD [Figure 4] Biomarker evaluation of M9 intratracheal lung challenge; results for IL-6 (A) and CD163 biomarkers (B)

[0079] It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., defined herein, as such may vary. The terminology used herein is for the purpose of describing embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0080] Unless otherwise defined, scientific and technical terms used in connection with the compounds of the invention defined herein shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. Generally, the nomenclature utilized in connection with and techniques of chemical synthesis, macrolides, and immunomodulation defined herein are those well known and commonly used in the art.

[0081] definition For purposes of the present invention, as described and claimed herein, the following terms and phrases are defined below.

[0082] As used herein, unless otherwise indicated, "additional agent(s)" refers to other pharmaceutical compounds or products that provide a therapeutically effective amount of the agent useful for treating bacterial or parasitic infections in an animal and / or modulate the immune response, as defined herein.

[0083] As used herein, "alkoxy," unless otherwise indicated, refers to an oxygen moiety having a further alkyl substituent. The alkyl portion (i.e., alkyl moiety) of an alkoxy group has the same definition as below. Non-limiting examples include -OCH, -OCHCH, -OCH(CH), -OC(CH), and the like.

[0084] As used herein, unless otherwise indicated, "alkyl" refers to a group of the general formula C n H 2n+1(C-C) alkyl refers to a saturated monovalent hydrocarbon alkane radical of the formula (I). The alkane radical can be straight-chained or branched, unsubstituted or substituted. For example, the term "(C-C) alkyl" refers to a monovalent straight-chain or branched-chain aliphatic group containing 1 to 6 carbon atoms; similarly, C-C alkyl refers to a monovalent straight-chain or branched-chain aliphatic group containing 1 to 3 carbon atoms. Non-exclusive examples of (C-C) alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl, and the like. The alkyl moiety can be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Alkyl groups are optionally substituted as defined herein. Additionally, when used in compound words such as alkylphenyl, the alkyl portion has the same meaning as defined herein and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Non-limiting examples of the compound word C0-C4 alkylphenyl include C0 phenyl (phenyl), C1 alkylphenyl (-CH2 phenyl; benzyl), C2 alkylphenyl (-CH2CH2 phenyl), and the like.

[0085] As used herein, "animal(s)" refers to individual animals that are mammals, unless otherwise indicated. Specifically, mammals refer to human and non-human vertebrates, and are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include companion animals and livestock. Non-exclusive examples of companion animals include dogs, cats, and horses. Non-exclusive examples of livestock include pigs, camels, rabbits, goats, sheep, deer, elk, and cattle (cattle and bison). A preferred livestock is cattle.

[0086] As used herein, "antibacterial" refers to a compound that has a minimum inhibitory concentration (MIC) of 64 μg / mL or less against any one strain of BRD pathogens, M. haemolytica, and P. multocida, unless otherwise indicated. As used herein, the term "non-antibacterial" refers to a compound that has an MIC of greater than 64 μg / mL against BRD pathogens (all strains tested), M. haemolytica, and P. multocida, unless otherwise indicated.

[0087] As used herein, unless otherwise indicated, "aryl" refers to an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring of 10 to 14 carbon members. Examples of such aryl rings include, but are not limited to, phenyl, naphthalenyl, or anthracenyl. Furthermore, when used in compound words such as alkylaryl (e.g., alkylphenyl), the alkyl and aryl moieties have the same meaning as defined herein and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain or ring carbon. Examples of CO-C3 alkylphenyl, e.g., CO alkylphenyl is phenyl, C1-alkylphenyl is -CH2 phenyl (benzyl), and C2-alkylphenyl is -CH2CH2 phenyl. The phenyl ring is optionally substituted as defined herein.

[0088] As used herein, unless otherwise indicated, "azalide" refers to a class of macrolides that contain a nitrogen atom in the macrolide ring, which confers different pharmacokinetic properties and is associated with greater stability of the molecule.

[0089] As used herein, "chiral," unless otherwise indicated, refers to the structural characteristic of a molecule that makes it non-superimposable on its mirror image (e.g., "R" and "S" enantiomers).

[0090] As used herein, unless otherwise indicated, a "composition" refers to a compound of the invention formulated with at least one pharmaceutically acceptable excipient for administration.

[0091] As used herein, "compounds of the invention" and "compounds," unless otherwise indicated, include azalide compounds of formulae (1), (1A), (1.1), (1-A0), (1-A1), (1-A1a), (1-A2), (1-A3), (1-A4), (1-A5), (1-A6), (2), (2A), (2.1), (2-A0), (2-A1), (2-A2), (2-A3), (2-A4), (2-A5), and (2-A6), their stereoisomers, and pharmaceutically acceptable salts thereof. The terms(s) also include the respective 13-membered macrolides in equilibrium with a 15-membered macrolide ring. Furthermore, whenever an example number is presented herein, for example, as a compound, a composition comprising the compound, a method of using the compound, and the use of the compound as a medicament, the example number is equivalent to the chemical name of the compound as further described herein. For example, B-113 is equivalent to (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, as defined in Table B.

[0092] As used herein, unless otherwise indicated, "cycloalkyl" includes fully saturated or partially saturated carbocyclic alkyl moieties, i.e., 3- to 6-membered rings, containing only carbon atoms, and may be monocyclic or part of a fused or bridged ring moiety. Examples of saturated carbocyclic (cycloalkyl) rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Non-limiting examples of partially saturated cycloalkyls include cyclopropene, cyclobutene, and the like. Preferred cycloalkyls are 3- to 6-membered saturated monocyclic rings, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may be attached to a chemical moiety by any one of the carbon atoms in the carbocyclic ring. A cycloalkyl group is optionally substituted with at least one substituent. Furthermore, when used in compound words such as alkylcycloalkyl, the alkyl and cycloalkyl moieties have the same meaning as defined herein and may be attached to a chemical moiety by any one of the carbon atoms in the aliphatic chain. Examples of C0-C4 alkylC3-C6 cycloalkyls include, for example: CO alkyl C3-C6 cycloalkyl is C3-C6 cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C1-alkyl C3-C6 cycloalkyl is -CH2C3-C6 cycloalkyl (e.g., -CH2-cyclopropyl, -CH2-cyclohexyl, etc.), C2-alkyl C3-C6 cycloalkyl is -CH2CH2C3-C6 cycloalkyl (e.g., -CH2CH2-cyclopropyl, -CH2CH2-cyclopentyl), etc. The cycloalkyl moiety is optionally substituted as defined herein.

[0093] As used herein, unless otherwise indicated, "cytokine" refers to a general class of biological molecules that affect / influence all types of cells and influence immunological responses and non-immunological biological processes. This definition includes, but is not limited to, biomolecules that act locally or systemically and, when used in the compositions or methods of the invention, play a role in controlling or regulating the immune response of an animal. Exemplary cytokines for use in practicing the invention include, but are not limited to, interleukins (e.g., IL-1 through IL-29, particularly IL-1, IL-1β, IL-6, IL-9, IL-10, and IL-12), chemokines (e.g., CCL2 through 5, CCL10, CCL11, CXCL8 (IL-8), and CXCL10), tumor necrosis factors (e.g., TNF-α and TNF-β), and NF-κB, which mediates the induction of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 in monocytes and macrophages, among others.

[0094] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine, unless otherwise specified. Furthermore, when used in compound words such as "haloalkyl" or "haloalkoxy," the alkyl and alkoxy may be partially or fully substituted with halogen atoms, which may be the same or different, and the alkyl and alkoxy moieties have the same meaning as above and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Examples of "haloalkyl" include F3C-, ClCH2-, CF3CH2-, and CF3CH2CH2-. The term "haloalkoxy" is defined analogously to the term "haloalkyl." Examples of "haloalkoxy" include CFO-, CCl3CHO-, HCF2CH2CH2O-, and CF3CHO-.

[0095] As used herein, unless otherwise indicated, "heteroaryl" or "Het" refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to 10-membered fused aromatic ring, wherein the monocyclic and fused ring moieties each independently contain one or more heteroatoms, preferably 1 to 4 heteroatoms, selected from N, O, and S. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Non-exclusive examples of fused heteroaryls include benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, and the like. Heteroaryl groups may be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms in the monocyclic or fused ring. Furthermore, when used in compound terms such as alkylheteroaryl (e.g., C0-C4 alkylheteroaryl), the alkyl and heteroaryl moieties have the same meaning as defined herein and may be attached to the chemical moiety by any one of the carbon atoms in the aliphatic chain. For example, a C0 alkylheterocycle is a heterocycle (e.g., pyrazolyl, imidazolyl, pyridinyl, piperazinyl, etc.), a C1 alkylheteroaryl is -CH2 heteroaryl (e.g., -CH2 imidazolyl, -CH2 pyridinyl, etc.), a C2 alkylheteroaryl is -CH2CH2 heteroaryl (e.g., -CH2CH2 pyrazolyl, -CH2CH2 oxazolyl, -CH2CH2 pyrimidinyl, etc.), etc. Heteroaryl is optionally substituted as defined herein.

[0096] As used herein, unless otherwise indicated, "heterocycle" refers to a partially saturated or saturated 3- to 10-membered monocyclic, fused, or bridged ring structure containing one or more heteroatoms, preferably 1 to 4 heteroatoms, each independently selected from N, O, and S. Non-exclusive examples of heterocycles include oxiranyl, thiaranyl, aziridinyl, oxetanyl, azetidinyl, thiatanyl, tetrahydrofuranyl, pyranyl, pyrazolidinyl, oxazolidinyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, tetrahydropyridinyl, 2H-azirinyl, 2,3-dihydro-azetyl, 3,4-dihydro-2H-pyrrolyl, and the like. The heterocyclic group may be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms in the ring. Furthermore, when used in compound words such as alkylheterocycle (e.g., C0-C4 alkylheterocycle), the alkyl and heterocycle moieties have the same meaning as defined herein and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. For example, a C0 heterocycle is a heterocycle (e.g., piperidinyl, morpholinyl, azetidinyl, etc.), a C1 alkylheterocycle is a -CH2 heterocycle (e.g., -CH2 morpholinyl, etc.), a C2 alkylheterocycle is a -CH2CH2 heterocycle (e.g., CH2CH2 pyrrolidinyl, -CH2CH2 thiomorpholinyl, etc.), etc. Heterocycles are optionally substituted as defined herein.

[0097] As used herein, unless otherwise indicated, "macrolide(s)" refers to compounds characterized by a large lactone ring containing 12 to 16 carbon atoms to which one or more deoxy sugars are attached via glycosidic bonds, and includes the class of azalides.

[0098] The term "optionally substituted" is used interchangeably herein with the phrases substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. An optionally substituted group may also have no substituents. Thus, "(R 9 ) n The phrase "optionally substituted with" means that the number of substituents can vary from 0 to 1, 2, or 3 possible substituents, where n is defined herein as an integer 0, 1, 2, or 3.

[0099] As used herein, unless otherwise indicated, "pharmaceutically acceptable" refers to a substance or composition that must be chemically and / or toxicologically compatible with other ingredients comprising the formulation, composition, and / or with the animal to be treated therewith.

[0100] As used herein, unless otherwise indicated, "protecting group" or "Pg" refers to a substituent commonly used to block or protect an alcohol on a compound, thereby preserving that functionality while allowing other functional groups on the compound to react. Non-exclusive examples of alcohol protecting groups include 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate ether (Ac), benzoate ether (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), ethoxyethyl acetal (EE), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), benzyloxycarbonyl (Cbz), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS, TBDMS), and tert-butylphenylsilyl ether (TBDPS).

[0101] As used herein, unless otherwise indicated, "saturated" or "partially saturated" refers to cycloalkyl rings having 3 to 6 carbon atoms and heterocyclic rings containing 2 to 5 carbon atoms and at least one heteroatom selected from N, O, and S, wherein each saturated ring contains a single bond between adjacent carbon atoms or carbon heteroatoms, e.g., cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, piperazine, etc. Partially saturated rings contain at least one double bond between adjacent carbon atoms or carbon heteroatoms, e.g., cyclobutene, cyclopentene, cyclohexa-1,3-diene, 2,3-dihydroazetate, 2,5-dihydrofuran, 2H-thiopyran, etc.

[0102] As used herein, "stereoisomer" refers to a compound of the present invention having two or more asymmetric carbon atoms, unless otherwise indicated. In the general formulae shown herein, a solid wedge-shaped bond indicates that the bond is above the plane of the paper, and a broken wedge-shaped bond indicates that the bond is below the plane of the paper. The compounds of the present invention can occur as individual enantiomers or diastereomers, or mixtures thereof (including racemic mixtures). All such isomers are included in the present invention.

[0103] As used herein, "stress" or "stressful" refers to a specific or non-specific response that varies in magnitude, unless otherwise indicated. A stressor is a specific event, experience, or environmental stimulus that affects an animal's health, which may be perceived as acute, chronic, disruptive, or uncontrollable. Non-exclusive examples of stressors in animal health include natural disasters (e.g., floods, fires, and earthquakes), significant life events (e.g., relocation / transportation, weaning, maternal and herd separation, proximity of animals from different sources, tail docking, needle teething, pain, lack of food and water, and acute or chronic illness), and acute / chronic disruptions (e.g., temperature and humidity fluctuations, confinement, shipping, inadequate nutrition and hydration, and storms), loud noises (e.g., thunder, barking, fireworks, etc.), changes in the environment, pollutants, etc.

[0104] As used herein, unless otherwise indicated, a "therapeutically effective amount" refers to an amount of a compound of the invention that (i) treats or prevents a particular disease or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or disorder.

[0105] As used herein, "treatment," "treating," and the like, unless otherwise indicated, refer to the control, prevention, reversal, alleviation, reduction, or suppression of inflammation caused by environmental, bacterial, viral, fungal, or parasitic infections, and / or internal diseases by modulating immunological responses. As used herein, these terms also encompass preventing the onset of a disorder or condition or symptoms associated with a disorder or condition, depending on the state of the animal, and also include reducing the severity of a disorder or condition or symptoms associated therewith. Treatment can also refer to the administration of a compound of the invention to an animal that is not suffering from an infection, immunological episode, or disease disorder or complex at the time of administration. As will be appreciated, it is not always possible to distinguish between "preventing" and "suppressing" a disease or disorder, as the ultimate initiating event may be unknown or may be latent.

[0106] Except in the operating examples, or where specifically indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." "About," as used herein, refers to the stated value of the variable and all values ​​of the variable that are within experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the stated value, whichever is greater.

[0107] The compounds of the present invention have several asymmetric centers. Compounds with asymmetric centers may give rise to enantiomers (optical isomers), diastereomers (constitutional isomers), or both, and it is intended that all enantiomers and diastereomers, whether in mixtures or as pure or partially purified compounds, are included within the scope of the present invention. The present invention is meant to encompass all stereogenic forms of the compounds of the present invention. The present invention includes all stereoisomers of the compounds of the present invention.

[0108] The independent synthesis of stereoisomerically enriched compounds or their chromatographic separation can be achieved by appropriate modification of the methodology disclosed herein, as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated so that individual enantiomers or diastereomers are isolated. Separation can be carried out by methods known in the art, such as coupling of racemic mixtures of compounds followed by separation of the individual stereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base.

[0109] The derivatives can then be converted to pure stereoisomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which are well known in the art. Alternatively, any stereoisomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0110] During any of the processes for the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P.G.W. Buts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0111] Macrolide Chemistry Macrolides are known to have strong binding affinity to the P site on the 50S subunit of bacterial ribosomes and inhibit protein synthesis. Modification of the desosamine group of macrolides, either by modifying the dimethylamino group to block salt bridges and / or by modifying the adjacent hydroxyl group to affect the hydrogen bond formed, disrupts this interaction, thereby eliminating the antibacterial activity of the compounds of the present invention. Cladinose modification has a relatively small effect on bacterial ribosome binding but may affect the physicochemical properties, pharmacokinetics, and cell permeability of the compound. Therefore, modifying the macrolide structure can reduce or eliminate antibacterial activity, even if the molecule retains its ability to bind to bacterial ribosomes, by either isolating the molecule from entering bacteria or enhancing its efflux from bacteria.

[0112] lipophilic The lipophilicity of an organic compound can be described by the partition coefficient, logP, which can be defined as the ratio of the concentrations of the non-ionized compound at equilibrium between the organic and aqueous phases. Generally speaking, more lipophilic compounds are less soluble in aqueous media. A negative logP value indicates that the compound has a higher affinity for the aqueous phase (hydrophilicity); when logP = 0, the compound is equally distributed between the lipid and aqueous phases, and a positive logP value indicates a higher concentration in the lipid phase (lipophilicity). Lipophilicity is a major determinant of a compound's absorption, distribution in the body, penetration across important membranes and biological barriers, metabolism, and excretion. The compounds of the present invention are lipophilic (logP approximately 1 to 5.758), which aids their transport and absorption into respiratory tissues, such as the lungs.

[0113] Composition / Formulation The pharmaceutical compositions of the present invention can be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, entrapping, or freeze-drying processes or spray-drying. Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which facilitate processing of the active compound into a preparation for administration to an animal in need thereof. The formulations of the present invention can be designed to be short-acting, immediate-releasing, long-acting, and sustained-releasing. Thus, pharmaceutical formulations can also be formulated for controlled release or slow release, depending on the selected route of administration.

[0114] Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present invention. Such excipients and carriers (including water) are described, for example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991).

[0115] For BRD and SRD, pharmaceutical compositions are typically formulated for parenteral administration, e.g., in a liquid carrier or suitable for reconstitution into a liquid solution or suspension for parenteral administration. In general, such compositions typically include a pharmaceutically acceptable carrier. Pharmaceutical carriers according to the present invention can be sterile liquids, such as water, saline, aqueous dextrose, aqueous glycerol, and / or oils, including those of petroleum, animal, vegetable, or synthetic origin, such as soybean oil, mineral oil, and sesame oil. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences," 18th Edition, by E.W. Martin. Pharmaceutical compositions containing the compounds of the present invention can be administered orally, topically, or parenterally (i.e., intramuscular, subcutaneous, intravenous, and intradermal injection). Pharmaceutical compositions containing the compounds of the present invention can also be administered by intramammary and intrauterine injection.

[0116] The pharmaceutical compositions and formulations defined herein can be prepared by mixing the compounds of the present invention having the desired purity with one or more pharmaceutically acceptable carriers in the form of a lyophilized formulation or an aqueous solution. The term "carrier" refers to a diluent, excipient, or vehicle with which the compounds of the present invention are administered. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and may include buffers (e.g., NaOH, KOH, HCl, phosphates, citrates and other organic acids (e.g., citric acid, acetic acid, benzoic acid, malic acid, etc.); antioxidants (e.g., butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, monothioglycerol, propyl gallate, etc.); preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, chlorobutanol, thimerosal parabens such as methyl or propylbenzyl, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc.); hydrophilic polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid, polyacrylamide, xanthan gum, etc.). gum, etc.); amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine, lysine, etc.); chelating agents such as EDTA; monosaccharides, disaccharides, and other carbohydrates (sugars such as sucrose, mannitol, trehalose, or sorbitol, glucose, mannose, or dextrin); and counterions that form salts, such as sodium; metal complexes (e.g., Zn-protein complexes). The carrier can be a solvent or reconstitution medium or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, water, or phosphate-buffered saline (PBS).Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0117] Solutions or suspensions used for parenteral administration typically contain one or more of the following: a sterile carrier such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid, BHA, BHT, monothioglycerol, or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and an agent for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid, citric acid, or sodium hydroxide. Such preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Formulations used for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through sterile filtration membranes and by irradiation. Injectable compositions can contain the active ingredient (drug) in an amount ranging from about 1 to 250 mg / mL, more preferably at a concentration ranging from about 1 to 100 mg / mL. Without limiting the scope of the compositional components, an injectable composition containing a compound of Formula (1) or a pharmaceutically acceptable salt thereof (e.g., acetate) can be prepared by dissolving the compound (e.g., 1 to 25 mg / mL) in a composition containing citric acid, propylene glycol, water, and, optionally, an antioxidant (e.g., monothioglycerol). As described herein, the composition can contain about 90% (± about 6%) lactone A and 10% (± about 6%) lactone B of the compound of Formula (1). The pH of the composition can be adjusted with NaOH and / or HCl, as needed. Methods for preparing such formulations will be apparent to those skilled in the art and can be prepared according to the procedures described in U.S. Pat. No. 6,514,945.

[0118] For oral use, the pharmaceutical compositions of the present invention can be administered in the form of, for example, tablets or capsules, powders, dispersible granules or cachets, or as an aqueous solution or suspension. Oral compositions generally include an inert or edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration, the therapeutic agent can be combined with a carrier and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, sodium starch glycolate, or corn starch; lubricants such as magnesium stearate or stearates; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents.

[0119] Dosage Pharmaceutical compositions suitable for use in the present invention include compositions containing the active ingredient in an amount sufficient to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound of the present invention effective to prevent, alleviate, or ameliorate symptoms / signs of disease or prolong the survival of the animal being treated. The amount of the active ingredient, a compound of the present invention, can vary widely or be adjusted in the pharmaceutical composition and unit dosage form depending on the method of administration, the potency of the particular compound, and the desired concentration. Determining a therapeutically effective amount is well within the capabilities of one skilled in the art. Generally, the amount of active ingredient ranges from 0.01% to 99% by weight of the composition.

[0120] Generally, a therapeutically effective dosage of the active ingredient ranges from about 0.01 mg / kg body weight to about 10 mg / kg body weight, preferably from about 0.02 mg / kg body weight to about 1 mg / kg body weight, more preferably from about 0.04 mg / kg body weight to about 0.8 mg / kg body weight, and even more preferably from about 0.06 mg / kg body weight to about 0.6 mg / kg body weight. A preferred administration regimen is parenteral administration of about 0.05 mg / kg body weight to about 0.8 mg / kg body weight via subcutaneous injection. It should be understood that dosages may vary depending on the requirements of each individual animal and the severity of the disorder or disease being treated. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals during the course of treatment. The preferred route of administration is parenteral. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection. The preferred route of administration is via subcutaneous injection. The compounds of the invention may be administered to animals at the first sign of stress or bacterial infection, prior to shipment from the farm or ranch, or upon arrival at the feedlot.

[0121] The compounds of the present invention can be administered alone or in combination with one or more additional agents that modulate the immune system of a mammal, or in combination with an anti-inflammatory agent, or in combination with one or more antibacterial agents, in a pharmaceutically acceptable form. Furthermore, the compounds of the present invention can also be co-administered with vitamins and / or minerals. Non-limiting examples of anti-inflammatory agents include ketoprofen, cyclosporin A, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). Non-limiting examples of antibacterial agents include novobiocin, aminoglycosides (e.g., gentamicin, neomycin, dihydrostreptomycin, spectinomycin, etc.), flufenicol, ceftiofur, cephapirin, ormetoprim, danofloxacin, enrofloxacin, bambermycin, ionophores (e.g., laidromycin, lasalocid, monensin, narasin, salinomycin, lincomycin, pirimicin), macrolides (e.g., erythromycin, gamithromycin, tildipirocin, tilmicosin, tulathromycin, tilavalosin ... Non-limiting examples of minerals include calcium, magnesium, phosphorus, potassium, sodium, sulfur, cobalt, copper, iodine, iron, manganese, selenium, chromium, and zinc. Non-limiting examples of vitamins include vitamins A, D, E, K, and B, including thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and B12.These additional co-agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different dosing schedules, in accordance with standard medical or veterinary practice known to those skilled in the art.

[0122] Medical and Veterinary Uses The methods defined herein are generally performed on an animal in need thereof. The animal in need may have, have been diagnosed with, be suspected of having, or be at risk for developing a disease, disorder, or condition associated with bacterial infection, viral infection, parasitic infection, inflammation, or an immune response. The disease or disorder may include respiratory disease, reproductive diseases such as mastitis or metritis, inflammatory bowel disease, bovine viral diarrhea virus (BVDV), infectious bovine rhinotracheitis (IBR), bovine respiratory syncytial virus (BRSV), parainfluenza virus, bovine coronavirus, psoriasis, multiple sclerosis, rheumatoid arthritis, allergic autoinflammatory disease, or autoimmune disease. Generally, a safe and effective amount of a compound of the invention is an amount that will elicit a desired therapeutic effect in an animal, e.g., while minimizing undesirable side effects. In various embodiments, an effective amount of a compound of the invention may substantially reduce inflammation or an immune response, slow the progression of a disease, disorder, or condition associated with inflammation or an immune response, or limit the onset of a disease, disorder, or condition associated with inflammation or an immune response.

[0123] The compounds of the present invention are macrolide (azalide) analogs that lack antibacterial activity against BRD pathogens and have been shown to have immunomodulatory properties that may prevent and / or control symptoms of BRD in cattle. Therefore, these macrolides are useful therapeutic agents for treating and / or controlling respiratory diseases that may be induced by environmental stimuli, stress, and bacterial infections. Some non-limiting macrolides used to treat BRD include Draxxin® (tulathromycin), Zuprevo® (tildipirosin), and Zactran® (gamithromycin).

[0124] Draxxin®, an injectable solution, is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis, and for the control of respiratory disease in cattle at high risk for developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. Cattle are administered 2.5 mg / kg of Draxxin® subcutaneously. In pigs, Draxxin® is indicated for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae, and for the control of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae in pig herds diagnosed with SRD. Pigs receive an intramuscular injection of 2.5 mg / kg of Draxxin®.

[0125] The compounds of the present invention can treat, reduce, or prevent diseases, disorders, or conditions associated with inflammation or immune responses. Inflammation is a potential danger signal and a critical response to organ damage in the body. The inflammatory response, commonly referred to as the inflammatory cascade, can be acute or chronic. Acute inflammation is part of the immune response and is the body's immediate response to injury or assault caused by physical trauma, infection, stress, or a combination of all three. Acute inflammation helps prevent further injury and promotes the healing and recovery process. However, if inflammation becomes self-perpetuating, it can lead to chronic or long-term inflammation.

[0126] Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. Initial inflammatory activation occurs, followed almost immediately by a reactive, suppressive anti-inflammatory response. This systemic inflammatory response (SIR) is typically manifested as an increased systemic expression of both pro- and anti-inflammatory species. The systemic inflammatory response begins with inflammation in response to exogenous (microbial, physical, or chemical) or endogenous (immunological or neurological) factors. The response begins when inflammatory cells at the site of inflammation, such as macrophages, become activated and rapidly produce TNF-α and IL-1. These cytokines then activate the cytokine cascade, resulting in the production of pro-inflammatory cytokines, IL-6, and IL-8, as well as other chemokines. Inflammatory stimuli also trigger the synthesis of anti-inflammatory cytokines and specific cytokine inhibitors to control the extent of the inflammatory response. Anti-inflammatory cytokines, such as IL-4, IL-10, IL-11, and IL-13, inhibit the synthesis of proinflammatory cytokines, while naturally occurring inflammatory cytokine inhibitors neutralize inflammatory cytokine activity by binding to proinflammatory cytokine receptors, decoy receptor antagonists, and cytokine-binding proteins. The interactions between these proinflammatory cytokines, anti-inflammatory cytokines, and naturally occurring cytokine inhibitors determine the inflammatory response and its effectiveness in suppressing the inflammatory response and leading to resolution of the initiating process. The main known mediators involved in the evolution of SIRS are cytokines, nitric oxide, platelet-activating factor (PAF), and eicosanoids. The systemic response to infection is mediated through macrophage-derived cytokines that target end-organ receptors in response to injury or infection. However, the production of anti-inflammatory proteins and lipid molecules also occurs to attenuate and terminate the inflammatory response. These mediators initiate overlapping processes that directly affect the endothelium, cardiovascular, hemodynamic, and coagulation mechanisms. If a balance between pro- and anti-inflammatory substances is not established and homeostasis is not restored, a massive pro-inflammatory response (i.e., SIRS) and multiple organ dysfunction syndrome (MODS) can occur.Thus, after the first proinflammatory mediators are released, the body mounts a compensatory anti-inflammatory response to the initial inflammatory response. The anti-inflammatory response can be as robust as the inflammatory response, and in some cases even more robust. In addition to proinflammatory cytokines, other mediators, such as NO, PAF, prostaglandins, and leukotrienes, are also produced. These molecules are also involved in the activation of complement, coagulation, and kinin cascades.

[0127] Diseases associated with inflammation or immune responses include, for example, bacterial infections; viral infections; fungal infections; parasitic infections; asthma; allergies; age-related macular degeneration; dermatitis; pain; mastitis; metritis; autoinflammatory diseases; autoimmune diseases; inflammatory bowel disease; dermatitis, multiple sclerosis; osteoarthritis; osteoporosis; psoriasis; rheumatoid arthritis and osteoarthritis; synovitis, acne, pustulosis, hyperostosis, airway and respiratory diseases (e.g., equine respiratory tract disease and canine infectious respiratory disease); respiratory disease complex (bovine and porcine), ischemia-reperfusion, feline chronic kidney disease, feline and canine degenerative mitral valve disease (inflammatory complex; e.g., due to upregulation of valvular and myocardial expression of cytokines, chemokines, and adhesion molecules in heart failure). and other inflammatory and immune diseases and disorders. The compounds of the present invention can treat diseases, disorders, or conditions associated with inflammation by modulating cytokines, chemokines, and inflammatory markers, such as IL6, IL-1β, NFKB, CSP136, LCN, CXCL8 (IL-8), TNFα, and induce TLR4 signaling.

[0128] Macrolide immunomodulatory The chemistry of macrolides provides a basis for understanding their immunomodulatory effects. Macrolides are defined as cationic amphiphilic drugs, and cell penetration is primarily determined by their lipophilicity and cationicity at physiological pH. Cell membrane penetration by macrolides results in phospholipid depolarization, resulting in the translocation of both the drug and phospholipids to the cytoplasm and lysosomes, ultimately resulting in the intracellular state of phospholipidosis. Their polar association with intracellular phospholipids, primarily phosphatidylcholine, inhibits their natural degradation by phospholipase enzymes, resulting in the reduction of primary cell signaling components, such as arachidonic acid. The reduction in arachidonic acid is hypothesized to prevent the normal production of eicosanoid metabolites, including prostaglandins, thromboxanes, leukotrienes, and lipoxins. Additionally, indirect inhibition of the COX family of inflammatory mediators, NFkB, and AP-1, and their associated proinflammatory cytokine production, has been observed. The reduction in the cell's ability to signal both intracellularly and extracellularly is host-dependent. In healthy animals, macrolide treatment has been demonstrated to stimulate neutrophil and macrophage responses upon disease stimulation, however, inhibition or reversal of inflammation is observed in the presence of acute or chronic inflammatory conditions.

[0129] Modulation of host defense by azithromycin and other macrolide antibiotics occurs through interactions with structural cells, such as epithelial or endothelial cells, smooth muscle cells, or fibroblasts, as well as leukocytes (macrophages, polymorphonuclear leukocytes or neutrophils, mononuclear leukocytes or monocytes, T cells, and dendritic cells). Cellular accumulation of macrolides occurs through passive transport into cells, which does not require cellular energy, carrier proteins, and is unsaturated. This mechanism is distinct from and therefore irrelevant to ribosome binding, which is associated with antibiotic activity. For example, azithromycin aglycone, which does not exhibit antibiotic activity, exhibits high levels of induced phospholipidosis (J. Parnham et al. / Pharmacology & Therapeutics 143 (2014) 225-245). Azithromycin penetrates the cell membrane bilayer, stabilizing the membrane, reducing its fluidity, and neutralizing the charge of phospholipids in the inner membrane. This results in reduced release and liberation of fatty acids from enzymes bound by electrostatic charges to membranes, resulting in the modulation of signaling pathways and the inhibition of activation of transcription factors, including AP-1 and NFκB. The signaling pathways most affected likely depend on the specific cell, its activation state, and the stimuli being activated. Molecules dependent on negatively charged phospholipids are also affected. Azithromycin accumulates in lysosomes and modulates MPR trafficking of enzymes and lipids through lipid remodeling in the lysosomal membrane. One well-documented aspect is their ability to neutralize inflammatory responses, as demonstrated by down-regulation of cytokine production (IL-1β, TNF-α, IL-6) via the NFκB pathway and effects on granulocytes and / or gene expression.

[0130] Immune activity can also be assessed by analyzing CD163, a scavenger receptor that binds hemoglobin / haptoglobin and is expressed on macrophages where it is thought to be involved in innate immune sensing, aiding in the clearance of activated macrophages, thereby preventing oxidative damage to tissues.

[0131] CD163 also functions as an innate immune sensor for Gram-positive and Gram-negative bacteria. Therefore, high CD163 expression in macrophages is considered a highly correlated biomarker of inflammation and is a characteristic of tissues responding to inflammation. Scavenging of oxidized and inflammatory hemoglobin, leading to stimulation of heme-oxygenase-1 and the production of anti-inflammatory heme metabolites, indicates that CD163 indirectly contributes to the anti-inflammatory response (Antioxid Redox Signal., Etzerodt et al., 2013, 18(17), pp. 2352-2363). CD163 may participate in processes leading to lung pathology in BRD. CD163 expression may also correlate with elevated levels of IL-6, as observed in BRD. CD163 surface expression has been experimentally induced by IL-6 incubation on monocytes and macrophages (Journal of Leukocyte Biology; Buechler et al., vol. 67, January 2020; pp. 97-103). Alternatively, cross-linking of CD163 on alveolar macrophages with a monoclonal antibody induced a protein tyrosine kinase-dependent signal that resulted in slow calcium mobilization, inositol triphosphate generation, and secretion of IL-6 and GM-CSF (Journal of Leukocyte Biology; Van de Heuvel et al., vol. 66, November 1999; pp. 858-866). The anti-inflammatory immunomodulatory drug tacrolimus has been shown to slightly increase CD163 expression (PLOS ONE; Kannegleter, et. al., January 2017; pp. 1-19), while a later study (HHS Public Access; Motta, et. al., Oral Dis. 2018, 24(4) pp. 580-590) reported no change in CD163 expression. Similarly, azithromycin (British Journal of Pharmacology, Vrancic, et. al.; 2012, 165; pp. 1348-1360) reported an increase in CD163 expression.CD163 expression upregulates glucocorticoids, IL-6, IL-10, and hemoglobin, and downregulates IL-4, IFN-γ, TNF-α, CXCL4, and GM-CSF. In contrast, CD163 was suppressed in M9-treated cattle, correlating with the proposed mechanism of reduced inflammatory status.

[0132] Cytokines are considered a broad and loose category of small proteins (5–20 kDa) that are important in cell signaling. Their release influences the behavior of surrounding cells. Cytokines can be described as immunomodulators, participating in autocrine, paracrine, and endocrine signaling. Cytokines are generally known to include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors (TNFs), but generally do not include hormones or growth factors. Cytokines can be produced by a wide range of cells, including immune cells such as macrophages, neutrophils, B lymphocytes, T lymphocytes, and mast cells, as well as epithelial cells, endothelial cells, fibroblasts, and various stromal cells, and a given cytokine can be produced by more than one type of cell. Cytokines can act through receptors and are particularly important in the immune system. Cytokines can regulate the balance between humoral and cell-based immune responses, and they can control the maturation, growth, or responsiveness of specific cell populations. Some cytokines can enhance or inhibit the action of other cytokines in complex ways. Cytokines can be important in health and disease, particularly the host response to infection, immune responses, inflammation, stress, trauma, sepsis, cancer, and reproduction.

[0133] Interleukin-6 (IL-6) is a proliferative cytokine that functions as both a proinflammatory cytokine and an anti-inflammatory myokine. IL-6 is produced and secreted by various cells, including B cells, T cells, endothelial cells, and macrophages. It stimulates immune responses during infection and after tissue trauma, triggering inflammation, either through the classical signaling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or through the trans-signaling pathway when it binds to the soluble form of IL-6R (sIL-6R). Trans-signaling is responsible for most of the proinflammatory and pathological effects of IL-6. Dysregulation of the IL-6 pathway has been reported to be associated with the development of several disease states, including various inflammatory disorders. IL-6 has been reported to induce vascular endothelial growth factor (VEGF) production, which enhances angiogenesis and increases vascular permeability, a hallmark of some inflammatory disorders. IL-6 is also involved in the recruitment of neutrophils, monocytes / macrophages, and the enhanced blockade of anti-inflammatory T regulatory cells. In chronic inflammation, IL-6 plays a detrimental role, leading to the accumulation of mononuclear cells at the site of injury. This can result in increased serum levels of IL-6 and sIL-6R, providing the basis for the amplification step of the chronic inflammatory response. IL-6 is involved in the development of pulmonary neutrophilia by improving both neutrophil recruitment from the blood and bone marrow and neutrophil survival. The role of IL-6 as an anti-inflammatory cytokine is mediated by its inhibitory effects on TNF-α and IL-1, as well as the activation of IL-1ra and IL-10.

[0134] IL-6, like other inflammatory cytokines, has been shown to be elevated in different lung diseases in humans and mice. IL-6 was elevated in bovine BRD (M. hemolytica) challenge and correlated with higher rectal temperature, lung lesions, and mortality. The compounds of the present invention, M9, and tulathromycin significantly reduced IL-6 levels, which also correlated with the overall survival time of animals. Thus, the immunomodulatory compounds of the present invention alleviate the pathological increase in IL-6, which is consistent with the dose and clinical outcome.

[0135] IL-36 is a member of the IL-1 superfamily of cytokines and includes three agonists (IL-36α, IL-36β, and IL-36γ) and an antagonist (IL-36RA). IL-36 agonists bind to the heterodimeric IL-36 receptor (IL-36R) complex to generate proinflammatory responses. The antagonist binds to IL-36R, thereby inhibiting IL-36 signaling. IL-36 signaling occurs through the formation of the heterotrimeric complex IL-36, IL-36R, and IL-1AcP (IL-1 accessory protein), which activates the adaptor protein myeloid differentiation protein 88 (MyD88), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathways, inducing inflammatory responses. IL-36RA prevents the interaction of IL-1AcP with the receptor-ligand complex. IL-36 protein is widely expressed in T cells, keratinocytes, and skin, lung, and intestinal cells. IL-36 agonists bind to and subsequently activate receptors [IL-36R and IL-1 receptor accessory protein (IL-1RAcP)]. Finally, these pathways initiate target gene regulation. Recent evidence suggests that IL-36 regulates the function of both non-immune and immune cells and is involved in immune cell activation, antigen presentation, and proinflammatory factor production. IL-36 has attracted considerable attention due to its dysregulation in inflammatory diseases. For example, serum and tissue IL-36 expression is increased in inflammatory and immune disorders, as well as disorders such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.

[0136] chemokines Chemokines are a family of small cytokines, or signaling proteins secreted by cells. Their name derives from their ability to induce directed chemotaxis in nearby responding cells (i.e., chemotactic cytokines), stimulating leukocyte recruitment. The primary function of chemokines is to direct leukocyte migration (homing) to their respective anatomical locations during inflammatory and homeostatic processes. They are secondary proinflammatory mediators induced by primary proinflammatory mediators, such as IL-1 or TNF. There are two major chemokine subfamilies, namely, CXC and CC, based on the position of cysteine ​​residues. All members of the CXC chemokine subfamily have an intervening amino acid between the first two cysteines, while members of the CC chemokine subfamily have two adjacent cysteines. As a general rule, CXC chemokine members are chemotactic for neutrophils, while CC chemokines are chemotactic for monocytes and a small subset of lymphocytes. Some chemokines are considered pro-inflammatory and can be induced at sites of infection or tissue damage during the immune response to recruit cells of the immune system, whereas other chemokines are considered homeostatic and are involved in regulating cell migration during normal processes of tissue maintenance or development (e.g., angiogenesis).

[0137] Inflammatory chemokines are formed under pathological conditions (in response to proinflammatory stimuli such as IL-1, TNF-α, LPS, or viruses) and actively participate in the inflammatory response, attracting immune cells to the site of inflammation. These chemokines include CXCL8 (IL-8), CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL10. These chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes to the damaged area. A typical example is CXCL8, which acts as a chemoattractant for neutrophils. In contrast to homeostatic chemokine receptors, there is a significant degree of heterogeneity (redundancy) associated with binding receptors and inflammatory chemokines.

[0138] Interleukin-8 (IL-8) is one of the proinflammatory chemokines that attracts and activates immune and inflammatory cells. IL-8 mediates numerous biological effects, including neutrophil activation and chemotaxis, production of reactive oxygen species, increased expression of integrin CD11b-CD18, enhanced cell adhesion to endothelial cells, promotion of angiogenesis, and modulation of histamine release. IL-8 is produced by many cells, including neutrophils, monocytes, macrophages, mast cells, vascular endothelial cells, stromal cells, and epithelial cells, in response to innate extrinsic and endogenous stimuli. In target cells, IL-8 increases intracellular Ca. 2+ and induces a series of physiological responses required for migration and phagocytosis, such as increased exocytosis (e.g., histamine release).

[0139] Recruiting inflammatory cells, such as neutrophils, in response to tissue injury, such as infection, is a normal physiological response to eliminate infectious agents, remove damaged or dead cells, and initiate the healing process. However, excessive recruitment, long residence time, and cell death of these cells result in tissue damage. Therefore, excessive inflammatory cell influx is thought to contribute to the pathophysiology of lung diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis, and human inflammatory conditions, such as bacterial pneumonia. This has also been observed in bovine respiratory disease (BRD) and bacterial pneumonia. Controlling the recruitment and activation of these cells in the lung is an attractive strategy for therapeutic intervention. In all of these conditions, IL-8 appears to be important for the recruitment and activation of neutrophils and T cells to the respiratory tract.

[0140] In experimental cattle challenge studies with M. hemolytica, one of the major causative agents of BRD, IL-8 levels were upregulated in serum and tissues. Compounds of the invention were shown to downregulate IL-8 production in this challenge model, which correlated with an attenuated anti-inflammatory response and disease.

[0141] Biology of BRD It has long been believed that the pathology of BRD stems from stress-induced immunosuppression, leaving calves vulnerable to the myriad microorganisms they encounter during the transition from the calf barn to the feedlot. This dogma suggests that stimulation of the innate immune system will have a positive impact on clinical outcomes. However, to date, interventions consistent with this dogma, including the use of DNA immunostimulants (Zelnate®), have met with little success. Aiming to better understand the progression of BRD, previous studies suggest that it is the enhancement of an initial, unresolved inflammatory state, rather than immunosuppression, that leads to progression to BRD.

[0142] Based on current research into the pathogenesis of BRD, a novel understanding of the immunological state indicates that a state of elevated inflammation is ubiquitous in at-risk cattle, but the persistence of this state or lack of resolution / remission is consistent with disease outcome. After arrival and distribution to feedlots, a proinflammatory state is particularly characterized by innate immune components such as nasal mucosal epithelial cell barrier damage and the release of preformed mediators such as members of the IL-1 cytokine family. Activation of danger-associated molecular patterns (DAMPs), including the pattern recognition receptor (PRR) TLR-4 and inflammasome signaling, signal a response by epithelial and resident myeloid cells to co-localized microorganisms in the upper respiratory tract. Bacterial components such as lipopolysaccharide (LPS; lipoglycan and endotoxin) induce TLR4 signaling, which in turn induces transcription factors such as NF-κB to induce the expression of key cytokines involved in the perpetuation of the inflammatory process, such as IL-1β, IL-6, and TNF-α, and recruits and activates bone marrow-derived granulocytes, including macrophages and neutrophils. These cascades create an environment in which bacteria normally restricted to the upper respiratory tract can invade the lungs and cause disease. Biomarkers of the inflammatory process, such as elevated levels of secreted cytokines, such as IL-6 and acute-phase proteins, are associated with clinical disease. Cell activation markers, such as expression of the scavenger receptor CD163 on macrophages and neutrophil-associated mediators, such as LCN and CXCL8, are also associated with clinical disease. Compounds of the present invention effectively mitigate the increased pro-inflammatory state in at-risk cattle by balancing the immune response and reducing the pathological inflammatory cascade. This mechanism of action of immunomodulators in the context of BRD progression is illustrated in Figure 1.

[0143] The compounds of the present invention represent a novel approach to highly complex diseases and have the potential to significantly reduce the incidence of BRD and the need for antibiotic treatment. They effectively counteract the pathological innate inflammation that occurs during the post-mortem period, allowing animals to restore homeostasis in a time frame consistent with clinical disease protection.

[0144] Scheme and Experiment Tulathromycin A is a 15-membered (lactone A) ring-closed antibacterial macrolide (azalide). The azalide converts to the 13-membered (lactone B) ring-closed, tulathromycin B. This conversion occurs in an equilibrium ratio of approximately 9:1 (A:B), as shown below. [ka]

[0145] Tulathromycin azalide may also be represented by the following structure: [ka]

[0146] Tulathromycin is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one. The precursor of isin, tulathromycin epoxide (tula-epx), is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one.

[0147] One of the metabolites of tulathromycin A is the des-methyl azalide (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)-tetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (M9), shown in the following diagram. [ka]

[0148] Tulathromycin B is also metabolized to B-des-methyl azalide.

[0149] M9 analogs can be used as starting materials for preparing compounds of the present invention. The process for making des-methyltulathromycin (M9) is a two-step process from tulathromycin A, and the intermediates are generally not isolated, but can be. The first step is oxidation of the tertiary amine to an N-oxide using any number of oxidizing agents known to oxidize tertiary amines. The second step is a Polonovski-type demethylation, which can use any metal known to effect this type of transformation. It is commonly iron, but copper salts (Cu(II)) can also be used.

[0150] To a cooled (<0°C) solution of tulathromycin A (4.0 g, 5.0 mmol) in n-butanol (20 mL) was added 1.22 g (5.1 mmol) of a commercially available 32% peracetic acid solution. After 30 minutes, the product was extracted into a 0.25 M aqueous solution of disodium ethylenediaminetetraacetic acid (EDTA, 15 mL). The aqueous solution was basified to pH 9.5 with concentrated aqueous ammonia and extracted with tert-butyl methyl ether (20 mL). The N-oxide product was concentrated to a thick oil but was not isolated, [M+H]. + =822. The oil was dissolved in methanol (16 mL). Copper(II) sulfate pentahydrate (1.5 g, 6.1 mmol) and acetic acid (0.28 mL) were added, and the reaction was heated to 60 °C for 1-2 h. The solution was cooled to 25 °C, and hydroxyamine hydrochloride (0.75 g, 10 mmol) in water (8 mL) was added. After 2 h, the product was partitioned between water (28 mL, adjusted to pH 9.5 with aqueous ammonia) and methylene chloride (20 mL). The organics were concentrated to an oil, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of M9. LCMS [M+H] + =792.5. HPLC purity >98%. 1 H NMR (600 MHz, d6-DMSO): N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe2 (6H, 2.26 ppm).

[0151] Alternatively, M9 can be prepared by mixing a 20°C solution of tulathromycin A (4.0 g, 5.0 mmol) in n-butanol (10 mL) and then adding hexafluoroacetone trihydrate (0.27 g, 1.2 mmol), followed by 30% aqueous hydrogen peroxide (0.62 g, 5.5 mmol). After 4 h, acetic acid (0.31 g, 5.5 mmol) was added, followed by methyl tert-butyl ether (6 mL) and water (25 mL). The upper organic layer was discarded. Methyl tert-butyl ether (8 mL) was added, and the pH of the aqueous layer was adjusted to 9.8 with aqueous ammonia. The lower aqueous layer was discarded. The N-oxide product was concentrated to a thick oil but was not isolated. [M+H] +=822. The oil was dissolved in methanol (12 mL). Anhydrous copper(II) sulfate (0.97 g, 6.1 mmol) and acetic acid (0.28 mL) were added, and the reaction was heated to 60° C. for 1 h. The solution was cooled to 25° C., and hydroxyamine hydrochloride (0.75 g, 10 mmol) in water (8 mL) was added. After 2 h, the product was partitioned between water (28 mL, adjusted to pH 9.5 with aqueous ammonia) and methylene chloride (20 mL). The organics were concentrated to an oil, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of product; LCMS [M+H] + =792.5. HPLC purity >98%. 1H NMR (600 MHz, d6-DMSO): N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe2 (6H, 2.26 ppm).

[0152] Alternatively, M9 can be prepared by mixing a solution of tulathromycin epoxide (20.0 g, 27 mmol) in methanol (40 mL), then adding acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol). [ka]

[0153] After 4 hours at 35°C, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction was heated to 60°C for 1 hour. After cooling to 20°C, 60 mL of methylene chloride and 80 mL of water were added. The mixture was basified to approximately pH 9.8 with concentrated aqueous ammonia. The organics were concentrated to a solid under vacuum, then 2-propanol (40 mL) and n-propylamine (40 mL) were added. The mixture was heated to 65°C and stirred for 15 hours. The mixture was concentrated under vacuum to remove the solvent. Acetonitrile (120 mL) was added and heated to 78°C. The mixture was cooled to 10°C and the product was isolated by filtration. The resulting white crystalline powder was dried to give 12 g of product; LCMS [M+H] +=792.5. HPLC purity >98%. 1H NMR (600 MHz, d6-DMSO): N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe2 (6H, 2.26 ppm).

[0154] Azalide similar to tulathromycin, azithromycin (shown below), is shown below, except that the core ring N is substituted with a methyl group (1') and the cladinose sugar is not further substituted with N-methylpropan-1-amine (2'). [ka]

[0155] Azithromycin can be derivatized to prepare desmethyl analogs similar to M9. Further derivatization can be carried out according to the schemes and experiments defined herein to prepare immunomodulatory azithromycin derivatives that are not active against BRD bacterial pathogens (i.e., are not antibacterial). In addition to azithromycin, other macrolides, such as erythromycin, tilmicosin, clarithromycin, gamithromycin, fidaxomicin, roxithromycin, telithromycin, dirithromycin, josamycin, midecamycin, oleandomycin, and roxithromycin, can be modified in a manner similar to M9 to prepare immunomodulatory analogs that lack antibacterial properties against BRD and other bacterial pathogens in animals, including humans.

[0156] For illustrative purposes, the following reaction schemes show potential routes for synthesizing key intermediates and compounds of the present invention. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other suitable starting materials, reagents, and synthetic routes can be used to synthesize the intermediates and compounds of the present invention, and their various derivatives. Additionally, many of the compounds prepared by the methods described below can be prepared and / or modified using conventional chemistry.

[0157] The compounds of the present invention can be used in their natural form or as salts. When the formation of a stable, non-toxic acid salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate. For purposes of the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with animal tissues and organs without exhibiting toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical evaluation, and that is commensurate with a reasonable benefit / risk ratio. Furthermore, the compounds of the present invention have a secondary or tertiary amine group that has basic properties and can therefore form acid addition salts with pharmaceutically acceptable acids. Thus, pharmaceutically acceptable salts according to the present invention include pharmaceutically acceptable acid addition salts formed with organic and inorganic acids, as well as pharmaceutically acceptable salts formed with optically active acids. Representative acid addition salts include acetate, adipate, alginate, ascorbate, citrate, aspartate, benzoate, benzenesulfonate, besylate, bicarbonate / carbonate, deuterium / sulfate, borate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, digluconate, edisylate, ethoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, benzoate, fumarate, and benzoates. salts of hydroxybenzoates, such as benzoate, benzoyl benzoate, benzophenone, benzoate, benzoyl ...

[0158] In the scheme below, the demethylation or Polonovski reaction occurs when an amine oxide reacts with an acylating agent. The acceptor mechanism involves proton removal, losing acetic acid (using acetic anhydride), to give a nitrogen ylide that attacks the carbon adjacent to the nitrogen atom to give an α-acetoxyamine.

[0159] The central feature of the Polonovski reaction is the conversion of an N-oxide to an iminium ion intermediate. Depending on the structure of the substrate and anhydride or other activating reagent used, iminium ion formation can occur by loss of the α-hydrogen or by fragmentation of the Cα-carbon bond. Again, depending on the conditions, the reaction may stop at this stage, resulting in the iminium ion becoming the Polonovski product, or yielding an enamine or tertiary amide, and / or a secondary amine and aldehyde.

[0160] In principle, any reagent capable of activating N-oxide oxygen can promote the Polonovski reaction. However, three main types of activators are commonly used: acid anhydrides and chlorides (including chloroformates), iron salts and complexes, and sulfur dioxide.

[0161] In the schemes and experimental preparations below, the following acronyms refer to methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), dichloroethane (DCE), hexafluoroisopropylsulfamate (HFIPS), trifluoroacetic acid (TFA), hydrogen peroxide (H2O2), potassium cyanide (KCN), triethylamine (TEA), ethylenediaminetetraacetic acid (EDTA), acetic acid (AcOH), ammonium hydroxide (NH4OH), acetonitrile (MeCN or Acn), ethyl acetate (EtOAc), tert-butyl alcohol (t-BuOH or TBA), sodium methoxide (MeONa), N-methyl-2-pyrrolidine (NMP), cerium(III) chloride (CeCl3), sodium azide (NaN3), sodium bicarbonate (NaHCO3), ammonium chloride (NH4OH), ammonium iodide (Na ... The following solvents were used: ammonium (NH4Cl), N-iodosuccinimide (NIS), magnesium sulfate (MgSO4), sodium sulfate (Na2SO4), ammonium sulfate ((NH4)2SO4), copper sulfate (CuSO4), sodium triacetoxyborohydride (STAB), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl), sodium cyanoborohydride (NaBH3CN), N,N-diisopropylethylamine (DIPEA), dimethylformamide (DMF), 1-butanol (N-BuOH), hexafluoroacetone ((CF3)2CO-HO), hydrochloric acid (HCl), water (HO), methoxy (OMe), fluoro (F), chloro (Cl), methyl (Me), trifluoromethyl (CF3), room temperature (RT), and overnight (ON).

[0162] In the following schemes, e.g., Scheme 1a, formulas are shown as s1a-A1 through s1a-A6, and reference to Scheme 1a (s1a) and -A1 refers to formula A1 as described herein, followed by s1a-A2, s1a-A3, s1a-A4, s1a-A5, and s1a-A6, which refer to the respective formulas A2, A3, A4, A5, and A6 as described herein.

[0163] Scheme 1a. Preparation of sulfonamide compounds 1-A1 to 1-A6 of formula (1): [ka] Sulfonamide analogs can be prepared according to the three-step procedure outlined in Scheme 1a above. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated under the Polonovski reaction to give M9 epoxide (M9-epx). N-oxides can be formed using different oxidizing agents, such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be induced with iron or copper salts. The secondary amines thus formed can be converted to various sulfonamides using sulfonylating reagents, such as sulfonyl chlorides and fluorides. A mild base, such as TEA or DIPEA, can sometimes be used to facilitate the sulfonamide-forming reaction. In the final step, the epoxide functionality can be opened to afford the final sulfonamide analogs using different nucleophiles, such as primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. This reaction can be completed overnight. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction in some cases. For any of the schemes presented herein, the "nucleophile" for the epoxide ring-opening step on the cladinose ring can be, but is not limited to, the following: HNR 5 R 6 , HOR 7 , HS(O) p R 7 , NaN3, CeCl3, TEA 3HF, and KCN, where R 5 , R 6 , R 7 , and p are as defined herein.

[0164] Scheme 1b: Details of Step 3 of Scheme 1a (Nucleophilic Epoxide Ring Opening):

change

[0165] Scheme 2a. Preparation of sulfonamide compounds 1-A1 to 1-A6 of formula (1): [ka] Alternatively, sulfonamide analogs can be prepared according to Scheme 2a. In the first step, the commercially available tulathromycin epoxide intermediate is treated with various nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at elevated temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. This reaction can occur overnight. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can sometimes accelerate the epoxide ring-opening reaction. In the second step, the tertiary dimethylamine on the desosamine sugar can be demethylated using Polonovski-type conditions described above. The final sulfonamide analog can be prepared by reacting the secondary methylamine moiety with a sulfonylating reagent, such as a sulfonyl chloride or fluoride.

[0166] Scheme 2b: Details of Step 1 (Nucleophilic Epoxide Ring Opening) of Scheme 2a: [ka] For (s2b-A1) compounds, the epoxide functionality can be opened using different primary or secondary amines in alcoholic solvents, such as, but not limited to, methanol, ethanol, and 1-propanol. For (s2b-A2) compounds, the epoxide functionality can be opened using different alcohols, such as, but not limited to, methanol, ethanol, and 1-propanol, as solvents. Weak bases, such as NaHCO3, or salts, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction in some cases. For (s2b-A3) compounds, the epoxide functionality can be opened using different thiols, such as, but not limited to, ethanethiol, propanethiol, and isopropyl mercaptan, in alcoholic solvents, such as, but not limited to, ethanol or 1-propanol. Weak bases, such as, but not limited to, NaHCO3, can accelerate the epoxide ring-opening reaction. For (s2b-A4) compounds, the epoxide functionality can be opened using different halides from reagents such as, but not limited to, CeCl or Br in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Weak bases such as NaHCO or salts such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases. For (s2b-A5) compounds, the epoxide functionality can be opened by azide ions using different sources of azide anions, such as, but not limited to, NaN in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Weak bases such as NaHCO or salts such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases. For (s2b-A6) compounds, the epoxide functionality can be opened by cyanide ions using different sources of cyanide anions, such as, but not limited to, KCN in alcoholic solvents, such as, but not limited to, IPA or 1-propanol.A weak base such as NaHCO3 or a salt such as NH4Cl or (NH4)2SO4 can in some cases accelerate the epoxide ring-opening reaction.

[0167] Scheme 2c: Details of Step 2 (demethylation) of Scheme 2a: [ka] All compounds (s2b-A1) to (s2b-A6) can be subjected to Polonovski-type demethylation as described above to give the corresponding compounds (s2c-A1) to (s2c-A6). The N-oxides can be formed using different oxidizing agents, such as iodine, NIS, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxides can be induced by reagents such as iron or copper salts.

[0168] Scheme 2d: Details of Step 3 of Scheme 2a: (Sulfonamide Formation) [ka] In the final step of the sequence, the final analogs can be prepared by reacting the Polonovski reaction products (s2c-A1 / A6) with sulfonylating reagents such as, but not limited to, sulfonyl chlorides and fluorides. Details of this final transformation are shown in Scheme 2d above.

[0169] Scheme 3a. Preparation of compounds 1-A1 to 1-A6 of formula (1): [ka] Alternatively, analogs can be prepared as shown in Scheme 3a. In the first step, commercially available tulathromycin epoxide can be demethylated using the Polonovski reaction described above. The M9-epoxide thus formed can be reacted with various nucleophiles, including but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at elevated temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol, to open the epoxide moiety. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can sometimes accelerate the epoxide ring-opening reaction. Details of this second step are shown below in Scheme 3b. In the final step, the final sulfonamide analog can be prepared by reacting the secondary methylamine moiety with a sulfonylating reagent, such as, but not limited to, a sulfonyl chloride or fluoride. Details of this final transformation are shown below in Scheme 3c.

[0170] Scheme 3b: Details of Step 2 of Scheme 3a (Nucleophilic Epoxide Ring Opening) [ka] The M9-epoxide formed from the demethylation of commercially available tulathromycin epoxide (Scheme 3a) can be reacted with various primary or secondary amines in alcoholic solvents, such as, but not limited to, methanol, ethanol, or 1-propanol, to give the following compounds having formula (s3b-A1), which can be reacted with various alcohols, such as, but not limited to, methanol, ethanol, or 1-propanol, to give the following compounds having formula (s3b-A2). A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can optionally accelerate the epoxide ring-opening reaction of (s3b-A3) with various thiols, such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan, in alcoholic solvents, such as, but not limited to, ethanol or 1-propanol. A weak base such as, but not limited to, NaHCO3 can be used to accelerate the epoxide ring-opening reaction of (s3b-A4) with a halide from a reagent such as, but not limited to, CeCl3 or Br2 in an alcoholic solvent such as, but not limited to, ethanol or 1-propanol. A weak base such as NaHCO3 or a salt such as NH4Cl or (NH4)2SO4 can optionally accelerate the epoxide ring-opening reaction of (s3b-A5) with an azide anion from a source such as, but not limited to, NaN3 in an alcoholic solvent such as, but not limited to, ethanol or 1-propanol. A weak base such as NaHCO3 or a salt such as NH4Cl or (NH4)2SO4 can optionally accelerate the epoxide ring-opening reaction of (s3b-A6) with a cyanide anion from a source such as, but not limited to, KCN in an alcoholic solvent such as, but not limited to, IPA or 1-propanol. A weak base such as NaHCO3 or a salt such as NH4Cl or (NH4)2SO4 can in some cases accelerate the epoxide ring-opening reaction.

[0171] Scheme 3c: Details of Step 3 of Scheme 3a (Sulfonamide Formation) [ka] In the final step of the sequence, the final analogs of formula (s3c-A1), (s3c-A2), (s3c-A3), (s3c-A4), (s3c-A5) and (s3c-A6) can be prepared by reacting the respective (s3b-A1 / A6) analogs with a sulfonylating reagent, such as, but not limited to, a sulfonyl chloride or fluoride, and a weak base, such as, but not limited to, TEA or DIPEA, in an aprotic solvent, such as DCM.

[0172] Scheme 4a. Preparation of sulfamide compounds 1-A1 to 1-A6 of formula (1): [ka] Sulfamide analogs can be prepared according to the three-step procedure outlined in Scheme 4a above. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated using, but not limited to, the Polonovski reaction to give M9 epoxide (M9-epx). The N-oxide can be formed using different oxidizing agents, such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be induced with iron or copper salts. The secondary amine thus formed can be converted to various sulfamides using sulfamoyl fluorides or chlorides. A mild base, such as TEA or DIPEA, can sometimes be used to promote the sulfamide formation reaction. Many sulfamoyl fluorides or chlorides are commercially available or can be easily prepared from the corresponding amines, for example, using the procedure described in Angew Chem. Int. Ed. 2018, 57, 2605-2610. In the final step, the epoxide functionality can be opened to give the final sulfamide analogs using different nucleophiles, such as primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. This reaction can be completed overnight. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction in some cases. For any of the schemes presented herein, the "nucleophile" for the epoxide ring-opening step on the cladinose ring can be, but is not limited to, the following: HNR 5 R 6 , HOR 7 , HS(O) p R 7 , NaN3, CeCl3, TEA 3HF, and KCN, where R 5 , R 6 , R 7 , and p are as defined herein.

[0173] Scheme 4b: Details of Step 3 (Nucleophilic Epoxide Ring Opening) of Scheme 4a: [ka] For the (s4b-A1) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different primary or secondary amines in alcoholic solvents, such as, but not limited to, methanol, ethanol, or 1-propanol. For the (s4b-A2) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different alcohols, such as, but not limited to, methanol, ethanol, or 1-propanol, as solvents. A weak base, such as NaHCO or a salt, such as NH Cl or (NH) SO , can accelerate the epoxide ring-opening reaction in some cases. For the (s4b-A3) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different thiols, such as, but not limited to, ethanethiol, propanethiol, or isopropyl mercaptan in alcoholic solvents, such as, but not limited to, ethanol or 1-propanol. A weak base, such as, but not limited to, NaHCO , can be used to accelerate the epoxide ring-opening reaction. For the (s4b-A4) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different halides from reagents such as, but not limited to, CeCl or Br in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. A weak base such as NaHCO or a salt such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases. For the (s4b-A5) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different sources of azide anions, such as, but not limited to, NaN in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. A weak base such as NaHCO or a salt such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases.For (s4b-A6) analogs, the epoxide functionality can be opened to give the final sulfamide analogs using different sources of cyanide anion, such as, but not limited to, KCN in alcoholic solvents, such as, but not limited to, IPA or 1-propanol. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction in some cases.

[0174] Scheme 5a. Preparation of sulfamide compounds 1-A1 to 1-A6 of formula (1): [ka] Alternatively, sulfamide analogs can be prepared according to Scheme 5a. In the first step, commercially available tulathromycin epoxide intermediates are treated with various nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at elevated temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. This reaction can occur overnight. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can sometimes accelerate the epoxide ring-opening reaction. In the second step, the tertiary dimethylamine on the desosamine sugar can be demethylated using Polonovski-type conditions described above. The final sulfamide analogs can be prepared by reacting the secondary methylamine moiety with, for example, sulfamoyl fluoride or chloride. A mild base, such as TEA or DIPEA, can sometimes be used to facilitate the sulfamide-forming reaction. Many sulfamoyl fluorides or chlorides are commercially available or can be readily prepared from the corresponding amines using procedures described, for example, in Angew Chem. Int. Ed. 2018, 57, 2605-2610.

[0175] Scheme 5b: Details of Step 1 (Nucleophilic Epoxide Ring Opening) of Scheme 5a:

change

[0176] Scheme 5c: Details of Step 2 (demethylation) of Scheme 5a: [ka] All compounds (s5b-A1) to (s5b-A6) can be subjected to Polonovski-type demethylation as described above to give the corresponding compounds (s5c-A1) to (s5c-A6). The N-oxides can be formed using different oxidizing agents, such as iodine, NIS, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxides can be induced by reagents such as iron or copper salts.

[0177] Scheme 5d: Details of Step 3 of Scheme 5a: (Sulfamide Formation) [ka] In the final step of the sequence, the final analogs can be prepared by reacting the Polonovski reaction product (s5c-A1 / A6) with a sulfamoyl fluoride or chloride, for example. A mild base, such as TEA or DIPEA, can sometimes be used to facilitate the sulfamide-forming reaction. Many sulfamoyl fluorides or chlorides are commercially available or can be readily prepared from the corresponding amines, for example, using procedures described in Angew Chem. Int. Ed. 2018, 57, 2605-2610. Details of this final transformation are shown in Scheme 5d above.

[0178] Scheme 6a. Preparation of Cyclic Sulfamates of Formula (1) by Intramolecular Fluorosulfonamide Cyclization [ka] Cyclic sulfamate analogs can be prepared according to Scheme 6a. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated using, but not limited to, the Polonovski reaction to give M9 epoxide (M9-epx). The N-oxide can be formed using different oxidizing agents, such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be induced with iron or copper salts. The secondary amine thus formed can be converted to a fluorosulfonamide by reacting the M9 epoxide with commercially available 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. In the final step, heating in an alcoholic solvent, such as 1-propanol, results in two transformations. First, the epoxide functionality can be opened using different nucleophiles, such as primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. This reaction can be completed overnight. Second, the fluorosulfonamide functionality undergoes intramolecular cyclization to yield a cyclic sulfamate moiety under the same conditions. Weak bases, such as NaHCO3, TEA, or DIPEA, or salts, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction and sulfamate cyclization in some cases. For any of the schemes presented herein, the "nucleophile" for the epoxide ring-opening step on the cladinose ring can be, but is not limited to, the following: HNR 5 R 6 , HOR 7 , HS(O) p R 7 , NaN3, CeCl3, TEA 3HF, and KCN, where R 5 , R 6 , R 7 , and p are as defined herein.

[0179] Scheme 6b: Details of Step 3 (Epoxide Opening and Cyclization) of Scheme 6a: [ka] For compounds (s6b-A1), the epoxide functionality can be opened using different primary or secondary amines in alcoholic solvents, such as, but not limited to, methanol, ethanol, or 1-propanol, with simultaneous cyclization to the cyclic sulfamate. For compounds (s6b-A2), the epoxide functionality can be opened using different alcohols, such as, but not limited to, methanol, ethanol, or 1-propanol, as solvents, with simultaneous cyclization to the cyclic sulfamate. A weak base, such as NaHCO or a salt, such as NH Cl or (NH) SO , can accelerate the epoxide ring-opening reaction in some cases. For compounds (s6b-A3), the epoxide functionality can be opened using different thiols, such as, but not limited to, ethanethiol, propanethiol, or isopropyl mercaptan, in alcoholic solvents, such as, but not limited to, ethanol or 1-propanol, with simultaneous cyclization to the cyclic sulfamate. A weak base, such as, but not limited to, NaHCO , can be used to accelerate the epoxide ring-opening reaction. For (s6b-A4) compounds, the epoxide functionality can be opened using different halides from reagents such as, but not limited to, CeCl or Br in alcoholic solvents such as, but not limited to, ethanol or 1-propanol, with concomitant cyclization to the cyclic sulfamate. A weak base such as NaHCO or a salt such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases. For (s6b-A5) compounds, the epoxide functionality can be opened by azide ions using different sources of azide anions, such as, but not limited to, NaN in alcoholic solvents such as, but not limited to, ethanol or 1-propanol, with concomitant cyclization to the cyclic sulfamate. A weak base such as NaHCO or a salt such as NH Cl or (NH) SO can accelerate the epoxide ring-opening reaction in some cases.For (s6b-A6) compounds, the epoxide functionality can be opened by cyanide ions using different sources of cyanide anions, such as, but not limited to, KCN in alcoholic solvents, such as, but not limited to, IPA or 1-propanol, with concomitant cyclization to the cyclic sulfamate. A weak base, such as NaHCO3, or a salt, such as NH4Cl or (NH4)2SO4, can accelerate the epoxide ring-opening reaction in some cases.

[0180] Scheme 7. Preparation of alkylated core nitrogen sulfonamide compounds of formula (1) by reductive amination [ka] Alkyl-tula-epx intermediates can be readily synthesized from tula-epoxides (tula-epx) by a variety of methods, including, but not limited to, reductive animation using the corresponding aldehyde and a hydride source, such as, but not limited to, STAB or NaBHCN in solvents such as alcohol or DMF and at temperatures between 0 °C and 60 °C. Subsequently, the macrolide core nitrogen can be converted to various R groups. 0 The chemical reactions for making compounds of the invention that are alkylated with an R group are shown in Schemes 1-3, e.g., by Polonovski-type demethylation, epoxide ring opening, and sulfonamide formation, converting the starting Tula-epoxide in Schemes 1-3 to an R group. 0 Alkylated tulathromycin epoxide intermediates (alkyl-tula-epx) (e.g., R 0 This can be achieved by replacing aryl with propyl.

[0181] Scheme 8. Preparation of alkylated core nitrogen sulfamides of formula (1) by reductive amination [ka] Alkyl-tula-epx intermediates can be readily synthesized from tula-epoxides (tula-epx) by a variety of methods, including, but not limited to, reductive animation using the corresponding aldehyde and a hydride source, such as, but not limited to, STAB or NaBHCN in solvents such as alcohol or DMF and at temperatures between 0 °C and 60 °C. Subsequently, the macrolide core nitrogen can be converted to various R groups. 0 The chemical reactions for making compounds of the invention that are alkylated with an R group are shown in Schemes 4-5, e.g., by converting the starting Tula-epoxide in Schemes 4-5 to an R group by Polonovski-type demethylation, epoxide ring opening, and sulfamide formation. 0 Alkylated tulathromycin epoxide intermediates (alkyl-tula-epx) (e.g., R 0 This can be achieved by replacing aryl with propyl.

[0182] Scheme 9. Preparation of alkylated core nitrogen cyclic sulfamates, compounds of formula (1), by reductive amination [ka] Alkyl-tula-epx intermediates can be readily synthesized from tula-epoxides (tula-epx) by a variety of methods, including, but not limited to, reductive animation using the corresponding aldehyde and a hydride source, such as, but not limited to, STAB or NaBHCN in solvents such as alcohol or DMF and at temperatures between 0 °C and 60 °C. Subsequently, the macrolide core nitrogen can be converted to various R groups. 0 The chemistry for making compounds of the invention alkylated with an R group is shown in Scheme 6, e.g., by Polonovski-type demethylation followed by epoxide ring-opening and simultaneous cyclization of the starting Tula-epoxide in Scheme 6(a / b) to the R group. 0 Alkylated tulathromycin epoxide intermediates (alkyl-tula-epx) (e.g., R 0 This can be achieved by replacing aryl with propyl.

[0183] Scheme 10. Various R 1 Preparation of Compounds of Formula (1) Substituted with a Group: Preparation of the Common Intermediate M8 Epoxide (M8-epx) [ka] The (M8-epx) intermediate can be readily synthesized from the M9 epoxide by a variety of methods, including a second demethylation with I2 and NaOMe, or a triple sequence in which the M9 epoxide is first protected with a 4-OMe benzyl group and then demethylated using Polonovski demethylation. The M8 epoxide is then deprotected under hydrogenolysis conditions using Pd / C and H2 gas in an alcohol solvent, such as, but not limited to, methanol, ethanol, or trifluoroethanol. The M8 epoxide can be used in a variety of methods to prepare compounds of the invention, as shown in Schemes 11, 12, and 14 below.

[0184] Scheme 11. Various R-forms from M8 epoxide (M8-epx) 1 Preparation of compounds of formula (1) which are sulfonamides substituted with a group: [ka] The M8 epoxide can be reacted with a sulfonamide-forming reagent, such as a sulfonyl chloride, fluoride, in an aprotic solvent such as DCM, and a weak base, such as, but not limited to, TEA or DIPEA, to give the sulfonamide compounds s11a-A1 to s11a-A6 of the invention as shown in Scheme 11. The M8 epoxide can also be converted to the corresponding R 2 epoxide by a weak base, such as, but not limited to, STAB or NaBH3CN in a solvent such as an alcohol, DMF, MeOH, DCM, or DCE. 1 It can be subjected to reductive amination with an aldehyde and a hydride source at temperatures between 0°C and 60°C. 1Subsequent chemical reactions to make sulfonamide compounds of the invention where is not CH can be accomplished using sulfonyl chloride or fluoride in an aprotic solvent such as DCM and a weak base such as, but not limited to, TEA or DIPEA as shown in Scheme 11 to give compounds s11b-A1 to s11b-A6 of the invention.

[0185] Scheme 12. Various R-forms from M8 epoxide (M8-epx) 1 Preparation of the compounds of formula (1) which are sulfamides substituted with a group: [ka] The M8 epoxide can be reacted with a sulfamide-forming reagent, such as sulfamoyl chloride or fluoride, in an aprotic solvent such as DCM, and a weak base, such as, but not limited to, TEA or DIPEA, to afford the sulfamide compounds s12a-A1 to s12a-A6 of the invention, as shown in Scheme 12. The M8 epoxide can also be converted to the corresponding R 2 epoxide by a weak base, such as, but not limited to, STAB or NaBH3CN in a solvent such as alcohol, DMF, MeOH, DCM, or DCE. 1 It can be subjected to reductive amination with an aldehyde and a hydride source at temperatures between 0°C and 60°C. 1 Subsequent chemical reactions to make sulfamide compounds of the invention where is not CH can be achieved using sulfamoyl chloride or fluoride in an aprotic solvent such as DCM and a weak base such as, but not limited to, TEA or DIPEA as shown in Scheme 12 to give compounds s12b-A1 to s12b-A6 of the invention.

[0186] Scheme 13. Various R-forms from tulathromycin epoxide (tula-epx) 0 Preparation of primary sulfonamides of compounds of formula (1) substituted with a group [ka] Tulathromycin epoxide can be demethylated using, but not limited to, the Polonovski reaction to give M9 epoxide (M9-epx). N-oxides can be formed using different oxidizing agents, such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be induced with iron or copper salts. The secondary amine thus formed can be converted to primary sulfonamides using various sulfonylating reagents, such as HFIPS, as described in OL, 2021, pp. 3373-3378. In the final step, the epoxide functionality is opened to form the final compounds s13a-A1 to s13a-A6 of the present invention using different nucleophiles, such as primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol, to give the final sulfonamide analogs. This reaction can be completed overnight. A weak base such as NaHCO or a salt such as NHCl or (NH)SO can accelerate the epoxide ring-opening reaction in some cases. For any of the schemes presented herein, the "nucleophile" for the epoxide ring-opening step on the cladinose ring can be, but is not limited to, HNR 5 R 6 , HOR 7 , HS(O) p R 7 , NaN3, CeCl3, TEA 3HF, and KCN, where R 5 , R 6 , R 7 , and p are as defined herein.

[0187] Similarly, tulathromycin epoxides can be alkylated on the core nitrogen to form alkyl-tula-epx intermediates by a variety of methods, including, but not limited to, reductive animation with the corresponding aldehyde and a hydride source, such as, but not limited to, STAB or NaBHCN in solvents such as alcohol or DMF and at temperatures between 0°C and 60°C. 0 Subsequent chemical reactions to make compounds of the invention s13b-A1 to s13b-A6, which are alkylated with the group, can be accomplished following the same steps as above, i.e., primary sulfonamide formation followed by ring-opening of the epoxide moiety.

[0188] Scheme 14. Various R-forms from M8 epoxide (M8-epx) 1 Preparation of compounds of formula (1) which are cyclic sulfamates substituted with a group: [ka] The M8 epoxide can be reacted with 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate to produce a fluorosulfonamide that can cyclize to a cyclic sulfamate upon epoxide ring-opening reaction, as previously described. Scheme 14 (left side) shows the reaction of R 1 The preparation of cyclic sulfamate compounds s14a-A1 to s14a-A6, in which M8 epoxide is ═H, is also shown. The M8 epoxide can be prepared by the addition of the corresponding R epoxide to a cyclohexane-2-hydroxybenzoate (S14a-A1) using a solvent such as, but not limited to, STAB or NaBH3CN in a solvent such as alcohol, DMF, MeOH, DCM, or DCE. 1 It can be subjected to reductive amination with an aldehyde and a hydride source at temperatures between 0°C and 60°C. 1 Subsequent chemistry to make cyclic sulfamate compounds of the invention where R is not CH can be accomplished in the same manner as detailed in Scheme 6. Scheme 14 (right side) shows the formation of cyclic sulfamate compounds of the invention where R is not CH. 1The preparation of cyclic sulfamate compounds s14b-A1 to s14b-A6, in which is different from H or methyl, is shown.

[0189] Scheme 15. Preparation of sulfonamide compounds of formula (1-A0) from azithromycin by reductive amination [ka] Azithromycin can be used as a starting material for the synthesis of sulfonamide compounds of formula (1) of the present invention, as shown in Scheme 15. Azithromycin can undergo a demethylation reaction similar to that of tulathromycin under similar conditions, such as, but not limited to, the Polonovski reaction defined herein. Demethylated azithromycin can be reacted with a sulfonamide-forming reagent, such as, but not limited to, a sulfonyl chloride or fluoride, in an aprotic solvent such as DCM, and a weak base, such as, but not limited to, TEA or DIPEA, as shown in Scheme 15, to provide compounds s15a-A0 of the present invention.

[0190] Additionally, des-methylazithromycin can be demethylated using I2 and NaOMe as described above, followed by the corresponding R 1 The compound s15b-A0 of the present invention can be prepared by reductive amination with an aldehyde. 1 Substituted azithromycins can be synthesized by reaction with a sulfonamide-forming reagent, such as, but not limited to, a sulfonyl chloride, fluoride, and a weak base, such as, but not limited to, TEA or DIPEA, in an aprotic solvent, such as DCM, as shown in Scheme 15.

[0191] Scheme 16. Preparation of the sulfamide of formula (1) from azithromycin by reductive amination. [ka] Azithromycin can be used as a starting material for the synthesis of sulfamide compounds of formula (1) of the present invention, as shown in Scheme 16. Azithromycin can undergo a demethylation reaction similar to that of tulathromycin under similar conditions, such as, but not limited to, the Polonovski reaction defined herein. Demethylated azithromycin can be reacted with a sulfamide-forming reagent, such as, but not limited to, sulfamoyl chloride, fluoride, and a weak base, such as, but not limited to, TEA or DIPEA, in an aprotic solvent, such as DCM, to provide compound s16a-A0 of the present invention.

[0192] Additionally, des-methylazithromycin can be demethylated using I2 and NaOMe as described above, followed by the corresponding R 1 Compounds s16b-A0 of the present invention can be prepared by the reaction of R 1 It can be synthesized by reacting a substituted azithromycin sulfamide-forming reagent and a weak base such as, but not limited to, TEA or DIPEA.

[0193] Scheme 17. Preparation of sulfonamide O-aryl / heteroaryl compounds of formula (1) [ka] Compounds of Formula (1) additionally substituted with aryl / heteroaryl R groups on the hydroxyl groups of the desosamine sugar can be synthesized according to the sequence shown in Scheme 17. The first three steps of the sequence are detailed in Schemes 2a, 2b, and 2c and consist of ring-opening of the epoxide moiety of the tula epoxide followed by Polonovski demethylation. The third step is a Chan-Lam-type coupling that is selective for the desosamine sugar hydroxyl. Aryl or heteroaryl boronic acids or boronic esters can be selectively coupled to the desosamine hydroxyl when stirred with a copper salt, such as, but not limited to, copper(II) acetate, in the presence of a weak base such as pyridine, a drying agent such as molecular sieves, and oxygen. The final step in the sequence is a sulfonamide-forming reaction using a reagent such as, but not limited to, a sulfonyl chloride, a fluoride, and a weak base such as, but not limited to, TEA or DIPEA in an aprotic solvent to give the desired O-aryl / heteroaryl sulfonamide combination compounds s17-A1 to s17-A6.

[0194] Scheme 18. Preparation of sulfamido O-aryl / heteroaryl compounds of formula (1) [ka] Compounds of Formula (1) additionally substituted with aryl / heteroaryl R groups on the hydroxyl groups of the desosamine sugar can be synthesized according to the sequence shown in Scheme 18. The first three steps of the sequence are detailed in Schemes 5a, 5b, and 5c and consist of ring-opening of the epoxide moiety of the tula epoxide followed by Polonovski demethylation. The third step is a Chan-Lam-type coupling that is selective for the desosamine sugar hydroxyl. Aryl or heteroaryl boronic acids or boronic esters can be selectively coupled to the desosamine hydroxyl when stirred with a copper salt, such as, but not limited to, copper(II) acetate, in the presence of a weak base such as pyridine, a drying agent such as molecular sieves, and oxygen. The final step in the sequence is a sulfamide-forming reaction using reagents such as, but not limited to, sulfamoyl chloride, fluoride, and a weak base such as, but not limited to, TEA or DIPEA in an aprotic solvent to give the desired O-aryl / heteroaryl sulfamide combination compounds s18-A1 to s18-A6.

[0195] Scheme 19. Preparation of des-cladinose sulfonamide compounds of formula (1.1) [ka] Descladinose sulfonamide compounds of formula (1.1) can be readily synthesized from compounds of formula (1A) by stirring the compound in aqueous acetic acid or hydrochloric acid at temperatures between 0°C and 60°C for 1 to 72 hours in a solvent such as, but not limited to, THF, MeCN, or HO, as shown.

[0196] Scheme 20. Preparation of des-cladinose sulfamide compounds of formula (1.1) [ka] Descladinose sulfamide compounds of formula (1.1) can be readily synthesized from compounds of formula (1A) by stirring the compound in aqueous acetic acid or hydrochloric acid at temperatures between 0°C and 60°C for 1 to 72 hours in a solvent such as, but not limited to, THF, MeCN, or HO, as shown. [Example]

[0197] Preparation of des-cladinose sulfonamide compound example (A-20) of formula (1.1). [ka] To crude Example B-18 (300.0 mg), 2N HCl (5.0 mL) was added, and the resulting mixture was heated at 45° C. for 2 hours, then cooled to room temperature. The crude reaction mixture was poured into an ice-cold solution of NH OH (pH>7) and stirred for 5 minutes, then concentrated and lyophilized. The crude material was purified by preparative HPLC using ammonium acetate as a buffer, and the purified material was passed through an SCX column to give the title compound as a free base.

[0198] The compound of formula (1.1) can be prepared similarly to that shown above for Example A-20, under similar conditions, except that the starting material is a compound of formula (1-A1) instead of that used in Example B-18.

[0199] Preparation of des-cladinose sulfamide compound Example A-37 of formula (1.1). [ka] To crude Example C-66 (100.0 mg) was added 2N HCl (2.0 mL), and the resulting mixture was heated at 45° C. for 2 hours, then cooled to room temperature. The crude reaction mixture was poured into an ice-cold solution of NH OH (pH>7) and stirred for 5 minutes, then concentrated and lyophilized. The crude material was purified by preparative HPLC using ammonium acetate as a buffer, and the purified material was passed through an SCX column to give the title compound as the free base.

[0200] The compound of formula (1.1) can be prepared similarly to that shown above for Example A-37, under similar conditions, except that the starting material is a compound of formula (1-A1a) instead of that used in Example C-66.

[0201] Preparation of sulfonamide compound example (B-8) of formula (1-A1): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4, To a solution of 6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula) (20.0 g, 24.8 mmol), hexafluoroacetone trihydrate (0.62 g, 2.8 mmol) and 30% aqueous hydrogen peroxide (2.88 mL, 28 mmol) were added and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added, and the reaction was heated to 60° C. for 2 hours. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated under vacuum to a solid and recrystallized from acetone / water to give 14.2 g of a white crystalline product (M9) that was >95% pure by LCMS and used directly in the next step.

[0202] Step 2: M9 (0.38 mmol, 300 mg, 1.0 equiv) from Step 1 was dissolved in DCM (5 mL) and DIPEA (1.5 equiv, 100 μL, 0.57 mmol), followed by the addition of propane-1-sulfonyl chloride (1.1 equiv, 59 mg, 0.42 mmol) at 0 °C. The reaction mixture was initially stirred at 0 °C and then warmed to room temperature over 2 h. After completion of the reaction, as determined by LCMS analysis, the reaction mixture was diluted with DCM and washed with water and brine. The organic portion was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by C18 reverse flash chromatography (0 to 100% MeCN in HO) using 0.5% AcOH as a modifier. Fractions containing the desired product were lyophilized to give the desired compound as the acetate salt (16 mg).

[0203] R 5 is H and R 6 Compounds of formula (1-A1) shown in Table B, where is propyl, can be made similarly to those shown above for Example B-8 under similar conditions by varying the sulfonamide-forming reagent or starting material, or by using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide, as shown in the schemes herein.

[0204] Preparation of sulfamide compound example (B-50) of formula (1-A1): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6 To a solution of 20.0 g (24.8 mmol) of 1,4-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula) was added hexafluoroacetone trihydrate (0.62 g, 2.8 mmol) and then 30% aqueous hydrogen peroxide (2.88 mL, 28 mmol) and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added, and the reaction was heated to 60° C. for 2 hours. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated under vacuum to a solid and recrystallized from acetone / water to give 14.2 g of a white crystalline product (M9) that was >95% pure by LCMS and used directly in the next step.

[0205] Step 2: M9 (0.51 mmol, 400 mg, 1.0 equiv) from Step 1 was dissolved in DCM (10 ml) and TEA (3.0 equiv, 210 μL, 0.56 mmol), followed by the addition of N-[4-(trifluoromethyl)phenyl]sulfamoyl fluoride (1.1 equiv, 135 mg, 0.42 mmol) at 0 °C. The reaction mixture was first stirred at 0 °C for 2 h and then warmed to room temperature over 4 h. After completion of the reaction, as determined by LCMS analysis, the reaction mixture was diluted with DCM and washed with water and brine. The organic portion was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by C18 reverse flash chromatography (0–100% MeCN in HO) using 0.5% AcOH as a modifier. Fractions containing the desired product (B-50) were lyophilized to afford the desired compound as the acetate salt (194 mg).

[0206] R 5 is H and R 6 Compounds of formula (1-A1) shown in Table B, where is propyl, can be made similarly to those shown above for Example B-50 under similar conditions by varying the sulfamide-forming reagent or starting material, or by using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide, as shown in the schemes herein.

[0207] Preparation of sulfonamide compound Example B-93 of formula (1-A1): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4, A solution of 8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) were mixed together and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction was heated to 60° C. for 1 hour. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone / water to give 60 g of a white crystalline product (M9-epx) that was 95% pure by LCMS and used directly in the next step.

[0208] Step 2: A solution of 10 g (13.14 mmol) of M9-epx from Step 1 and 10.9 mL of N-ethylamine (10.0 equiv., 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 h. After completion of the reaction as judged by LCMS analysis, the volatiles were removed under reduced pressure, then the residue was dissolved in 100 mL of DCM and HO and the pH was adjusted to approximately 9.8 with NH4OH. The aqueous layer was extracted three times with DCM, and the organic layers were combined and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to give the crude material, which was purified on C18 silica using reverse flash chromatography (0 to 100% MeCN in HO) with 1.0% AcOH as a modifier. The desired fractions were combined, the pH adjusted to approximately 9.8 with NH4OH, and extracted three times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate and the volatiles removed under reduced pressure to give the desired material as an off-white amorphous solid.

[0209] Step 3: A mixture of the product from Step 2 (250 mg, 0.32 mmol, 1.0 equiv.), (3,4-dimethoxyphenyl)boronic acid (88 mg, 0.47 mmol, 1.5 equiv.), copper(II) acetate (143 mg, 2.5 equiv., 0.79 mmol), molecular sieves (4 Å, activated, 0.2 g), and pyridine (51 μL, 2 equiv., 0.63 mmol) in DMF (5.0 mL) was stirred at room temperature in dry air for 3 days. Upon completion of the reaction as determined by LCMS analysis, the mixture was filtered over Celite and the volatiles were removed under reduced pressure. The crude material was purified on C18 silica using reverse flash chromatography (0–100% MeCN in HO) with 1.0% AcOH as a modifier. The desired fractions were combined, the pH adjusted to approximately 9.8 with NH4OH, and extracted three times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate and the volatiles removed under reduced pressure to give the desired material as an off-white amorphous solid.

[0210] Step 4: The material from Step 3 (150 mg, 0.16 mmol, 1.0 equiv.) was dissolved in dry DCM (3 mL) in a dry round-bottom flask, and DIPEA (69 μL, 2.5 equiv.) was added, followed by benzenesulfonyl chloride (32 mg, 1.2 equiv., 0.19 mmol). The mixture was stirred overnight, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N2, and the crude material was purified by reverse-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were lyophilized to afford the desired product (99 mg, 55% yield) as the acetate salt.

[0211] Preparation of sulfonamide compound Example B-107 of formula (1-A1) [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4, A solution of 8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) were mixed together and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction was heated to 60° C. for 1 hour. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone / water to give 16 g of a white crystalline product (M9-epx) that was 95% pure by LCMS and used directly in the next step.

[0212] Step 2: A solution of 10 g (13.14 mmol) of M9-epx from Step 1 and 10.9 mL of n-propylamine (10.0 equiv., 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 h. After completion of the reaction as determined by LCMS analysis, the volatiles were removed under reduced pressure, and the remaining solid was then dissolved in 100 mL of DCM and HO, and the pH was adjusted to approximately 9.8 with NH4OH. The aqueous layer was extracted three times with DCM, and the organic layers were combined and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to give the crude material, which was purified on C18 silica using reverse flash chromatography (0–100% MeCN in HO) with 1.0% AcOH as a modifier. The desired fractions were combined, the pH adjusted to approximately 9.8 with NH4OH, and extracted three times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate and the volatiles removed under reduced pressure to give the desired material as an off-white amorphous solid.

[0213] Step 3: A mixture of the product from Step 2 (3.6 g, 4.5 mmol), (4-fluorophenyl)boronic acid (2.5 g, 18.0 mmol, 4 equiv.), copper(II) acetate (1.24 g, 1.5 equiv., 6.8 mmol), molecular sieves (4 Å, activated, 4.0 g), and pyridine (1.5 mL, 4 equiv., 18.0 mmol) in DMF (35.0 mL) was stirred at room temperature in dry air for 3 days. Upon completion of the reaction as determined by LCMS analysis, the mixture was poured into MTBE (70 mL) and 20 mL of 10% NH3 before filtering through Celite. The mixture was then separated and washed with water (50 mL), 2 M NaOH (10 mL), and brine (10 mL) before being evaporated to give a crude lilac solid (5.0 g). The crude material was purified by reverse phase chromatography on a C18 column using 0.5% AcOH as a modifier. Fractions containing the desired product were lyophilized to give the desired compound as the acetate salt.

[0214] Step 4: The material from Step 3 (642 mg, 0.72 mmol, 1.0 equiv.) was dissolved in dry DCM (20 mL) in a dry round-bottom flask, and TEA (203 μL, 2.0 equiv.) was added, followed by 1-methyl-1H-imidazole-2-sulfonyl chloride (165 mg, 1.2 equiv., 0.87 mmol) at 0 °C. The mixture was stirred overnight while the reaction temperature slowly rose to room temperature, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N2, and the crude material was purified by reverse-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were lyophilized to afford the desired product (B-107) as the acetate salt (150 mg, 19% yield).

[0215] Preparation of sulfamide compound example (B-113) of formula (1-A1): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4, A solution of 8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) were mixed together and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction was heated to 60° C. for 1 hour. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone / water to give 16 g of a white crystalline product (M9-epx) that was 95% pure by LCMS and used directly in the next step.

[0216] Step 2: To a solution of 5.0 g (6.83 mmol) of M9-epx from Step 1 and 1.8 mL of TEA (1.5 equiv., 10.2 mmol) in 50 mL of dry DCM at 0 °C, a solution of N-methyl-4-(trifluoromethyl)phenylsulfamoyl chloride (1.2 equiv.) in DCM (5 mL) was added over 5 min. The reaction mixture was initially stirred at 0 °C and then slowly warmed to room temperature over 24 h. After completion of the reaction, as determined by LCMS analysis, the reaction mixture was diluted with DCM and washed with water followed by brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the resulting material was triturated with 30% Et2O in pentane to give the free solid material (approximately 5.2 g), which was used directly in the next step.

[0217] Step 3: The product from Step 2 (0.22 mmol, 200 mg, 1.00 equiv.) was dissolved in n-PrOH (2.5 mL) and n-propylamine (5.0 equiv., 0.11 mL, 1.10 mmol) was added. The resulting solution was stirred at 70 °C overnight. After completion of the reaction as determined by LCMS analysis, the volatiles were removed under a stream of N2, and the crude material was purified by C18 reverse flash chromatography (0 to 100% MeCN in HO) using 0.5% AcOH as a modifier. Fractions containing the desired product were lyophilized to afford the desired compound (B-113) as the acetate salt (48 mg, 25%).

[0218] The nucleophile used in the final step to open the epoxide is N-propylamine, R 1 The preparation of Example B-142, a sulfonamide compound of Formula (1-A1), using a modification of Scheme 7 such that is propyl from a reductive amination reaction with propionaldehyde is shown below. [ka] Step 1: 1.0 g (1.36 mmol, 1.00 equiv.) of M9 epoxide was dissolved in 10 mL of dry DMF in a 50 mL round-bottom flask, and 2.0 equiv. of anisaldehyde (0.332 mL, 2.73 mmol) was added, followed by 1.17 g of sodium triacetoxyborohydride (STAB, 4.0 equiv., 5.5 mmol). The resulting solution was heated to 40 °C for 2 h. An additional 0.6 g (2.7 mmol, 2.0 equiv.) of STAB was added, and the resulting solution was heated to 40 °C overnight, after which LCMS analysis indicated complete consumption of the starting material. The reaction mixture was then cooled to 0 °C, and 5 mL of saturated NH4Cl solution was added, and the solution was stirred for 5 min. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to pH 12 with NH4OH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude material, which was purified by reverse-phase chromatography on a C18 column eluting with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to pH 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (1008 mg, 87%).

[0219] Step 2: 1008 mg of the product from Step 1 (1.18 mmol, 1.00 equiv.) was dissolved in 10 mL of dry EtOH, and peracetic acid (32% diluted solution in acetic acid, 1.5 equiv., 304 μL) was added. The resulting solution was stirred at room temperature for 45 minutes, after which LCMS showed complete conversion to the corresponding N-oxide. Anhydrous copper(II) sulfate (3.0 equiv., 566 mg) was then added, and the solution was stirred at 65 °C for 4 hours, after which LCMS showed complete reaction with 41% debenzylated product and 44% demethylated product. The reaction mixture was diluted with 20 mL of DCM and HO, and the pH was adjusted to approximately 12 with NH4OH. The crude material was extracted three times with DCM, the organics were combined, dried over MgSO4, and the volatiles were removed under reduced pressure. The crude material was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to about 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (250 mg, 25% yield).

[0220] Step 3: The product from Step 2 (250 mg, 0.30 mmol, 1.0 equiv) was dissolved in 10 mL of CF3CH2OH. 5% Pd / C (25 mg) was added, and the resulting slurry was hydrogenated under balloon pressure H2 at 40 °C overnight, after which LCMS indicated complete reaction. The Pd / C was filtered over Celite, and the volatiles were removed under reduced pressure to give the desired product (M8 epoxide; M8-epx) as a white powder (195 mg, 91%).

[0221] Step 4: The product from Step 3 (M8-epx, 250 mg, 1.0 equiv., 0.35 mmol) was dissolved in 5 mL of dry MeOH in a 25 mL round-bottom flask, and the solution was cooled to 0 °C. Propionaldehyde (1.2 equiv., 30 μL) was added, followed by the portionwise addition of sodium triacetoxyborohydride (5 equiv., 369 mg). The solution was stirred at 0 °C for 2 h at room temperature, after which LCMS showed complete conversion to the desired product. The reaction mixture was then cooled to 0 °C, and 1 mL of saturated NH4Cl solution was added, and the solution was stirred for 5 min. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to pH 12 with NH4OH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4 and removed under reduced pressure to give the desired product (250 mg) as a white solid material with approximately 80% LCMS purity, which was used directly in the subsequent epoxide ring-opening section.

[0222] Step 5: The material from Step 4 (200 mg, 0.32 mmol, 1.0 equiv.) was dissolved in dry DCM (5 mL) in a dry round-bottom flask, and DIPEA (0.141 mL, 2.5 equiv.) was added, followed by 4-chlorobenzenesulfonyl chloride (1.2 equiv.) in DCM (5 mL). The mixture was stirred overnight, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N2, and the crude material was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (93 mg, 32% yield).

[0223] Step 6: To a pressure vial was added the product from Step 5 (93 mg, 0.10 mmol, 1 equiv) and EtOH (2 mL), followed by N-propylamine (103 μl, 1.25 mmol, 12 equiv). The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then concentrated in vacuo, and the crude product was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were lyophilized to afford the desired product (35 mg, 33% yield) as the acetate salt as a white solid.

[0224] Following this example, the alkyl group R on the desosamine nitrogen 1 can be varied by replacing the propionaldehyde in the fourth step of the sequence with acetaldehyde or isobutyraldehyde, or a carbaldehyde such as benzaldehyde, or any other alkyl aldehyde such as 2-pyridylcarbaldehyde. As with other examples shown herein, the epoxide can be ring-opened in the final step with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol.

[0225] Preparation of sulfonamide compound example C-4 of formula (1-A1a): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4, A solution of 8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) were mixed together and stirred at 35° C. for 4 hours. After consumption of the starting material as determined by LCMS, the reaction was cooled to 20° C., anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction was heated to 60° C. for 1 hour. After completion of the reaction as determined by LCMS, the reaction mixture was cooled to 20° C., and 60 mL of DCM and 80 mL of HO were added. The mixture was basified to a pH of about 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone / water to give 60 g of a white crystalline product (M9-epx) that was 95% pure by LCMS and used directly in the next step.

[0226] Step 2: To a solution of 5.0 g (6.83 mmol) of M9-epx from Step 1 and 1.8 mL of DIPEA (1.5 equiv., 10.2 mmol) in 50 mL of DCM at 0 °C was slowly added a solution of 4-chlorobenzenesulfonyl chloride (1.2 equiv.) in DCM (5 mL). The reaction mixture was initially stirred at 0 °C and then slowly warmed to room temperature over 24 h. After completion of the reaction, as determined by LCMS analysis, the reaction mixture was diluted with DCM and washed with water followed by brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the resulting material was triturated with 30% Et2O in pentane to give the free solid material (approximately 5.2 g), which was used directly in the next step.

[0227] Step 3: The product from Step 2 (0.22 mmol, 200 mg, 1.00 equiv.) in n-BuOH (1.5 mL) was added to piperidine (5.0 equiv., 0.11 mL, 1.10 mmol), and the resulting solution was stirred at 90 °C overnight. After completion of the reaction as determined by LCMS analysis, the volatiles were removed under a stream of N2, and the crude material was purified by C18 reverse flash chromatography (0 to 100% MeCN in HO) with 0.5% AcOH as a modifier. Fractions containing the desired product were lyophilized to afford the desired compound as the acetate salt (48 mg).

[0228] Compounds of formula (1-A1a) shown in Table C can be made similarly to those shown above for Example C-4 under similar conditions by varying the amine or sulfonamide forming reagent or starting material used in the third step to open the epoxide functionality, or by using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide, as shown in the schemes herein.

[0229] Preparation of sulfamide compound example (C-54) of formula (1-A1a): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy)-2H-pyran-2-yl)oxy) in dry DMF (10 mL) To a solution of 4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula~epx) (1.0 g, 1.34 mmol) and acetaldehyde (3.0 equiv.), STAB (6.0 equiv.) was added, and the resulting solution was stirred at 30 °C for 2 h. After consumption of the starting material as determined by LCMS, the reaction was cooled to 0 °C, 2 mL of saturated NH4Cl solution was added, and the solution was stirred for 5 min. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to pH 12 with NH4OH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude material, which was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (590 mg, 53% yield).

[0230] Step 2: 590 mg of the product from Step 1 (0.76 mmol, 1.00 equiv.) was dissolved in 10 mL of dry EtOH, and peracetic acid (192 μL of a 32% diluted solution in acetic acid, 1.2 equiv.) was added. The resulting solution was stirred at room temperature for 45 minutes, after which LCMS indicated complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to approximately 12 with NHOH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv.) was dissolved in 10 mL of dry ethanol, and copper(II) sulfate pentahydrate (5.0 equiv., 950 mg) was added. The solution was stirred at 65 °C for 16 hours, after which LCMS indicated complete reaction. The reaction mixture was diluted with 20 mL of DCM and HO and the pH was adjusted to about 12 with NHOH. The crude material was extracted three times with DCM, the organics were combined, dried over MgSO, and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >90%, which was used directly in the next step.

[0231] Step 3: The material from Step 2 (250 mg, 0.32 mmol, 1.0 equiv.) was dissolved in dry DCM (5 mL) in a dry round-bottom flask, and DIPEA (0.141 mL, 2.5 equiv.) was added, followed by N-[4-(trifluoromethyl)phenyl]sulfamoyl fluoride (1.3 equiv., 135 mg, 0.42 mmol). The reaction was stirred at room temperature for 16 h, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N2, and the crude material was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product (150 mg, 51% yield) as the free base.

[0232] Step 4: To a pressure vial was added the product from Step 3 (150 mg, 0.17 mmol, 1 equiv.) and n-propanol (5 mL), followed by piperidine (117 μl, 2.0 mmol, 12 equiv.). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was then concentrated in vacuo, and the crude product was purified by reverse-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and HO. The fractions containing the desired product were lyophilized to afford the desired product (C-54) (90 mg, 53% yield) as the acetate salt.

[0233] Following this example, the alkyl group R on the core nitrogen 0 can be varied by replacing acetaldehyde in the first step of the sequence with any other alkyl aldehyde, such as, but not limited to, formaldehyde or propionaldehyde. As with other examples shown herein, the epoxide can be ring-opened in the final step with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcohol solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol.

[0234] Compounds of formula (1-A1a) shown in Table C can be made similarly to those shown above for Example C-54 under similar conditions by varying the amine or sulfonamide or sulfamide-forming reagent or starting material used in the fourth step to open the epoxide functionality, or by using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide as shown in the schemes herein.

[0235] Preparation of Cyclic Sulfamate Compound Example (C-17) of Formula (1-A1a): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl To a solution of (1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (1.0 g, 1.34 mmol) and propionaldehyde (2.0 equiv., 2.68 mmol) was added STAB (4.0 equiv., 5.36 mmol), and the resulting solution was heated at 45 °C for 4 h. After consumption of the starting material as determined by LCMS, the reaction was cooled to 0 °C, 2 mL of saturated NH4Cl solution was added, and the solution was stirred for 5 min. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to pH 12 with NH4OH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude material, which was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (600 mg, 57% yield).

[0236] Step 2: 590 mg of the product from Step 1 (0.76 mmol, 1.00 equiv.) was dissolved in 10 mL of dry EtOH, and peracetic acid (192 μL of a 32% diluted solution in acetic acid, 1.2 equiv.) was added. The resulting solution was stirred at room temperature for 45 minutes, after which LCMS indicated complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to approximately 12 with NHOH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv.) was dissolved in 10 mL of dry ethanol, and copper(II) sulfate pentahydrate (5.0 equiv., 950 mg) was added. The solution was stirred at 65 °C for 16 hours, after which LCMS indicated complete reaction. The reaction mixture was diluted with 20 mL of DCM and HO and the pH was adjusted to about 12 with NHOH. The crude material was extracted three times with DCM, the organics were combined, dried over MgSO, and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >85%, which was used directly in the next step.

[0237] Step 3: The material from Step 2 (150 mg, 0.19 mmol, 1.0 equiv.) was dissolved in dry DCM (1.4 mL) in a dry round-bottom flask, and pyridine (0.6 mL, 40.0 equiv.) was added, followed by [2,2,2-trifluoro-1-(trifluoromethyl)ethyl]sulfamate (Organic Letters, Vol. 23, 2021, pp. 3373-3378) (1.2 equiv., 0.57 mg, 0.23 mmol). The solution was then stirred at 40 °C for 24 h, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N, and the crude material was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to about 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (105 mg, 64% yield).

[0238] Step 4: To a pressure vial was added the product from Step 3 (250 mg, 0.29 mmol, 1 equiv.) and n-propanol (4 mL), followed by piperidine (434 μl, 4.4 mmol, 15 equiv.). The reaction mixture was stirred at 75° C. for 16 h. The reaction mixture was then concentrated in vacuo, and the crude product was purified by reverse-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and HO. The fractions containing the desired product were lyophilized to afford the desired product (C-17) (58 mg, 20% yield) as the acetate salt.

[0239] Following this example, the alkyl group R on the core nitrogen 0 can be varied by replacing acetaldehyde in the first step of the sequence with any other alkyl aldehyde, such as, but not limited to, formaldehyde or propionaldehyde. The sequence can also start with tulathromycin epoxide, and the reductive amination step is 0 =H. As with other examples shown herein, the epoxide can be ring-opened in a final step with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol.

[0240] Preparation of Cyclic Sulfamate Compound Example (D-2) of Formula (2-A1): [ka] Step 1: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl To a solution of (1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (1.0 g, 1.34 mmol) and propionaldehyde (2.0 equiv., 2.68 mmol) was added STAB (4.0 equiv., 5.36 mmol), and the resulting solution was heated at 45 °C for 4 h. After consumption of the starting material as determined by LCMS, the reaction was cooled to 0 °C, 2 mL of saturated NH4Cl solution was added, and the solution was stirred for 5 min. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to pH 12 with NH4OH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude material, which was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (600 mg, 57% yield).

[0241] Step 2: 590 mg of the product from Step 1 (0.76 mmol, 1.00 equiv.) was dissolved in 10 mL of dry EtOH, and peracetic acid (192 μL of a 32% diluted solution in acetic acid, 1.2 equiv.) was added. The resulting solution was stirred at room temperature for 45 minutes, after which LCMS indicated complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and HO) and transferred to a separatory funnel. The pH was adjusted to approximately 12 with NHOH and extracted three times with 20 mL of DCM. The organics were combined, dried over MgSO4, and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv.) was dissolved in 10 mL of dry ethanol, and copper(II) sulfate pentahydrate (5.0 equiv., 950 mg) was added. The solution was stirred at 65 °C for 16 hours, after which LCMS indicated complete reaction. The reaction mixture was diluted with 20 mL of DCM and HO and the pH was adjusted to about 12 with NHOH. The crude material was extracted three times with DCM, the organics were combined, dried over MgSO, and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >85%, which was used directly in the next step.

[0242] Step 3: The material from Step 2 (150 mg, 0.19 mmol, 1.0 equiv.) was dissolved in dry MeCN (1.5 mL) in a dry round-bottom flask. DIPEA (0.338 mL, 10.0 equiv.) was added, followed by 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (1.3 equiv., 0.84 mg, 0.25 mmol), and the solution immediately turned orange. The reaction was stirred at room temperature for 15 minutes, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N2, and the crude material was purified by reverse-phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were combined, the pH adjusted to about 12 with NH4OH, and extracted three times with 50 mL of DCM to give the desired product as the free base (39 mg, 24% yield).

[0243] Step 4: To a pressure vial was added the product from Step 3 (39 mg, 0.046 mmol, 1 equiv.) and ethanol (3 mL), followed by 1-propylamine (187 μl, 2.27 mmol, 50 equiv.). The reaction mixture was stirred at 75 °C for 6 h, after which LCMS analysis indicated completion of the reaction. The reaction mixture was then concentrated in vacuo, and the crude product was purified by reverse-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and HO. Fractions containing the desired product were lyophilized to afford the desired product (D-2) (20 mg, 49% yield) as the acetate salt.

[0244] Following this example, the alkyl group R on the core nitrogen 0 can be varied by replacing acetaldehyde in the first step of the sequence with any other alkyl aldehyde, such as, but not limited to, formaldehyde or propionaldehyde. The sequence can also start with tulathromycin epoxide, and the reductive amination step is 0 =H. As with other examples shown herein, the epoxide can be ring-opened in a final step with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanides, azides, or halogen anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol.

[0245] Compounds of formula (1-A1a) shown in Table C can be made similarly to those shown above for Example C-54 under similar conditions by varying the amine or sulfonamide or sulfamide-forming reagent or starting material used in the fourth step to open the epoxide functionality, or by using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide as shown in the schemes herein.

[0246] The following compounds of formula (1.1) were prepared according to the schemes and procedures described herein and are shown in Table A. [ka] The compound names are provided in the table below. [Table 1-1] [Table 1-2] [Table 1-3]

[0247] Formula (1.1) Table A Example Name: A-1. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, A-2. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-3. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-4. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-11-[(2R,3S,4R,6S)-6-methyl-4-[methyl(phenylsulfamoyl)-amino]-3-phenoxyoxan-2-yl]oxy-15-oxo-1-oxa-6-azacyclopentadecane, A-5. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, A-6. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, A-7. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-8. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-10. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-11. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-methylbenzenesulfonamide, A-12. 3-Bromo-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,2-dimethylbenzenesulfonamide, A-13. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3,4-difluoro-N-methylbenzenesulfonamide, A-14. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, A-15. 3-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, A-16. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-17. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, A-18. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-2-nitrobenzenesulfonamide, A-19. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-nitrobenzenesulfonamide, A-20. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-methylbenzenesulfonamide, A-21. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-6-morpholinopyridine-3-sulfonamide, A-22. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthiophene-2-sulfonamide, A-23. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-24.N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6- Azacyclopentadeca -11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methyl-1-benzofuran-2-sulfonamide, A-25. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide A-26. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthiazolyl-5-sulfonamide, A-27. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, A-28. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide, A-29. 6-Chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-2-sulfonamide A-30. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, A-31. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, A-32. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methylcyclopropanesulfonamide, A-33. 5-Bromo-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-2-sulfonamide, A-34. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, A-35. N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, A-36. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2R,3S,4R,6S)-3-(4-methoxyphenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, and A-37. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2R,3S,4R,6S)-3-(4-fluorophenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane.

[0248] The following compounds of formula (1-A1) were prepared according to the schemes and procedures described herein and are shown in Table B. The names of each compound are provided in the table below. [ka]

[0249] For clarity, the substituted -NH-4-CF3 phenyl in the table below is [ka] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0250] Formula (1-A1) Table B Example Name: B-1. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-2-methoxy-N-methylethane-1-sulfonamide, B-2. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-nitrobenzenesulfonamide, B-3. ​​N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylcyclohexanesulfonamide, B-4. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,3,5-trimethylisoxazole-4-sulfonamide, B-5. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,1,2-trimethyl-1H-imidazole-4-sulfonamide, B-6. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-6-fluoro-N-methylpyridine-3-sulfonamide, B-7. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-8. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpropane-1-sulfonamide, B-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthieno[3,2-b]pyridine-6-sulfonamide, B-10. 1-Cyclopropyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylmethanesulfonamide, B-11. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide, B-12. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-3-sulfonamide, B-13. 4-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-14. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide, B-15. N1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N1-methylbenzene-1,4-disulfonamide, B-16. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-4-sulfonamide, B-17. 6-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-3-sulfonamide, B-18. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-methylbenzenesulfonamide, B-19. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(1H-pyrazol-1-yl)benzenesulfonamide, B-20. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((benzylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, B-21. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopentylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-22. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopentylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-23. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopropylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-24. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-25. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)benzyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-26. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, B-27. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((4-methoxybenzyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-28. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-29. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(pyridin-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-30. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((4-chlorophenyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-31. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)phenethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-32. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((phenylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-33. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10...

Claims

1. A compound of formula (1-A1): 【Chemistry 1】 wherein R is H, phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl ring, or a 9- or 11-membered fused heteroaryl ring, each of said heteroaryl rings containing at least one heteroatom selected from N, O, and S, wherein each of said heteroaryl rings contains at least one heteroatom selected from N, O, and S, and said phenyl, naphthyl, and heteroaryl rings are each substituted with (R 9 ) n ; R 2 is H, C 1 -C 6 alkyl, —R c OR b , C 1 -C 6 haloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, —R c NR a R b , —NR a R c S(O) p R 8 , —NR a R c C(O)NR a R c , R c CN, —R c S(O) p R 8 , —NR a R b , —NR b R b , C 0 -C 3 alkylaryl, C 0 -C 3 alkyl heterocycle which is a 5- or 6-membered saturated or partially saturated heterocycle, C 0 -C 3 alkylheteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl ring, the heterocyclic and heteroaryl rings each contain at least one heteroatom selected from N, O, and S, and the cycloalkyl, aryl, heterocyclic, and heteroaryl rings are each substituted with (R 9 ) n , and each ring is optionally fused to Y; or or R and R 2 are joined together to form a bond to form a fused dioxo-oxathiazole ring: 【Chemistry 2】 R a , R 0 and R 1 are each independently H or C 1 -C 6 alkyl; or R 1 is benzyl optionally substituted with (R 9 ) n ; or R 1 is —CH 2 Het, where Het is a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S, said heteroaryl ring being optionally substituted with (R 9 ) n ; or R 1 is C 3 -C 6 cycloalkyl optionally substituted with (R 9 ) n ; R b is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylheterocycle, C 0 -C 3 alkylheteroaryl, wherein the heterocycle is a 5- or 6-membered saturated or partially saturated monocyclic ring, the heteroaryl is a 5- or 6-membered monocyclic ring, the heterocycle and heteroaryl ring each contain at least one heteroatom selected from N, O, and S, and the cycloalkyl, phenyl, heterocycle, and heteroaryl ring are each substituted with (R 9 ) n ; R c is C 1 -C 4 alkyl; R 5 and R 6 are each independently H, C 1 -C 6 alkyl optionally substituted with hydroxy, C 1 -C 6 alkoxy, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —C(O)R 8 , —C(O)NR a R 8 , —C(O)R c NR a R b , —C(O)OR c R 8 , —C(O)ONR a R b , —R c NR a C(O)R 8 , —R c C(O)R b , —R c C(O)OH, —R c C(O)NR a R b , —R c NR a C(O)H, —R c S(O) p R 8 , —R c or selected from NR a R b , —R c OR b , —S(O) p R 8 , —S(O) p R 8 NR a R b , —R c S(O) p NR a R b or —R c NR a S(O) p R 8 , or C 0 -C 4 alkylaryl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, C 0 -C 4 alkylheterocycle and C 0 -C 4 alkylheteroaryl, wherein said heterocycle and heteroaryl rings are each a 5- or 6-membered monocyclic ring or a 9- or 10-membered fused ring containing at least one heteroatom selected from the group consisting of N, O and S, and said aryl, cycloalkyl, heterocycle and heteroaryl rings are each substituted with (R 9 ) n ; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring or a 5-membered heteroaryl ring, which is ring B, each optionally containing at least one additional heteroatom selected from N, O, and S, each ring optionally substituted with (R 9 ) n , and each ring optionally fused to Y; R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 0 -C 4 alkyl, C 3 -C 6 cycloalkyl, —NR a R b , phenyl, a 5- or 6-membered heterocyclic or heteroaryl ring each containing at least one heteroatom selected from N, O, and S, and said cycloalkyl, phenyl, heterocyclic, and heteroaryl ring are each substituted with (R 9 ) n independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, —NH 2 , —N(CH 3 ) 2 , —CF 3 , —CHF 2 , and —OCHF 2 ; R 9 is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with hydroxy, C 1 -C 6 alkoxy, C 0 -C 4 alkyl, C 3 -C 6 cycloalkyl, halo, oxo, nitro, hydroxy, —R c OR b , cyano, —NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —S(O) p R 8 , —SF 5 , phenyl, and 5- or 6-membered heterocyclic or heteroaryl rings each containing at least one heteroatom selected from the group consisting of N, O, and S, wherein said phenyl, heterocyclic, and heteroaryl rings are optionally further substituted with F, Cl, cyano, or —CF 3 ; Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, or tetrahydrothiophenyl, each substituted with methyl, F, Cl, cyano, oxo, or —CF 3 ; n is an integer 0, 1, 2, or 3; compounds in which p is an integer 0, 1, or 2; its stereoisomers, and pharmaceutically acceptable salts thereof.

2. R ０ is H, methyl, ethyl, or propyl; R is H, or each (R ９ ) ｎ phenyl, pyridinyl, or thiophenyl substituted with R １ But C １ ~C ６ alkyl or cyclohexyl, or R １ are respectively (R ９ ) ｎ benzyl substituted with -CH ２ pyridinyl, or —CH ２ is thiazolyl, R ２ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ２ OCH ３ , -(CH ２ ) ２ OCH ３ , -CH ２ CF ３ , -CF ３ , -NHR ｂ , -NCH ２ R ｂ and R ｂ is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are not F, Cl, cyano, or —CF ３ or optionally replaced by or R ２ are respectively (R ９ ) ｎ cyclopropyl substituted with —CH ２ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl; or R ２ is phenyl or pyridinyl, each substituted with morpholine; R ５ is H or C １ ~C ６ is alkyl, R ６ C optionally substituted with H, hydroxy １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, -OCF ３ , —C(O)NR ａ R ８ , -R ｃ S (O) ｐ R ８ , -R ｃ NR ａ R ｂ , -R ｃ OR ｂ Or -S(O) ｐ R ８ , or each (R ９ ) ｎ C substituted with ０ ~C ３ Alkylphenyl, C ０ ~C ３ Alkyl C ３ ~C ６ Cycloalkyl, oxazolidinyl, C ０ ~C ３ Alkylpyrrolidinyl, C ０ ~C ３ Alkylpiperidinyl, C ０ ~C ３ Alkylpiperazinyl, C ０ ~C ３ Alkylmorpholinyl, C ０ ~C ３ Alkyltetrahydropyranyl, tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridazinyl, C ０ ~C ３ Alkylpyridinyl, pyrimidinyl, C ０ ~C ３ alkylthiazolyl or pyrazinyl, and each R ９ are independently methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ２ , -N(CH ３ ) ２ , -CF ３ , -CHF ２ , -OCHF ２ , -S(O) ２ NH ２ , -SCH ３ , -S(O)CH ３ , and -S(O) ２ CH ３ selected from the group consisting of The compound of formula (1-A1) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts thereof.

3. R １ is methyl, R ２ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ２ OCH ３ , -(CH ２ ) ２ OCH ３ , -CH ２ CF ３ , -CF ３ , -NHR ｂ , -NCH ２ R ｂ wherein R ｂ is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are not F, Cl, cyano, or —CF ３ or optionally substituted with R ２ However, each (R ９ ) ｎ cyclopropyl substituted with —CH ２ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl; or R ２ is phenyl or pyridinyl, each substituted with morpholine; R ６ But H, C １ ~C ６ Alkyl, methoxy, ethoxy, C １ ~C ６ Haloalkyl, -OCF ３ , -CH ２ OCF ３ , -(CH ２ ) ２ OCF ３ , -CH ２ CN, -R ｃ S (O) ｐ CH ３ , -R ｃ S (O) ｐ NR ａ R ｂ , -R ｃ S (O) ｐ Phenyl, -R ｃ NR ａ R ｂ , R ｃ OR ｂ , -R ｃ NHC(O)CH ３ wherein R ａ and R ｂ are each independently H, methyl and ethyl, or R ６ However, each (R ９ ) ｎ C substituted with ０ ~C ３ Alkylphenyl, C ０ ~C ３ Alkyl C ３ ~C ６ Cycloalkyl, C ０ ~C ３ Alkylpyrrolidinyl, C ０ ~C ３ Alkylpiperidinyl, piperazinyl, morpholinyl, C ０ ~C ３ Alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridazinyl, C ０ ~C ３ alkylpyridinyl, or C ０ ~C ３ alkylthiazolyl, wherein each R ９ are independently methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ２ , -N(CH ３ ) ２ , -CF ３ , -CHF ２ , -OCHF ２ , -S(O) ２ NH ２ , -SCH ３ , -S(O)CH ３ , and -S(O) ２ CH ３ and n is an integer of 0, 1, or 2. The compound of formula (1-A1) according to claim 2, its stereoisomers, and pharmaceutically acceptable salts thereof.

4. A non-antibacterial compound selected from the group consisting of B-1 to B-160 below, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof; B-1. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-2-methoxy-N-methylethane-1-sulfonamide, B-3. ​​N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylcyclohexanesulfonamide, B-4. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,3,5-trimethylisoxazole-4-sulfonamide, B-5. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,1,2-trimethyl-1H-imidazole-4-sulfonamide, B-6. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-6-fluoro-N-methylpyridine-3-sulfonamide, B-7. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-8. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpropane-1-sulfonamide, B-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthieno[3,2-b]pyridine-6-sulfonamide, B-10. 1-cyclopropyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylmethanesulfonamide, B-11. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide, B-13. 4-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-14. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide, B-15. N1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N1-methylbenzene-1,4-disulfonamide, B-16. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-4-sulfonamide, B-17. 6-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-3-sulfonamide, B-18. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-methylbenzenesulfonamide, B-19. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(1H-pyrazol-1-yl)benzenesulfonamide, B-20. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((benzylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, B-21. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopentylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-22. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopentylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-24. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-25. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)benzyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-26. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, B-27. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((4-methoxybenzyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-28. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-29. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(pyridin-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-30. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((4-chlorophenyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-32. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((phenylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-33. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-34. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-35. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-36. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((2-methoxyethyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-37. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((thiazol-4-ylmethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-38. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-39. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((pyridazin-4-ylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-41. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-42. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide, B-43. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(2,2,2-trifluoroethylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-44. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[benzyl(methyl)sulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-45. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylisoindoline-2-sulfonamide, B-46. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((pyridin-4-ylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-47. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperidine-1-sulfonamide, B-48. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-49. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-50. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-51. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[dimethylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-52. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[benzylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-53. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2S,3R,4S,6R)-4-[(4-fluorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-54. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(pyridin-4-ylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-55. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(methylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-56. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[cyclohexylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-57. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl(phenyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-58. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-59. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylmethanesulfonamide, B-60. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-61. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2S,3R,4S,6R)-4-[[(4-fluorophenyl)-methylsulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-62. 4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-methylsulfamoyl]-methylamino]benzonitrile, B-63. 2-(cyclopropylamino)-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-64. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-(anilinomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-66. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[2-(oxan-4-yl)ethylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-67. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(2-cyclopropylethylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-68. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(2-pyrrolidin-1-ylethylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-69. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclohexylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-70. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclopropylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-71. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(3,3-dimethylbutylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-72. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-(butylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-73. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(3-methylbutylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-74. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[3-(dimethylamino)propylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-75. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(3-piperidin-1-ylpropylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-76. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(methylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-77. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-(ethylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-78. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-(ethylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-80. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclobutylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-81. N-(2-((((2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-(((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methyl(N-(4-(trifluoromethyl)phenyl)sulfamoyl)amino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)amino)ethyl)acetamide, B-82. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[2-(dimethylamino)ethylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-83. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(2-ethoxyethylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-84. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(2-methoxyethylamino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-85. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(2-methylpropylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-86. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[(4-phenylphenyl)methylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-87. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[3-(2-oxopyrrolidin-1-yl)propylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-88. N-[3-[[(2S,3S,4R,6R)-6-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-13-yl]oxy]-3-hydroxy-4-methoxy-2,4-dimethyloxan-3-yl]methylamino]propyl]acetamide, B-89. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(pyridin-4-ylmethylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-90. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(benzylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-91. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-[(3-fluoropropylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-92. 2-[[(2S,3S,4R,6R)-6-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-13-yl]oxy]-3-hydroxy-4-methoxy-2,4-dimethyloxan-3-yl]methylamino]-N,N-dimethylethanesulfonamide, B-93. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-94. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((N-ethylphenylsulfonamido)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-95. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-96. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, B-97. N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-98. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, B-99. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-100. N-(((2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyl-4-(N-methylphenylsulfonamido)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)-N-propylbenzenesulfonamide, B-101. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, B-102. 3-chloro-N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide, B-103. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,5-dimethyl-1-phenylpyrazole-4-sulfonamide, B-104. 4-Bromo-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-106. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-107. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-108. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-4-fluoro-N-methylbenzenesulfonamide, B-109. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-110. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoro-6-methylphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-111. 5-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-4-sulfonamide, B-112. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-113. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, B-114. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,4-dimethyl-1,3-thiazole-5-sulfonamide, B-115. 6-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylpyridine-2-sulfonamide, B-117. 5-bromo-6-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylpyridine-3-sulfonamide, B-118. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylimidazo[1,2-a]pyridine-3-sulfonamide, B-119. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-121. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluoro-2-methylphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-122. N-[(2S,3R,4S,6R)-3-(3-cyano-4-fluorophenoxy)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-123. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]pyrazole-4-sulfonamide, B-124. 2-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylpyridine-3-sulfonamide, B-125. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(4-methoxyanilino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-126. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(methylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide, B-127. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(2-oxopiperidin-1-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide, B-128. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[2-(benzenesulfonyl)ethylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-129. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[2-(trifluoromethoxy)ethylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-130. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-pyridin-2-yloxyoxan-4-yl]-N-methylbenzene-sulfonamide, B-131. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-pyridin-2-yloxyoxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-132. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-thiophen-3-yloxyoxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-133. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-[3-(hydroxymethyl)phenoxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-134. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-[3-(hydroxymethyl)phenoxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-135. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, B-136. N-[(2S,3R,4S,6R)-3-(4-chlorophenoxy)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-137. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-138. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-(3-methylsulfinylphenoxy)oxan-4-yl]-N-methylbenzenesulfonamide, B-139. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-(3-methylsulfinylphenoxy)oxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, B-140. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, B-141. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((4S,5R,6R)-5-((benzylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide, B-142. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-propylbenzene-sulfonamide, B-143. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-imidazole-2-sulfonamide, B-144. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxybenzenesulfonamide, B-145. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide, B-146. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-imidazole-2-sulfonamide, B-147. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-(4-methoxybenzyl)benzenesulfonamide, B-148. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide, B-149. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-isobutyl-4-methoxybenzenesulfonamide, B-150. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-isobutylbenzenesulfonamide, B-151. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-152. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-153. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, B-154. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, B-155. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, B-156. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, B-157. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(4-methoxyanilino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane, B-158. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane, and B-160. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, or A compound selected from the group consisting of: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, and The compound of formula (1-A1) according to claim 3, which is N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide, its stereoisomer, and a pharmaceutically acceptable salt thereof.

5. A compound of formula (1-A1a), wherein: 【Transformation 3】 R ０ is H, R is H, or each (R ９ ) ｎ phenyl, pyridinyl, or thiophenyl substituted with R １ is methyl, R ２ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ２ OCH ３ , -(CH ２ ) ２ OCH ３ , -CH ２ CF ３ , -CF ３ , -NHR ｂ , -NCH ２ R ｂ wherein R ｂ is methyl, cyclohexyl, phenyl, or pyridinyl, and the phenyl and pyridinyl rings are not F, Cl, cyano, or —CF ３ or optionally replaced by or R ２ are respectively (R ９ ) ｎ cyclopropyl substituted with —CH ２ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, or pyrimidinyl; or R ２ is phenyl or pyridinyl, each substituted with morpholine; Ring B is each (R ９ ) ｎ 2. The compound of claim 1, wherein n is an integer 0, 1, or 2, and wherein n is an integer 0, 1, or 2;

6. A non-antibacterial compound selected from the group consisting of C-1 to C-56 below, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof; C-1. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-2. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azetidin-1-ylmethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, C-3. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(pyrrolidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-4. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-5. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-imidazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, C-6. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(thiomorpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-7. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-8. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-pyrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, C-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-tetrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide, C-10. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, C-11. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-12. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-[(4-ethylpiperazin-1-yl)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-13. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-14. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(4-propan-2-ylpiperazin-1-yl)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-15. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(4-methylsulfonylpiperazin-1-yl)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-16. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-17. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane, C-18. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methyl-4-(trifluoromethyl)benzene-sulfonamide. C-19. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-fluoro-N-methylbenzenesulfonamide, C-20. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-21. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane, C-22. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(4-tert-butylphenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-23. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3-chlorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-28. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3,4-dichlorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-29. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(4-bromophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-30. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2R,3S,4R,6S)-3-hydroxy-4-[(4-iodophenyl)sulfamoyl-methylamino]-6-methyloxan-2-yl]oxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-31. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[[4-chloro-3-(trifluoromethyl)phenyl]sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-32. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-6-methyl-4-[methyl-[(4-methylphenyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-33. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3,4-dimethylphenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-34. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-6-methyl-4-[methyl-[(1-methylimidazol-2-yl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-35. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[diethylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, C-36. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-37. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methyl-1-methylsulfonylmethanesulfonamide, C-39. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[pyridin-3-ylmethyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-40. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclo-pentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-propylbenzenesulfonamide, C-41. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-methoxy-N-propylbenzenesulfonamide, C-42. 4-chloro-N-cyclohexyl-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]benzenesulfonamide, C-43. N-cyclohexyl-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-methoxybenzene-sulfonamide, C-44. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[2-methylpropyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-45. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[cyclohexyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-46. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[[1,3-triazol-2-ylmethyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-47. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(pentafluoro-16-sulfanayl)benzenesulfonamide, C-48. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, C-49. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoropyridin-4-yl)oxy-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, C-50. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-(4-methoxyphenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-51. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2R,3S,4R,6S)-3-(4-fluorophenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, C-52. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-11-[(2R,3S,4R,6S)-6-methyl-4-[methyl(phenylsulfamoyl)amino]-3-phenoxyoxan-2-yl]oxy-15-oxo-1-oxa-6-azacyclopentadecane, C-53. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-phenoxyoxan-4-yl]-N-methylbenzenesulfonamide, C-54. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, C-55. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoropyridin-4-yl)oxy-6-methyloxan-4-yl]-N-methylbenzenesulfonamide, and C-56. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, or The following compound: 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide or (2R,3S,4R,5R,8R 10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, its stereoisomers, and pharmaceutically acceptable salts thereof.

7. R and R ２ are linked to form a bond to form a di-oxo-oxathiazolyl ring, 【Chemistry 4】 During the ceremony, R ０ is H, methyl, ethyl, or propyl; R １ But C １ ~C ６ Is it alkyl? or R １ are respectively (R ９ ) ｎ benzyl substituted with -CH ２ pyridinyl, or —CH ２ is thiazolyl, R ５ is H, methyl, ethyl, or propyl; R ６ is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF ３ , -OCF ３ , —C(O)NR ａ R ８ , -R ｃ S (O) ｐ R ８ , -R ｃ NR ａ R ｂ , -R ｃ OR ｂ , or -S(O) ｐ R ８ Or or R ６ are respectively (R ９ ) ｎ phenyl substituted with C １ Alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C １ ~C ２ Alkylcyclopropyl, and C １ ~C ２ Alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C １ ~C ２ Alkyl oxazolidinyl, C １ ~C ２ Alkylpyrrolidinyl, C １ ~C ２ Alkylpiperidinyl, C １ ~C ２ Alkylpiperazinyl, C １ ~C ２ Morpholinyl, C １ ~C ２ Tetrahydropyranyl, C １ ~C ２ Tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C １ ~C ２ Alkylpyrazolyl, C １ ~C ２ Alkyl imidazolyl, C １ ~C ２ Alkylpyridinyl, C １ ~C ２ alkylpyrimidinyl, or C １ ~C ２ alkylpyrazinyl, R ａ and R ｂ are each independently H, methyl, or ethyl; R ｃ is methyl, ethyl, or propyl; R ８ is methyl or ethyl, or R ８ are respectively methyl, methoxy, F, Cl, Br, oxo, cyano, and —CF ３ or cyclopropyl or phenyl optionally substituted with one or two substituents independently selected from Or R ５ and R ６ together with the nitrogen atom to which they are attached, each represents (R ９ ) ｎ forming Ring B which is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, tetrazolyl or 3,4-dihydroisoquinolinyl substituted with R ９ are independently methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ２ , -N(CH ３ ) ２ , -CF ３ , -CHF ２ , -OCHF ２ , -S(O) ２ NH ２ , -SCH ３ , -S(O)CH ３ and -S(O) ２ CH ３ is selected from the group consisting of The compound of formula (1-A1) according to claim 1, wherein n is an integer of 0, 1, or 2, its stereoisomers, and pharmaceutically acceptable salts thereof.

8. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide, 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide, and The compound of formula (1-A1) according to claim 1, its stereoisomer, and pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane.

9. A composition comprising the compound of formula (1-A1) according to any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof, further comprising a pharmaceutically acceptable carrier.

10. 10. A composition for treating or preventing an inflammatory response in an animal, comprising a therapeutically effective amount of a compound of any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein said treating or preventing an inflammatory response in said animal prevents or alleviates the progression of a respiratory disease or disorder in said animal.

11. 10. Use of a compound of formula (1-A1) according to any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal, wherein said treating or preventing an inflammatory response in said animal prevents or reduces the progression of a respiratory disease or disorder in said animal.

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